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  • 2000-2004  (59)
  • 1990-1994
  • 1975-1979  (175)
  • 1890-1899
  • 2000  (59)
  • 1978  (175)
  • Industrial Chemistry and Chemical Engineering
  • Molecular Cell Biology
  • Rat
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  • 2000-2004  (59)
  • 1990-1994
  • 1975-1979  (175)
  • 1890-1899
Year
  • 1
    ISSN: 1530-0358
    Keywords: Pravastatin ; ras p21 isoprenylation ; Colon carcinogenesis ; Flat colon tumor ; Azoxymethane ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PURPOSE: The effect of pravastatin, an inhibitor ofras p21 isoprenylation, on the gross type of colon tumors induced by azoxymethane was investigated in Wistar rats. METHODS: Rats received ten weekly subcutaneous injections of 7.4 mg/kg body weight of azoxymethane and intraperitoneal injections of 10 or 20 mg/kg body weight of pravastatin every other day until the end of the experiment at Week 45. RESULTS: Administration of pravastatin at both dosages had no significant effect on the incidence of colon tumors but significantly increased the incidence of rats with adenomas only. In contrast to the elevated adenomas in control rats, flat adenomas were significantly more prevalent in rats given pravastatin. Pravastatin at both doses significantly decreased the labeling index, but not the apoptotic index, of elevated adenomas, whereas it significantly decreased the labeling index but increased the apoptotic index of flat adenomas. Administration of pravastatin at both dosages also significantly decreased the amounts of membrane-associatedras p21 in colon tumors. CONCLUSIONS: These findings suggest that theras oncogene may be closely related to the development of adenocarcinomas from adenomas and the development of elevated or polypoid tumors of the colon.
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  • 2
    ISSN: 1436-2023
    Keywords: Key words Adriamycin ; Rat ; Embryo ; VATER association ; Synovial joint ; Bones ; Limbs ; Vertebra ; Sirenomelia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The adriamycin-induced rat model of the Vertebral, Anorectal, Tracheo-Esophageal, Radial and Renal (VATER) association produces a variety of vertebral, rib, and limb abnormalities. This study was designed to document accurately the nature of these abnormalities and to determine whether synovial joints are affected. Fetuses from pregnant Sprague Dawley rats that had received intraperitoneal injections of 1.75 mg/kg of adriamycin on days 6–9 or 10–13 of gestation were harvested. Double-stained skeletal preparations and histological sections were examined for vertebral, rib, and limb anomalies. The incidence of anomalies was high in the group treated on gestational days (GD) 6–9, while it was low in the GD 10–13 group. The length and thickness of the long bones were reduced, with bowing and reduction in their endochondral ossification. Sirenomelia occurred in the group treated on GD 6–9, and was often associated with a short tail and anal atresia. The joint cavities, and intra-articular structures such as menisci and the cruciate ligaments developed normally from the mesenchymal interzone. These data indicate that adriamycin inhibits skeletal growth and differentiation without any interference in the differentiation of the mesenchymal interzone, thus producing normal synovial joints.
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  • 3
    ISSN: 1432-2307
    Keywords: Keywords 7 ; 12-dimethylbenz(a)anthracene ; Rat ; Submandibular gland ; Adenocarcinoma Myoepithelial cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In an attempt to induce adenocarcinoma containing myoepithelial cells (MECs) in the rat submandibular gland, we injected 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in acetone into the glands of rat pups at the age of 10 days. In both male and female pups, the glands, including their developing terminal secretory units, contained far greater numbers of cells positive for proliferating cell nuclear antigen (PCNA) than did adult glands. A single administration of 1% DMBA (0.05 ml/130 g b.w.) did not produce adenocarcinoma, but did induce occasional sarcomas, such as rhabdomyosarcoma and fibrosarcoma, in 2 months. Most glands regenerated with minimal scar formation. Microscopically, these glands were atypical in that they contained increased numbers of PCNA-positive cells, underdeveloped granular ducts, and striated ducts surrounded by MECs positive for alpha smooth muscle actin (αSMA). Though these features were also observed in the regenerated glands after acetone injection, the number of PCNA-positive cells was relatively high in the glands of DMBA-treated females, especially in the terminal secretory unit. The second DMBA injection at 10 weeks of age produced adenocarcinoma made up of αSMA-positive MECs and keratin 19-positive duct cells. Such MEC-associated adenocarcinoma was induced in the glands of more than half the female but not the male animals. Replacement of either of the double DMBA treatments with acetone, or DMBA treatment, single or double, of adult glands did not produce adenocarcinoma, but did produce sarcoma and squamous cell carcinoma. These results suggest that (1) at least two genetic mutations are necessary for induction of adenocarcinoma with MECs in the rat submandibular gland, (2) the mutation is efficiently introduced to pup glands whose terminal secretory units exhibit extreme proliferative activity, and (3) the second mutation is difficult to introduce in male glands, whose proliferative activity is relatively low, and/or transformed cells need some female hormone after the mutation to propagate.
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Journal of cancer research and clinical oncology 126 (2000), S. 27-32 
    ISSN: 1432-1335
    Keywords: Key words Heart irradiation ; Plasma enzyme levels ; Myocardial enzyme levels ; Rat ; AbbreviationsCK creatine kinase ; LDH lactate de-hydrogenase ; AST aspartate aminotransferase ; ALT alanine aminotransferase ; α-HBDHα-hydroxybutyrate dehydrogenase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Plasma levels of myocardial enzymes present after local heart irradiation were studied in a rat model. The purpose was to investigate whether, within days after irradiation, these enzyme levels change to such an extent that they may be helpful in assessing the severity of cardiac damage after radiotherapy. Therefore, activities of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and α-hydroxybutyrate dehydrogenase (α-HBDH) were determined in the plasma and left ventricular myocardium of rats following local heart irradiation with a single dose of 20 Gy. A dose of 20 Gy is known to cause irreversible cardiac damage and to reduce survival times of the animals. Cardiac enzyme assays were performed directly after and twice daily for up to 2 weeks after radiation. Plasma CK, LDH, AST and α-HBDH levels were increased between 2 h and 24 h after irradiation. Plasma ALT levels remained unchanged. Myocardial enzyme levels, measured between 24 h and 16 days after radiation, did not differ between irradiated and control animals, although acute (first 12 h) reductions were observed in the irradiated group. The elevated enzyme levels in plasma appeared to correlate with the acutely reduced myocardial enzyme levels. Although irradiation with a dose of 20 Gy induced acute rises of cardiac enzyme levels in plasma, it is doubtful that fractionated radiation, as applied clinically for treatment of solid tumors, will induce plasma enzyme elevations that are large enough to indicate the extent of cardiac damage occurring acutely or chronically.
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  • 5
    ISSN: 1437-7799
    Keywords: Key words VEGF ; Glomeruli ; Ribonuclease protection assay ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background. Vascular endothelial growth factor (VEGF) is a selective endothelial growth factor which potently enhances microvascular permeability. In the kidney, VEGF mRNA is known to be highly expressed in visceral epithelial cells in glomeruli. However, the physiological role of VEGF in glomerular function and its involvement in the pathogenesis of proteinuria are not clear. The present studies were designed to determine whether altered expression of VEGF mRNA was observed in the course of puromycin aminonucleoside (PAN) nephrosis in rats (a model of human minimal change nephrosis). Methods. The message level of VEGF in isolated glomeruli of PAN nephrosis rats was measured using a ribonuclease protection assay. Results. VEGF expression began to decrease 4 days after PAN injection and could not be detected in the nephrotic stage of PAN nephrosis (on days 8 and 16). In the remission of stage of PAN nephrosis (on day 28), mRNA was restored to the control level. Conclusions. According to our results, a functional defect in the VEGF expression of visceral epithelial cells was observed in PAN nephrosis. VEGF could be a functional marker of visceral epithelial cells, and the loss of normal expression of VEGF after damage to visceral epithelial cells could affect glomerular endothelial cell function in PAN nephrosis.
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Pediatric surgery international 16 (2000), S. 485-487 
    ISSN: 1437-9813
    Keywords: Key words Duodenum ; Apoptosis ; Fetus ; Rat ; Duodenal atresia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Duodenum is thought to go through a solid-core stage followed by recanalization during its development. This study investigates the role of apoptosis in normal duodenal development, especially during widening of the lumen, and hence, the possible role of apoptosis in duodenal atresia (DA). Twenty-four time-mated Sprague-Dawley rats were killed from day 13 to day 20 of gestation. Duodenums of 3 fetuses were chosen randomly from each rat and processed. Apoptosis was determined by the terminal deoxytransferase-mediated biotin dUTP nick-end labeling (TUNEL) technique (ApopTag). Apoptosis count and cross-sectional areas were measured with an image analyzer (MetaMorph). The number of apoptotic cells per unit area duodenum peaked on day 15 for the mucosal/submucosal layer and on day 14 for the muscular/mesenchymal layer. The maximal number of apoptotic cells per cross-section of duodenum was between 7 and 8. The cross-sectional areas of the duodenal wall and lumen increased exponentially between day 17 and day 19 while duodenal-wall thickness remained relatively constant throughout duodenal development. The localization, timing, and intensity of apoptosis do not suggest that apoptosis is responsible for the widening of the duodenal lumen; enlargement of the lumen is related to the increase in duodenal circumference. Apoptosis thus may not be involved in the pathogenesis of DA.
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Pediatric surgery international 16 (2000), S. 285-292 
    ISSN: 1437-9813
    Keywords: Key words Major histocompatibility complex (MHC) ; Rat ; Immunohistochemistry ; Distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present study systematically investigated the expression and distribution of the major histocompatibility complex (MHC) classes I and II in the rat. About 150 native tissue probes from eight adult Lewis rats were taken, representative for most organs, tissues, and the vascular system. MHC expression was analyzed by two monoclonal antibodies (mAb) generated against the non-polymorphic determinants of rat MHC class I (Ox-18) and class II (Ox-6). Immunoreactivities were compared to those of different endothelial (HIS52, TLD-3A12, Ox-43, REHA-1 antigen), histiocytic (ED1, ED2), B-cell (RLN-9D3), and T-cell (MRC Ox-52) markers. A nonspecific mAb (MR12/53) served as a negative control. Pretested concentrations on various tissues and the alkaline phosphatase-anti-alkaline phosphatase technique allowed semiquantitative evaluation of serial cryostat tissue sections. MHC class I expression was detected on most immunocompetent cells. Endothelial cells were stained heterogeneously along the vascular system and the organ-specific microcirculation. Furthermore, some organs showed staining of parenchymal cells. MHC class II was found on all immunocompetent cells positive for the B-cell marker and about 15% of cells positive for the histiocytic markers. Besides the well-known expression of MHC class II in the outer zone of the renal proximal tubule, further organ-specific cell forms were found positive. In conclusion, the present study outlines tissue-specific distribution of MHC I/II and implies that each organ carries a variable immunologic burden that needs to be considered for any transplantation model.
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  • 8
    ISSN: 1437-9813
    Keywords: Key words Fetal transplantation ; Proliferation ; Adrenal glands ; Addisonian crisis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present study investigated the histologic maturation, proliferative capacity, and steroid production of fetal adrenal transplants (Tx) in adrenalectomized rats. A pair of fetal adrenal glands (18–20 days of gestation) was transplanted into the omentum of syngeneic Lewis rats (n=45). Four weeks later, in 5 animals the grafts were excised for morphologic evaluation. Proliferation was investigated by immunohistochemical staining for KI-67 protein and quantified by the proliferation index (PI = positive cells/100 counts). All other hosts (Tx; n = 40) underwent bilateral adrenalectomy (AE) to induce Addisonian crisis. Postoperatively, survival and concentrations of potassium, sodium, aldosterone, and corticosterone were recorded for 6 months. These data were compared to controls (C = only AE; n = 30) and a sham group (S; n = 10). At the end of the study period all surviving hosts were killed for histologic examination of grafts. At 4 weeks post-Tx the adrenal grafts demonstrated a distinct zona glomerulosa and frequent proliferation with a PI of 0.084, comparable to normal control (0.092). Following AE survival was significantly prolonged in Tx (86% vs 12% of C, P 〈 0.05). Control animals developed severe hyponatremia and hyperkalemia, whereas in Tx only transient signs of Addisonian crisis were recorded. Levels of aldosterone dropped within 7 days in the Tx and C groups, but returned to normal for Tx within 8 weeks. Corticosterone levels of Tx animals fell to 25% within week, but steadily increased to 70% by the end of the study. At 6 months, grafts revealed a mature adrenocortical structure with little proliferative activity, which was comparable to controls. In a syngeneic rat model fetal adrenal transplants thus mature and proliferate to provide sufficient steroid production for adrenalectomized hosts.
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  • 9
    ISSN: 1437-9813
    Keywords: Key words Congenital diaphragmatic hernia ; Hypoplastic lung ; Bromodeoxyuridine (BrdU) ; Antenatal glucocorticoids ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The aim of this study was to investigate the effect of antenatal glucocorticoid therapy on smooth-muscle-cell (SMC) DNA synthesis in the pulmonary arteries (PA) in a nitrofen-induced congenital diaphragmatic hernia (CDH) rat model following nitrofen administration on day 9.5 of gestation. Antenatal dexamethasone (DEX) was given intraperitoneally on days 18.5 and 19.5 of gestation. Bromodeoxyuridine (BrdU) was injected via a jugular vein into the dam 1 h before the fetuses were killed by cesarean section at term. The fetuses were divided into three groups: group I (n = 10): normal controls; group II (n = 10): nitrofen-induced CDH; group III (n = 10): nitrofen-induced CDH with antenatal DEX treatment. Immunostaining of the lungs with anti-BrdU antibody was obtained by a standard avidin-biotin complex method. The number of immunopositive cells in the PA media and adventitia were counted using an image analyzer and analyzed statistically. The number of BrdU-immunopositive cells in the media was significantly increased in group II (16.83 ± 3.01) compared to groups I (9.16 ± 2.20) and III (6.83 ± 1.70) (P 〈 0.01). There was no significant difference between groups I and III. The number of BrdU-immunopositive cells in the adventitia was not significantly different between the three groups. Antenatal DEX treatment inhibits SMC DNA synthesis in PA media in CDH lungs. This may be a possible mechanism by which antenatal DEX prevents structural PA changes in nitrofen-induced CDH in rats.
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  • 10
    ISSN: 1432-2277
    Keywords: Key words Small bowel transplantation ; Split tolerance ; FK 506 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Functional long-term allograft survival after experimental small bowel transplantation (SBT) is limited by chronic rejection. Initial application of high-dose FK 506 has been shown to induce stable long-term graft function. In order to examine whether this long-term function is associated with donor-specific tolerance, we analyzed the functional status of recipient T cells in vivo and in vitro. One-step orthotopic SBT was performed in the allogeneic Brown Norway (BN)-to-Lewis rat strain combination. FK 506 was given daily at a dose of 2 mg/kg from days 0–5 in the rejection model and from days 0–9 in the long-term functional model. Mean survival time in the rejection model was 98 ± 2.8 days. Histological examination of these small bowel allografts disclosed signs of chronic rejection. In contrast, all animals of the long-term functional model survived long term ( 〉 250 days) without clinical signs of chronic rejection. The latter model, furthermore, produced evidence of donor-specific tolerance. Whereas heterotopic Dark Agouti (DA) hearts were rejected regularly within 7 days, BN hearts survived indefinitely ( 〉 70 days). In vitro, mixed leukocyte reactivity of CD4 + T cells was similarly strong against donor (BN) antigens as against third-party (DA) antigens. The split tolerance revealed by our in vivo and in vitro results enabled acceptance of both the small bowel allograft without signs of chronic rejection and of donor-specific heart allografts.
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  • 11
    ISSN: 1432-2277
    Keywords: Key words Implantation model ; Aortic valves ; Valve dysfunction ; Rejection ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Structural failure of heart valve allografts may be related to technical factors or immunological reactions. To circumvent nonimmunological factors a new rat implantation model was developed to study whether alloreactivity results in histopathological changes and valve dysfunction. Syngeneic (WAG-WAG, DA-DA) and allogeneic (WAG-BN, WAG-DA) transplantation was carried out using this new technique, and the function of explanted valves was assessed 21 days later by retrograde comptence testing. Additionally, grafts were examined using standard histological and immunohistochemical techniques. There was no leakage during retrograde injection in nine of tem syngeneic and two of ten allogeneic grafts. Microscopically, syngeneic valves appeared normal without fibrosis or intimal thickening, although CD8+ lymphocytes and macrophages were found in necrotic myocardial rim and adventitia. In contrast, allogeneic valves were deformed and noncellular, with extensive infiltration of CD4+, CD8+ and CD68+ cells in adventitia and media. Absence of fibrosis and intimal thickening in syngeneic transplanted valves indicated circumvention of nonimmunological factors. Allogeneic valve transplantation induces cellular infiltration in the graft with subsequent graft failure.
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  • 12
    ISSN: 1432-2277
    Keywords: Key words Hypoxia-reoxygenation ; JNK1/SAPK1 ; Rat ; Hepatocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Organ injury after ischemia and reperfusion (I/R) remains one of the most important limiting factors in liver surgery and transplantation. Oxygen-free radical (OFR) generation is considered a major cause of this damage. JNK1/SAPK1, a member of MAPK family, regulates cell adaptation to stressful conditions. The aim of this study was to determine if hypoxia-reoxygenation (H/R) can activate JNK1/SAPK1 and if OFR are involved in this activation. Primary cultured rat hepatocytes isolated from other liver cells and blood flow were submitted to warm and cold H/R phases mimicking surgical and transplant conditions. JNK1/SAPK1 was activated by both warm and cold H/R. Deferoxamine (1 mM), di-phenyleneiodonium (50 μM) and N-acetylcysteine (10 mM) significantly inhibited this kinase activation.
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  • 13
    Electronic Resource
    Electronic Resource
    Springer
    Urological research 28 (2000), S. 141-146 
    ISSN: 1434-0879
    Keywords: Key words Kidney ; Nitric oxide ; Ischemia-reperfusion injury ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In this study we attempted to clarify the release of nitric oxide (NO) and its role in the ischemia-reperfusion rat kidney. After right nephrectomy, male Wistar rats were divided into four groups: one sham operated and three groups who underwent ischemia (30 min) and reperfusion of the left renal artery. Thirty minutes prior to ischemia-reperfusion, two groups were injected intraperitoneally with 10 and 30 mg/kg of NG-nitro-l-arginine methylester (L-NAME). Real-time monitoring of blood flow and NO release in the rat kidney was measured with a laser Doppler flowmeter and an NO-selective electrode, respectively. Serum creatinine and blood urea nitrogen (BUN) levels were measured 1 and 7 days after the induction of ischemia-reperfusion. Clamping of the renal artery decreased blood flow to 1–5% of the basal level measured before clamping. After removal of the clip, the blood flow of the 30 mg/kg L-NAME rats was significantly lower than that of the controls. Immediately following the clipping of the renal artery, NO release rapidly increased. After removing the clip, NO release immediately returned to three-quarters of the basal level. Serum creatinine and BUN levels of the ischemia-reperfusion rats were slightly but not significantly higher and those of 30 mg L-NAME rats were significantly higher than those of the control or ischemia-reperfusion rats 1 day and 7 days after ischemia-reperfusion. Our data suggest that NO acts as a cytoprotective agent in ischemia-reperfusion injury of the rat kidney.
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  • 14
    ISSN: 1434-0879
    Keywords: Key words Castration ; Epidermal growth factor ; Insulin-like growth factor I ; Prostate ; Testosterone ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are strong inducers of proliferation to prostate cells cultured in serum-free medium. Accordingly we wanted to study the growth of the prostate gland in castrated rats after treatment with EGF, IGF-I and testosterone. Castrated Wistar rats were treated with growth factors (EGF 35 μg/rat per day; IGF-I 350 μg/rat per day) or testosterone (2 mg/rat per day) for 3 days either immediately after or 10 days after castration. Prostate tissue was examined by stereological and immunohistochemical techniques and by enzyme-linked immunosorbent assay (ELISA). Treatment with EGF inhibited the involution of the prostate (P 〈 0.05), whereas treatment with IGF-I did not affect the prostate involution as compared to castrated controls. EGF treatment significantly increased the endogenous rat EGF in the ventral prostate, but cellular proliferation was not affected. Testosterone treatment increased the weight of the prostate, by increase of all tissue components of the prostate, and significantly increased cellular proliferation. Systemic administration of EGF but not IGF-I decreased the involution of the rat prostate induced by castration. Compared with testosterone, the effects of EGF treatment on the prostate involution were moderate, and the effects of EGF were not related to cellular proliferation.
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  • 15
    ISSN: 1434-0879
    Keywords: Key words Bladder ; Rat ; Aging ; Obstruction ; Cystometrics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bladder dysfunction in the aging population is a significant problem. However the concomitant presence of other diseases in many patients can make it difficult to distinguish between changes in bladder function and other influences. The present study was designed to study, in aging rats, bladder function and the effect of partial bladder outlet obstruction (BOO) on bladder function. Cystometrics were performed in awake, female Fischer 344 rats of four age groups (6, 12, 18 and 24 months) following subcutaneous implantation of a mediport catheter. Cystometric evaluations were carried out in control rats or those subject to three weeks of BOO. Bladder compliance significantly decreased with aging, which reflected an increase in threshold pressure without changes in bladder capacity. Partial BOO caused development of severe bladder instability. Following BOO, bladder capacity and compliance were significantly increased in all age groups. Threshold pressure was lower in obstructed animals, except for 6-month rats. Younger animals were able to generate a higher contraction pressure to compensate for the BOO, whereas older animals did not. Using an awake model of cystometric measurement, we have demonstrated that aging, by itself can affect bladder function. Furthermore, aged animals respond differently to BOO than younger animals. These results demonstrate that both aging and disease can contribute to bladder dysfunction, and suggest that treatment of bladder dysfunction may require a combination of therapies targeted to multiple etiologies.
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  • 16
    ISSN: 1432-0568
    Keywords: Key words Nerve repair ; Nerve fiber regeneration ; Sciatic nerve ; Muscle-vein-combined graft ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Clinical data have shown that a vein segment filled with fresh skeletal muscle can be considered a good autologous grafting conduit for the repair of peripheral nerve lesions. In this study, the long-term morphological organization of rat sciatic nerve fibers regenerated along a muscle-vein-combined graft conduit is further analysed by light and electron microscopy. Regenerated nerve fibers were organized into fascicles of various sizes that were clearly delimited by perineurial-like shells made by long and thin cytoplasmic processes of perineurial-like bipolar cells and by densely packed collagen fibrils. Grafted skeletal muscle fibers were still detectable among nerve fiber fascicles. However, in spite of the persistence of skeletal muscle along the graft, regenerated nerve fibers showed a good morphological pattern of regeneration, providing further evidence that the muscle-vein-combined grafting technique represents an effective surgical alternative to the classical fresh nerve autograft for the repair of peripheral nerve defects.
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  • 17
    ISSN: 1432-0568
    Keywords: Key words GABAB receptor ; CNS ; Dorsal root ganglia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The anatomical distribution of the GABAB receptor (GBR) splice variants GBR1a and 1b in the CNS has not previously been studied. In the present study, distribution of the splice variants was mapped using immunohistochemistry. Polyclonal antibodies against splice variant unique epitopes were raised in rabbits. Affinity purified antibodies were used according to routine immunohistochemical procedures in sections from the rat CNS or dorsal root ganglia (DRG). The staining intensity was high in the cerebral cortex but lower in basal ganglia and the hippocampus. In the cerebellum, there was a marked difference in the distribution of GBR1a- and 1b-like immunoreactivity (LI). GBR1a-LI was preferentially localised in the granule cell layer whilst GBR1b-LI was mostly found in Purkinje cells and in the molecular layer. Cell bodies of the deep cerebellar nuclei stained for the GBR1a antibody while terminals surrounding the cell bodies were strongly labelled with the GBR1b antibody. A similar pre- vs postsynaptic pattern was seen in several nuclei ventral or caudal to the cerebellum (e.g. the cochlear nucleus, the facial nucleus, the spinal cord) but not in regions rostral to the cerebellum. In the spinal cord, strong labelling for both antibodies was seen in the dorsal horn. The GBR1b but not the GBR1a antibody stained tanycytes in the epithelium of the 3rd ventricle and in the central canal at the brain stem level. DRG neurons were positive for both the GBR1a and 1b antibody, but the former stained the cells much more intensely. Satellite cells were labelled with the GBR1b antibody. The most important aspect of these findings is that in some nuclei, GBR1b may mediate inhibition of transmitter release while in the same regions, GBR1a may mediate postsynaptic inhibition. Further, the observations support previous findings that GBR1b is the predominant splice variant in Purkinje cells.
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  • 18
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 202 (2000), S. 247-255 
    ISSN: 1432-0568
    Keywords: Key words Enteric neurons ; Interstitial cells of Cajal ; Smooth muscle cells ; Guinea-pig ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Tachykinin receptors NK1r, NK2r and NK3r bind tachykinins with different affinities and share pharmacological and molecular differences among animal species. NK1r, NK2r, NK3r and tachykinin (SP/NKA) distribution was studied by immunohistochemistry in the ileum of mouse since no data are available for this species. The results were then compared to those obtained in the rat and guinea pig either by us or by others to ascertain interspecies similarities and/or differences. NK1r- and NK3r-immunoreactivity (IR) were detected in neurons and NK1r-IR in the interstitial cells of Cajal at the deep muscular plexus. At variance with rat and guinea pig, NK1r-IR was also found in the myoid cells of the villi, while NK2r-IR was never detected in nerve varicosities. This latter datum suggests that the NK2r does not play a presynaptic role in the mouse. Unexpectedly, a high NK2r-IR and the presence of NK3r-IR were observed at the inner portion of the circular muscle layer in the mouse as well as in the rat and guinea pig, demonstrating a subregional distribution of these receptors. Tachykinin distribution did not show noticeable species-related differences. The present findings show species-related differences in the tachykinin receptor distribution that might be related to a different tachykinin controlof intestinal motility.
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  • 19
    ISSN: 1432-0533
    Keywords: Key words Hypothermia ; Immunohistochemistry ; Microtubule-associated protein 2 (MAP2) ; Rat ; Spinal cord injury
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Systemic hypothermia has been shown to exert neuroprotective effects in experimental ischemic CNS models caused by vascular occlusions. The present study addresses the question as to whether systemic hypothermia has similar neuroprotective qualities following severe spinal cord compression trauma using microtubule-associated protein 2 (MAP2) immunohistochemistry combined with the avidin-biotin-peroxidase complex method as marker to identify neuronal and dendritic lesions. Fifteen rats were randomized into three equally sized groups. One group sustained thoracic laminectomy, the others severe spinal cord compression trauma of the T8-9 segment. The control group contained laminectomized animals submitted to a hypothermic procedure in which the esophageal temperature was reduced from 38 °C to 30 °C. The two trauma groups were either submitted to the same hypothermic procedure or kept normothermic during the corresponding time. All animals were sacrificed 24 h following the surgical procedure. The MAP2 immunostaining in the normothermic trauma group indicated marked reductions in MAP2 antigen in the cranial and caudal peri-injury zones (T7 and T10, respectively). This reduction was much less pronounced in the hypothermic trauma group. In fact, the MAP2 antigen was present in almost equally sized areas in both the hypothermic groups independent of previous laminectomy alone or the addition of trauma. Our study thus indicates that hypothermia has a neuroprotective effect on dendrites of rat spinal cords subjected to compression trauma.
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  • 20
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 100 (2000), S. 75-81 
    ISSN: 1432-0533
    Keywords: Key words Fas ; Fas ligand ; Rat ; Spinal cord ; Trauma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This immunohistochemical study evaluated Fas and Fas ligand (FasL) in the rat nervous system and their changes in the spinal cord subjected to compression. Normal spinal cord showed a low level of Fas and FasL immunoreactivity in the white matter except in the corticospinal tracts. Fas and FasL immunoreactivity seemed to be located in axons and their myelin sheaths. Other regions of the nervous system did not show immunoreactivity to Fas and FasL. Moderate and severe compression injury of the spinal cord resulted in a reduction of Fas and FasL immunoreactivity in the white matter of injured T8–9 segments at 4 h and a complete loss at 1 day after trauma. This was seen even in the remaining white matter. In contrast, increased immunoreactivity to Fas and FasL was present in the cranial T7, caudal T10 (moderate injury) and T12 (severe injury) segments at day 4 with most intense staining were seen at day 9 after trauma. Increased Fas and FasL immunoreactivity may have pathophysiological implications for the development of secondary injuries after trauma to the spinal cord. Fas-FasL interactions may for instance be involved in apoptosis of oligodendrocytes which occurs as a delayed phenomenon after trauma to the spinal cord. The integrity of myelin sheaths may in this way be jeopardized by apoptosis of oligodendrocytes.
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  • 21
    ISSN: 1432-0843
    Keywords: Key words 7-Hydroxymethotrexate ; Methotrexate ; Maximum tolerated dose ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: After more than 50 years of methotrexate (MTX) treatment of acute lymphoblastic leukaemia (ALL), it is currently believed that as long as dose escalations are followed by adequate leucovorin rescue guided by monitoring MTX serum concentrations, hydration and urinary alkalinization, high-dose MTX (HD-MTX) can be tolerated without life-threatening toxicity. However, our recent experimental animal studies of the major metabolite of MTX, 7-OH-MTX, indicate that this concept may have some limitations. Animals with levels of 7-OH-MTX of 1 mM, which is below the levels routinely found in patients on HD-MTX, demonstrate intolerable toxicity and some animals die within 8 h. Electron microscopy indicates that endothelial cell and platelet functions are perturbed. Since animal data are lacking, and interspecies differences not known, we wanted to investigate the maximum tolerated doses of MTX and 7-OH-MTX in a rat model of short-term effects. The maximum tolerated dose was chosen instead of LD50 for reasons of animal welfare. Methods: We infused MTX and 7-OH-MTX into anaesthetized male Wistar rats and monitored the animals for 8 h. The drugs were given as a bolus plus continuous infusion. The dose-finding ranges were 1.8–11.3 g/kg MTX and 0.1–1.2 g/kg 7-OH-MTX. Results: The maximum tolerated dose was between 3 and 5 g/kg for MTX and lower than 0.1 g/kg for 7-OH-MTX. The mean serum concentrations of MTX and 7-OH-MTX in animals that did not survive the 8-h period were 21.9 and 1.6 mM, respectively. The animals that received the highest MTX or 7-OH-MTX doses and concentrations died after sudden reductions in heart rate and blood pressure. Conclusions: We demonstrated a lower maximum tolerated dose of 7-OH-MTX than of MTX in rats after 8 h. The 7-OH-MTX concentrations were in the therapeutic range after HD-MTX. If the rat/human interspecies differences are not large, our data may indicate that HD-MTX regimens should not be further dose intensified, due not so much to the effects of MTX as to those of 7-OH-MTX.
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  • 22
    ISSN: 1432-1211
    Keywords: Key words Vβ13 ; CD4/CD8 ratio ; Rat ; Tcrb ; Polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. Three rat BV13S1 alleles (T-cell receptor β-chain variable gene 13) were characterized by new BV13S1-allele specific monoclonal antibodies (18B1 and 17D5) and sequence analysis of expressed and genomic BV13S1. Two alleles were functional and designated BV13S1A1 present in strains LEW, BUF, PVG, and BV13S1A2 present in BN and WF. Their products differed by six amino acids, two of them in complementarity-determing region (CDR)1 and one in CDR2. A third nonfunctional allele, BV13S1A3P, was found in strains F344 and DA. Apart from a single nucleotide insertion, it was identical to BV13S1A2. All 12 rat strains tested showed association of TCRBC1 with BV8S2/4 alleles but not with the BV13S1 alleles, which may reflect a different gene order of the rat BV compared to mouse. BV13S1A1-encoded T-cell receptors (TCRs) which bind both monoclonal antibody (mAb) 18B1 and mAb 17D5 are over-represented in the CD4 lymphocyte subset. BV13S1A2-encoded TCRs which are stained by mAb 18B1 but not by mAb 17D5 show a slight CD8-biased expression. Preferential usage of BV13S1A1-positive TCRs by CD4 but not by CD8 cells in (LEW×WF)F1 hybrids and cosegregation of BV13SA1 and increased frequency of BV13S1 TCR-positive CD4 cells in a (LEW×BN)×BN backcross suggest structural differences of the two allelic products as the reason for their contrasting CD4/CD8 subset bias.
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  • 23
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 130 (2000), S. 100-104 
    ISSN: 1432-1106
    Keywords: Key words NF-κB ; p65 ; Hippocampal neurons ; Glia ; Astrocytes ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  NF-κB is found in many neuronal cell types in different states of activity. This study aimed to define which conditions induce constitutive NF-κB activity in cultured hippocampal neurons using activity-specific antibody staining. In co-culture with astroglia, hippocampal neurons were devoid of activated NF-κB. In these co-cultures, NF-κB could not be activated via kainate or glutamate. In contrast, separating neurons from the glial compartment resulted in a time-dependent increase of activated neuronal NF-κB. In this line, activation of NF-κB by kainate or glutamate is very effective in freshly separated cultures, but inhibited when the cultures are reassembled after stimulation. These findings suggests that a neuronal-glial interaction may regulate gene expression via NF-κB.
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  • 24
    ISSN: 1432-119X
    Keywords: Endothelin-A receptor ; Endothelin-B receptor ; Rat ; Pulmonary fibrosis ; Immunohistochemistry ; Quantitative PCR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: AbstractPulmonary fibrosis is characterized by excessive extracellular matrix deposition with concomitant loss of gas exchange units, and endothelin-1 (ET-1) has been implicated in its pathogenesis. Increased levels of ET-1 from tissues and bronchoalveolar lavage have been reported in patients with pulmonary fibrosis and in animal models after intratracheal bleomycin. We characterized the cellular distribution of alveolar ET receptors by immunohistochemistry in bleomycin-induced pulmonary fibrosis in the rat and determined the regulation by bleomycin of ET receptor mRNA expression in isolated alveolar macrophages and rat lung fibroblasts. We found significant increases in the numbers of fibroblasts and macrophages at day 7 compared to day 28 and control animals. ETB receptor immunoreactivity was observed on fibroblasts and invading monocytes. Isolated fibroblasts expressed both ETA and ETB receptor mRNA, and ETA receptor mRNA was upregulated by bleomycin. Isolated resident alveolar macrophages expressed neither ETA nor ETB receptor mRNA which were also not induced by bleomycin. We conclude that, while ETB receptor stimulation of fibroblasts and monocytes recruited during bleomycin-induced lung injury exerts antagonistic effects on fibroblast collagen synthesis, the observed increase in the number of fibroblasts in vivo and upregulation of fibroblast ETA receptor mRNA by bleomycin in vitro point to a predominance of the profibrotic effects of ET receptor engagement.
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  • 25
    ISSN: 1432-198X
    Keywords: Key words Metabolic acidosis ; Growth ; Growth hormone ; Insulin-like growth factor-I ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Growth impairment induced by chronic metabolic acidosis is associated with an abnormal growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. To examine the potentially beneficial effects of IGF-I on acidosis-induced growth impairment and the influence of GH and IGF-I treatment on the GH/IGF-I axis, three groups of acidotic young rats (untreated, AC, n=12; treated with recombinant human GH, GH, n=8; treated with recombinant human IGF-I, IGF-I, n=8) were studied, and compared with nonacidotic rats fed ad libitum (C, n=9)) or pair-fed with the AC group (PF, n=12). After 14 days of acidosis and 7 days of treatment, growth rate, hepatic abundance of 4.7-kilobase (kb) and 1.2-kb GH receptor transcripts and 7.5-kb and 1.8- to 0.8-kb IGF-I transcripts, serum GH-binding protein (GHBP), and IGF-I concentrations (mean±SEM) were analyzed. Significant decreases of 4.7-kb GH receptor [26±2 vs. 49±6 arbitrary densitometry units (ADU)] and 7.5 kb IGF-I (41±3 vs. 104±10 ADU) transcripts and low serum GHBP (25±1 vs. 32±1 ng/ml) and IGF-I (279±50 vs. 366±6 nmol/l) levels were found in the AC compared with the C rats. The majority of these alterations were also observed in PF rats. Compared with acidotic untreated rats, GH and IGF-I therapy produced no improvement in growth rate. GH treatment normalized the levels of IGF-I mRNA, aggravated the acidosis-related inhibition of the GH receptor gene, and did not modify the serum levels of GHBP and IGF-I. In contrast, IGF-I administration depressed the hepatic expression of all GH and IGF-I transcripts and normalized serum IGF-I concentrations. Our results confirm that sustained metabolic acidosis alters the GH/IGF-I axis, in part because of associated malnutrition, and induced growth retardation that is resistant to GH therapy. Our study also shows that administration of IGF-I does not accelerate the growth of acidotic rats, suggesting a peripheral mechanism, at the level of target tissues, is responsible for the resistance to the growth-promoting actions of GH and IGF-I.
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  • 26
    ISSN: 1432-198X
    Keywords: Key words Apoptosis ; Ceramide ; Development ; Kidney ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Ceramide is emerging as an important hydrophobic sphingolipid involved in cell differentiation and apoptosis. Since apoptosis plays a significant role in cellular remodeling during renal morphogenesis, we measured ceramide content and apoptosis in the fetal (18 days gestation), neonatal (3, 7, and 14 days postnatal), and adult rat kidney. In addition, to determine whether developmental changes in ceramide content are tissue-specific, we compared renal ceramide content with that in lung and liver. Ceramide was measured by the diacylglycerol kinase assay, and apoptosis was determined by the TUNEL technique. Renal ceramide content fell over 100-fold from the fetus to the 7th postnatal day. Renal apoptosis paralleled ceramide content, with a greater than 300-fold decrease in apoptosis from fetal to adult life. Ceramide content of the lung and liver was significantly less than that of the kidney, and changed less with maturation. We conclude that maturational changes in ceramide content are tissue-specific, and that the high rate of apoptosis in the developing kidney may be related to the elevated ceramide content.
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  • 27
    ISSN: 1432-2072
    Keywords: Keywords Novelty ; Context ; Environment ; Stress ; 6-OHDA ; Rotational behavior ; Striatum ; Nucleus accumbens shell ; Caudate ; Amphetamine ; Dopamine ; Glutamate ; Aspartate ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: We have previously shown that environmental novelty enhances the behavioral activating effects of amphetamine and amphetamine-induced expression of the immediate early gene c-fos in the striatal complex, particularly in the most caudal portion of the caudate. In contrast, we found no effect of novelty on the ability of amphetamine to induce dopamine (DA) overflow in the rostral caudate or in the core of the nucleus accumbens. Objectives: The twofold aim of the present study was to determine the effect of environmental novelty on (1) amphetamine-induced DA overflow in the shell of the nucleus accumbens and in the caudal portions of the caudate, and (2) glutamate and aspartate overflow in the caudal portions of the caudate. Methods: Two groups of rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopaminergic system received amphetamine (0.5 mg/kg, i.v.) in physically identical cages. For one group, the cages were also the home environment, whereas, for the other group, they were a completely novel environment. In vivo microdialysis was used to estimate DA, glutamate, and aspartate concentrations. Results: Environmental novelty enhanced amphetamine-induced rotational behavior (experiments 1–3) but did not alter amphetamine-induced DA overflow in either the shell of the nucleus accumbens (experiment 1) or the caudate (experiment 2). In addition, the ability of environmental novelty to enhance amphetamine-induced behavioral activation was not associated with changes in glutamate or aspartate efflux in the caudate (experiment 3). Conclusions: The present data indicate that the psychomotor activating effects of amphetamine can be modulated by environmental context independent of its primary neuropharmacological actions in the striatal complex.
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  • 28
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    Electronic Resource
    Springer
    Psychopharmacology 148 (2000), S. 106-110 
    ISSN: 1432-2072
    Keywords: Key words Interferon ; Depression ; Forced swimming test ; Locomotor activity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Objectives: We examined the immobility of the forced swimming test induced in an animal model by human interferon (IFN), which has often been reported to induce depression in clinical use. Methods: In the present study, we examined the effects of human IFNs on results of the forced swimming test in rats. Results: Single intravenous (IV) administration of human IFN-α (6×104 IU/kg), but not of human IFN-β or -γ, significantly increased immobility time in the forced swimming test in rats. Repeated administration of human IFN-α (6×103 IU/kg) also significantly increased the immobility time. On the other hand, none of the rat IFNs (rat IFN-α, -β and -γ, 6×104 IU/kg, IV) changed the immobility time. Neither human IFNs nor rat IFNs changed the locomotor activity of rats. Conclusions: These findings suggest that human IFN-α has a greater potential for inducing increase of the immobility in the rat forced swimming test than human IFN-β and -γ, and that the effect of human IFN-α might not be mediated through IFN-α/β receptors.
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  • 29
    ISSN: 1432-2072
    Keywords: Key words Opiate receptor ; Antinociception ; Habituation ; Novelty ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: There is now extensive evidence demonstrating that exposure to novel stimuli induces hypoalgesia and that this effect habituates over repeated exposure to the stimuli. Moreover, it has been shown that administration of the nonselective opiate receptor antagonist naloxone can attenuate the rate of habituation of novelty-induced hypoalgesia. Objectives: The present experiments were conducted to determine the relative influence of different opiate receptor subtypes in the attenuation of the habituation of novelty-induced hypoalgesia. Methods: In experiments 1–3, different groups of male, Wistar rats (275–300 g) were administered vehicle, 0.5, 1.0 or 2.0-nmol doses of the µ-selective antagonist Cys2-Tyr3-Orn5-Pen7-amide (CTOP), the δ-receptor selective antagonist naltrindole, or the κ-selective antagonist nor-binaltorphimine (nor-BNI). In experiment 4, animals were administered vehicle, 5, 25 or 75-nmol doses of nor-BNI. All injections were delivered to the right lateral ventricle 30 min prior to exposure to a novel hot-plate apparatus (48.5°C), once a day for eight consecutive days. Results: Paw-lick latencies in vehicle-treated animals were long during the initial exposures and declined over repeated tests, suggesting the habituation of novelty-induced hypoalgesia. The rate of habituation was significantly attenuated by administration of 1.0-nmol and 2.0-nmol doses of CTOP, by a 2.0-nmol dose of naltrindole, but was unaffected by all doses of nor-BNI. Conclusions: These results support the involvement of the µ and δ, but not the κ, opiate receptor subtypes in the habituation of novelty-induced hypoalgesia.
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  • 30
    ISSN: 1432-2072
    Keywords: Key words Morphine ; Opioid receptor ; NMDA ; Tolerance ; Rat ; Tail flick
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Pairings of a sweet taste and injection of morphine result in a learned avoidance of that taste and learned analgesic tolerance. This avoidance is mediated by the drug’s peripheral effect, while learned tolerance involves activation of N-methyl-d-aspartate (NMDA) receptors. Exposure to a sweet taste also reduces morphine analgesia. We studied whether this taste-mediated reduction was reversed by an NMDA or peripheral opioid receptor antagonist. Objectives: To determine whether an intraoral infusion of saccharin would modulate morphine analgesia in rats, and to study the contribution of NMDA as well as peripheral opioid receptors to this modulation. Methods: Six experiments used the rat’s tail-flick response to study the effect of an intraoral infusion of a sodium saccharin solution on morphine analgesia, and the effects of the quaternary opioid receptor antagonist methylnaltrexone as well as the non-competitive NMDA receptor antagonist MK-801 on this modulation of analgesia. Results: An intraoral infusion of saccharin reduced the analgesic effects of an intraperitoneal (i.p.) injection of morphine across a range of doses (experiment 1a), which was not attributable to an influence on tail-skin temperature (experiment 1b). This reduction was mediated by opioid receptors in the periphery and activation of NMDA receptors because morphine analgesia was reinstated by an i.p. injection of either methylnaltrexone (experiment 2a) or MK-801 (experiment 3a), which was not due to the effect of methylnaltrexone (experiment 2b) or MK-801 (experiment 3b) on morphine analgesia in the absence of saccharin. Conclusions: These results document evidence for an antagonism of morphine analgesia by actions of the drug at peripheral opioid receptors and excitatory amino-acid activity at NMDA receptors. They are discussed with reference to the aversive motivational effects of peripheral opioid receptors and pain facilitatory circuits.
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  • 31
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    Psychopharmacology 149 (2000), S. 115-120 
    ISSN: 1432-2072
    Keywords: Key words Opiate ; Withdrawal ; Place aversion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Administration of low doses of opiate antagonists to morphine-dependent rats produces an aversive response as measured by a conditioned place aversion, but the time course of such a learned aversion is largely unknown. Objectives: The purpose of this experiment was to examine the time course for the expression of a place aversion to opiate withdrawal. Methods: Morphine-dependent rats were tested in a three-chamber place- aversion apparatus. The conditioning phase consisted of three pairings of either naloxone (15 µg/kg s.c.) or vehicle with two compartments, with the most similar time allotments during the preconditioning test. During the testing phase, rats were again allowed to explore the entire apparatus. Different groups were tested at 24 h, 1 week, 2 weeks, 4 weeks, 8 weeks, and 16 weeks post-conditioning (morphine-free tests). Results: A robust place aversion was recorded at every time point tested, including at 16 weeks. In previously published work, placebo-pelleted rats tested with naloxone at the same dose failed to show a place aversion and nondependent rats showed a stable lack of aversion at tests up to 56 days. Dependent animals without naloxone also failed to show a place aversion at any of those time points. Conclusions: In the absence of any active intervention, the place aversion produced by opiate withdrawal is very long lasting and provides a model for protracted abstinence that may be useful for delineating the neurobiological substrate for vulnerability to relapse.
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  • 32
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    Springer
    Psychopharmacology 149 (2000), S. 181-188 
    ISSN: 1432-2072
    Keywords: Key words Acoustic startle response ; Prepulse inhibition ; Sensorimotor gating ; Schizophrenia ; Dopamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Prepulse inhibition of acoustic startle is the reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Prepulse inhibition occurs normally in humans and experimental animals, but schizophrenic persons often exhibit a marked impairment in this measure. Previous studies have shown that dopamine (DA)-dependent neuronal mechanisms are involved in the modulation of prepulse inhibition. Objective: Experiments were conducted in rats to elucidate further the involvement of DA-ergic mechanisms in prepulse inhibition. Results: In line with previous studies, the indirect DA agonist, amphetamine, was shown to decrease prepulse inhibition. A close reverse relationship over time between DA overflow in the nucleus accumbens and prepulse inhibition was obtained using a technique allowing concomitant measurement of these parameters in awake, freely moving rats. This effect was more pronounced in amphetamine-treated rats compared to rats treated with equimolar doses of cocaine, which increased DA overflow without affecting prepulse inhibition. In other experiments, the combined treatment with subthreshold doses of the selective DA D1 agonist, SKF 38393, and the selective DA D2 agonist, quinpirole, was also shown to decrease prepulse inhibition. Finally, the selective DA D2 antagonist, raclopride, was shown to enhance prepulse inhibition. Conclusions: In line with previous studies, it is concluded that DA neurotransmission is involved in the modulation of prepulse inhibition and that the ventral part of the mesostriatal DA system may serve an important role in this modulation. Furthermore, the possibility is discussed that the discrepant results on prepulse inhibition obtained with amphetamine and cocaine may disclose functionally relevant differences in their mechanisms of action, and that the enhancement of prepulse inhibition induced by some antipsychotics in rats may reflect their propensity to induce adverse mental effects in humans.
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  • 33
    ISSN: 1432-2072
    Keywords: Key words Prefrontal cortex ; Dopamine ; Anxiety ; Drug discrimination ; Pentylenetetrazol ; Chlordiazepoxide ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The prefrontal cortical (PFC) dopamine (DA) system has been implicated in anxiety-related behavioral changes, but direct, unequivocal support for this idea is sparse. Objectives: The present aim was to study the functional significance of prefrontal DA using the pentylenetetrazol (PTZ) discrimination model of anxiety. A comparison was made with its role in the cue of the anxiolytic drug chlordiazepoxide (CDP). Methods: Two groups of rats were trained to discriminate either PTZ (20 mg/kg, s.c.) or CDP (10 mg/kg, i.p.) from saline using an operant drug discrimination procedure. After prolonged training, half of each group was used to assess biochemical changes induced by both drugs in different sub areas of the PFC. For the remaining rats, discrimination training continued and generalization tests with PTZ and CDP were performed. Rats were then provided with bilateral guide cannulae aimed at the ventromedial (vm) PFC, and the effects of local infusions of DAergic drugs on discriminative performance were evaluated. Results: CDP did not affect PFC DA activity, but PTZ increased the DOPAC/DA ratio in the vmPFC selectively. Generalization tests showed that the cues of PTZ and CDP were dose dependent. In PTZ-trained rats, infusions of the DA receptor antagonist cis-flupenthixol into the vmPFC blocked the PTZ cue dose dependently, whereas the agonist apomorphine partially generalized to this cue. In CDP-trained rats, neither drug antagonized or generalized to the CDP cue, showing that PFC DA is not critically involved in the CDP cue and that local pharmacological manipulations of PFC DA do not affect discriminative abilities per se. Conclusions: The DAergic innervation of the PFC is directly involved in the behavioral effects of PTZ, suggesting a role for it in anxiety.
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  • 34
    ISSN: 1432-2072
    Keywords: Key words 5-HT1A agonist ; Intrinsic activity ; Efficacy ; Irreversible antagonism ; Lower-lip retraction ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Maximal responses are often used as a measure of intrinsic activity or efficacy, but cannot be directly equated to efficacy. Using irreversible antagonists, estimates of efficacy can be obtained that may be less dependent on specific conditions. Objectives: To characterize the intrinsic activity of serotonin (5-HT)1A agonists by examining the effects of an irreversible antagonist on their ability to produce 5-HT1A receptor-mediated responses. Methods: The effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on the ability of 5-HT1A agonists to produce lower-lip retraction (LLR) in rats were studied. Results: In the absence of EEDQ, each 5-HT1A agonist produced full effects, the rank order of potency being: S 14506 〉 8-OH-DPAT 〉 buspirone 〉 ipsapirone. EEDQ decreased the number of 5-HT1A binding sites and shifted the dose–response curves (DRCs) of each agonist either to the right or, at higher EEDQ doses, to the right and downward. The manner in which these shifts occurred, however, differed among the compounds. For each agonist, all DRCs obtained after different doses of EEDQ were fitted to models proposed by Furchgott and Black and Leff, and the results indicated the following rank order of efficacy: ipsapirone 〈 buspirone ≈ 8-OH-DPAT 〈 S 14506. 5-HT1A agonist-induced LLR appears to be mediated by 5-HT1A receptors, because the 5-HT1A antagonist, WAY 100635, shifted the agonist DRCs to the right in a parallel and dose-related manner, with pA2 values ranging from 7.8 to 8.1. Moreover, pretreatment with WAY 100635 protected against the antagonist activity of EEDQ. Conclusions: The results suggest that the effects of EEDQ on the ability of 5-HT1A agonists to produce LLR in rats may be useful to obtain estimates of their apparent efficacy at 5-HT1A receptors.
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  • 35
    ISSN: 1432-0738
    Keywords: Key words Flutamide ; Androgen antagonist ; Rat ; Enhanced OECD Test Guideline 407 ; Endocrine disrupters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In association with the international validation project to establish a test protocol for the `Enhanced OECD Test Guideline 407', we performed a preliminary 28-day, repeated-dose toxicity study of flutamide, a non-steroidal androgen antagonist, and assessed the sensitivity of a list of parameters for detecting endocrine-related effects of endocrine-disrupting chemicals (EDCs). Seven-week-old CD(SD)IGS rats were divided into four groups, each consisting of 10 males and 10 females, and administered flutamide once daily by oral gavage at doses of 0 (control), 0.25, 1 and 4 mg/kg body weight/day. Male rats were killed 1 day after the 28th administration. Female rats were killed on the day they entered the diestrus stage in the estrous cycle following the last treatment. Male rats receiving flutamide at dose levels of 1 and 4 mg/kg showed lobular atrophy of the mammary gland and a decrease in epididymal weight. In addition, 4 mg/kg flutamide-treated males exhibited raised serum testosterone and estradiol levels and decreased weight of the accessory sex glands. In females, a slight prolongation of the estrous cycle was also observed in the 4 mg/kg flutamide-treated group. No dose-related changes could be detected by haematology, serum biochemistry and sperm analysis. Thus, among the parameters tested in the present experimental system, the weight of endocrine-linked organs and their histopathological assessment, serum hormone levels, and estrous cycle stage allowed the detection of endocrine-related effects of flutamide.
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  • 36
    ISSN: 1432-0738
    Keywords: Key wordsα2u-Globulin ; Diethylstilbestrol ; Endocrine disrupter ; Rat ; Screening
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract α2u-Globulin (AUG) is a major rat urinary protein, which has a molecular weight of 16 kDa (kidney type) or 19 kDa (native type). The biosynthesis of this protein is under multi-hormonal regulation. In this study, we investigated changes in serum AUG level and their association with changes in the reproductive organs of male rats after the administration of the estrogenic chemical, diethylstilbestrol (DES) at doses ranging from 0.01 mg/kg per day to 100 mg/kg per day by gavage for 14 days. Our aim was to establish basic data for the development of a new screening method for endocrine disrupting chemicals based on serum AUG levels. DES treatment decreased the weight of testes in a dose-dependent manner; and was accompanied by atrophic histopathological changes in testes. Testis weights were significantly decreased by the group given 1 mg/kg per day DES; however, histopathological abnormalities were found in the group given 0.1 mg/kg per day DES. In four of five animals in the group given 1 mg/kg per day there was no significant decrease in testis weight and only a slight or moderate degeneration of the pachytene spermatocytes. Despite these findings, serum AUG levels in this group decreased markedly, while the serum AUG level markedly decreased even in the animals with no histopathological change in the 1 mg/kg per day or 0.1 mg/kg per day groups with no histopathological change also showed decreased serum AUG level. These results suggest that the serum AUG level may be a sensitive parameter for detecting the activity of estrogenic chemicals in intact male rats. Although a uterotropic assay has been proposed for immature female or ovariectomized female rats and is currently undergoing validation studies internationally, there is no screening method for estrogenic chemicals in intact male animals. More data on AUG changes by treatment with other estrogenic chemicals are needed in order to determine the sensitivity and specificity of this response to estrogens. Nonetheless, an AUG-based screening test for estrogenic chemicals may be useful owing to its applicability to conventional toxicity studies and an apparently higher sensitivity of this parameter compared to organ weight change or histology of testis in intact male rats and applicability to conventional toxicity studies.
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  • 37
    ISSN: 1432-2307
    Keywords: Key words T-type calcium channel blockade ; Mibefradil ; Myocardial infarction ; Cardiac remodeling ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Fibrillar collagen accumulates within the interstitium and around coronary arteries following cardiac failure and is responsible for abnormal myocardial stiffness and reduced coronary performance associated with impaired cardiac function. The aim of the study was to determine the effects of long-term treatment with the T-type calcium channel antagonist mibefradil on myocardial remodeling and cardiac function after chronic myocardial infarction (MI). MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Animals were assigned to sham-operated, placebo-treated or mibefradil-treated (10 mg/kg per day p.o.) MI groups. Treatment with mibefradil was started either 7 days before, 24 h after, or 7 days after ligation and continued for 6 weeks after MI. At this time point, mean arterial blood pressure (MAP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP) and cardiac contractility (dP/dtmax) were measured in conscious rats. Morphometric parameters were determined in picrosirius red-stained hearts: total heart weight (THW), interstitial and perivascular collagen volume fraction (ICVF, PCVF), myocardial infarct size (IS), vascular perimeter (VP), inner vascular diameter (IVD) and media thickness (MT). Six weeks after MI, MAP and dP/dtmax were decreased, and LVEDP was increased in placebo-treated animals. In mibefradil-treated animals whose treatment started 7 days before or 24 h after MI, MAP and dP/dtmax were higher, and LVEDP was lower than in placebo-treated controls. THW, ICVF, PCVF and MT were higher in placebo-treated animals. Mibefradil treatment resulted in higher ICVF and IS, higher VP and IVD (when started 7 days before MI) and lower PCVF and MT (when started 7 days before or 24 h after MI) than were observed in placebo-treated controls. Chronic treatment with mibefradil reduced interstitial and perivascular fibrosis and improved cardiac function in MI-induced heart failure in rats. Cardiac remodeling was best prevented when treatment was begun before the ischemic event.
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  • 38
    ISSN: 1432-2072
    Keywords: Key words  m-Chlorophenylpiperazine ; Drug discrimination ; Ethanol withdrawal ; Anxiety ; 17β-estradiol ; Sex difference ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The serotonergic system plays a role in regulation of anxiety and ethanol withdrawal (EW). Nevertheless, few studies have assessed sex differences in serotonergic effects on EW. Objectives: This study examined sex differences in the anxiogenic stimu-li induced by a serotonin (5-HT)1b/2 agonist, meta- chlorophenylpiperazine (mCPP), prior to ethanol and during EW. Methods: Gonadectomized or sham-operated adult male and female rats and 17β-estradiol (2.5 mg, 21-day release, s.c.) -replaced ovariectomized (OVX) rats were trained to discriminate mCPP (1.2 mg/kg, i.p.) from saline in a two-lever choice task for food. Latency to the first lever press and mCPP lever selection were measured following mCPP (0–1.2 mg/kg). Rats then received chronic ethanol-containing liquid diet (6.5%) for 10 days and were tested for mCPP lever selection 12 h and 36 h after removal of ethanol. Results: Fewer sham female and β-estradiol-replaced OVX rats selected the mCPP lever than male or OVX rats, and showed an increased initiation latency after mCPP injection. During EW (12 h and 36 h), fewer sham female and β-estradiol-replaced OVX rats responded on the mCPP-lever after saline injection as well as after mCPP challenge than male or OVX rats. Castration did not alter any response of male rats to mCPP. Conclusions: (1) mCPP discrimination is a useful measure of EW in male and female rats; and (2) sham female and β-estradiol-replaced OVX rats are less sensitive to the discriminative stimulus prior to and during EW, but more sensitive to impaired behavioral initiation induced by mCPP than male or OVX rats.
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  • 39
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    Child's nervous system 16 (2000), S. 451-456 
    ISSN: 1433-0350
    Keywords: Keywords Intracranial pressure ; CSF dynamics ; Infusion test ; Rat ; H-Tx rat ; Outflow resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Although the hydrocephalic H-Tx rat is a widely used model, data on the cerebrospinal fluid (CSF) dynamics in hydrocephalic rats are rare or – as the pressure volume index (PVI) – not available. We used hydrocephalic and nonhydrocephalic H-Tx rats, a stock with a high percentage of inherited hydrocephalus, for the evaluation of such data. In addition, a new, simple mathematical algorithm (”dynamic infusion test”), which has not formerly been used in animal experiments, was used as a pathophysiological model of CSF dynamics. Compared with classical methods for evaluation of these data, the dynamic infusion test gives a deeper insight into the relation between ICP and CSF dynamics. It was found that the resistance to outflow (ROF) in hydrocephalic rats was at least twice that in nonhydrocephalic rats. The PVI measured was similar in hydrocephalic and nonhydrocephalic animals, but clearly higher than the values reported in the literature. This may be attributable to the fact that the classically used bolus test, in contrast to the ”dynamic infusion test”, is representative only for the CSF compartment which is directly exposed to the bolus application.
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  • 40
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    Psychopharmacology 151 (2000), S. 219-225 
    ISSN: 1432-2072
    Keywords: Keywords Amphetamine ; Wheel running ; Behavioral sensitization ; Pharmacological sensitization ; Novelty ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: This study explored whether repeated injections of amphetamine (AMP), which increase general locomotion, also increase acute wheel running, a highly structured, rewarding, motor behavior not correlated with other locomotor activities. Objectives: The experiments determine how 1–5 mg/kg d-AMP affects wheel running and see if, over repeated injections, the AMP effects show context specific sensitization. Methods: In experiment 1, 2 mg/kg AMP or saline (SAL) was injected on days 1, 3, 6, 8, and 10 to male Sprague-Dawley rats with either limited or no wheel experience. 20 min after the injection animals were tested in an open field for 5 min and then in a running wheel for 1 h. Rats were injected with SAL or AMP on the days following testing. On days 13 and 15, animals were tested for conditioning (following SAL) and sensitization (following AMP). In experiment 2, the effects on wheel running of repeated 1, 2, or 5 mg/kg AMP were tested. Results: In experiment 1, AMP (2 mg/kg) elevated open field ambulation but suppressed wheel running. Limited wheel experience potentiated the AMP-induced suppression. At test, the suppression of running was found to be context specific. In experiment 2, 1 mg/kg did not affect running, while 2 and 5 mg/kg resulted in dose-dependent running suppression. Acquisition and test AMP dose both influenced the running suppression at test; context had a marginal influence. Conclusions: The degree of running suppression induced by repeated AMP is determined by both psychological (the injection context) and pharmacological (the acquisition dose) factors. This AMP-induced running suppression is consistent with the sensitization of stereotyped behavior.
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  • 41
    ISSN: 1432-2072
    Keywords: Key words Fentanyl ; mu opioids ; Drug discrimination ; Training dose ; pA2 analysis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Discriminative stimulus effects of mu opioids vary systematically as a function of training dose. Differences among training doses may arise from multiple mechanisms. Objectives: In vivo apparent pA2 analyses were used to examine the contributions of opioid mechanisms to stimulus control by low and high training doses of the mu opioid fentanyl. Methods: Saline and one of two doses of fentanyl, administered s.c., were established as discriminative stimuli in two groups of rats (low training dose group: 0.01 mg/kg; high training dose group: 0.04 mg/kg). Generalization tests and in vivo apparent pA2 analyses were used to evaluate receptor mechanisms of stimulus control. Results: Fentanyl, etonitazene, methadone, and morphine evoked full fentanyl generalization in both groups but were more potent in the low-dose group. Spiradoline and d-amphetamine did not evoke generalization in either group. Naltrexone antagonized stimulus and rate-altering effects of fentanyl in both groups, with apparent pA2 values of 7.6 in the low-dose group and 7.5 in the high-dose group. Nalbuphine and nalorphine evoked full generalization in the low-dose group but less than 40% generalization in the high-dose group. In the high-dose group, nalbuphine and nalorphine antagonized the stimulus and rate-altering effects of fentanyl with apparent pA2 values of 5.3 and 6.1, respectively, demonstrating lower efficacy mu actions. Conclusions: Changes in fentanyl training dose preserved the mu opioid selectivity of stimulus control but altered the intensity of the transduced mu opioid stimulus required for generalization. These differences in intensity of the fentanyl stimulus determined whether low efficacy mu opioids would evoke or antagonize fentanyl generalization.
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  • 42
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    Psychopharmacology 148 (2000), S. 146-152 
    ISSN: 1432-2072
    Keywords: Key words Alprazolam ; Drug discrimination ; Benzodiazepines ; Antidepressant ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The triazolobenzodiazepine alprazolam has a unique clinical profile compared to most other benzodiazepines (e.g. diazepam, chlordiazepoxide), in that it is used to treat panic disorder and is effective in depression, two disorders that are usually treated with anti-depressants. Previous drug discrimination studies suggested that alprazolam has stimulus properties in common with antidepressants. Objective: In the present study, the discriminative stimulus properties of alprazolam were investigated to test more conclusively the role of benzodiazepine receptors and whether alprazolam has stimulus properties in common with antidepressants. Methods: Male Wistar rats (n=12) were trained to discriminate between alprazolam (2.0 mg/kg, PO) and vehicle in an operant two-lever drug discrimination procedure under a tandem VI40”-FR10 schedule of reinforcement. Generalization and antagonism tests were carried out under 2 min extinction. Results: In generalization tests, a number of benzodiazepines (alprazolam, chlordiazepoxide, midazolam, lorazepam) and the barbiturate pentobarbital substituted completely, while zolpidem and abecarnil substituted partially for alprazolam. In contrast, no significant degree of generalization to the antidepressants imipramine and fluvoxamine and the putative antidepressants buspirone and flesinoxan was found. In antagonism studies alprazolam could be antagonized (almost) completely by flumazenil, partially by pentylenetetrazole, but not by methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), N-methyl-β-carboline-3-carboxamide (FG-7142) and picrotoxin. Conclusions: These results show that the discriminative stimulus properties of alprazolam are mediated by benzodiazepine receptors and that the finding that antidepressants share discriminative stimulus effects with alprazolam may have limited generality.
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  • 43
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    Psychopharmacology 148 (2000), S. 209-216 
    ISSN: 1432-2072
    Keywords: Key words Methamphetamine ; Drug-discrimination ; Dopamine ; Cocaine ; GBR-12909 ; Nomifensine ; Bupropion ; Chloro-PB ; Chloro-APB ; NPA ; 7-OH-DPAT ; SCH-23390 ; Spiperone ; cis-Flupenthixol ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Dopamine plays a major role in the behavioral effects of methamphetamine. Objective: In the present experiments, the effects of different dopaminergic agonists, antagonists, and uptake inhibitors were evaluated in rats discriminating methamphetamine from saline. Methods: In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline under a fixed-ratio schedule of food delivery, the ability of various dopaminergic agonists and uptake inhibitors to substitute for methamphetamine was evaluated. Subsequently, the ability of various dopaminergic antagonists to block the discriminative-stimulus effects of the training dose of methamphetamine was tested. Results: The dopamine-uptake inhibitors cocaine (10.0 mg/kg), nomifensine (3.0 mg/kg), GBR-12909 (18.0 mg/kg), and bupropion (30.0 mg/kg) fully substituted for the 1.0 mg/kg training dose of methamphetamine. Chloro-APB (SKF-82958), a full agonist at D1 dopamine receptors, produced about 85% methamphetamine-appropriate responding, but the dose required (0.18 mg/kg) markedly decreased rates of responding. Chloro-PB (SKF-81297), another agonist at D1 receptors with a lower intrinsic activity than Chloro-APB, produced only partial generalization (maximum about 55%) at a dose of 1.0 mg/kg. Full substitution for the training dose of methamphetamine was observed with 0.03 mg/kg of the D2 agonist NPA and 0.56 mg/kg of the D3/D2 agonist 7-OH-DPAT. Both NPA and 7-OH-DPAT markedly decreased rates of responding at these doses. The D1 antagonist SCH-23390 (0.056 mg/kg), the D2 antagonist spiperone (0.18 mg/kg), and the mixed D1,D2 antagonist cis-flupenthixol (0.56 mg/kg) all completely blocked the discriminative-stimulus actions of the training dose of methamphetamine. Conclusions: The present findings in rats support previous research findings in other species indicating a major role of dopamine in the discriminative-stimulus effects of methamphetamine. These findings further indicate involvement of dopamine uptake sites as well as D1 and D2 receptors.
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  • 44
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Drug discrimination ; Self-administration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The cellular effects of nicotine underlying its addictive liability are thought to be mediated by neuronal nicotinic receptors (nACHRs) in the central nervous system. It is believed that densely expressed β2-containing nACHRs in the central nervous system are responsible for these actions, but few data are available that can directly assess subtype mediation of nicotine’s acute subjective and reinforcing effects. Objective: The present study compared the effects of the competitive nACHR antagonist erysodine and the noncompetitive antagonist mecamylamine in rats trained to discriminate or self-administer nicotine. Methods: Adult male rats were trained to disciminate 0.4-mg/kg injections of nicotine from vehicle in a two-lever procedure of food-maintained behavior, or to self-administer 0.03-mg/kg injections of nicotine under fixed-ratio 5 or progressive-ratio schedules of reinforcement. Additional rats were trained under a food-maintained procedure of lever pressing. Results: Erysodine (0.3–10 mg/kg) and mecamylamine (0.1–1.0 mg/kg) blocked nicotine discrimination, although only erysodine produced the rightward shift that would be predicted of a competitive antagonist. Erysodine (0.32–32 mg/kg) and mecamylamine (0.32–3.2 mg/kg) also selectively reduced nicotine self-administration on a fixed-ratio schedule and lowered break points on a progressive-ratio schedule. Conclusions: Based on the known affinity of erysodine for α4β2 nACHRs and its selectivity relative to α7 and α1β1γδ receptors, the present data support a critical role of β2-containing nACHR constructs in the discriminative and reinforcing actions of nicotine.
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  • 45
    ISSN: 1432-2072
    Keywords: Key words Drug discrimination ; Olanzapine ; Clozapine ; Chlorpromazine ; Haloperidol ; Thioridazine ; Raclopride ; Risperidone ; Scopolamine ; Ritanserin ; Atypical antipsychotic ; Neuroleptic ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Analysis of the preclinical behavioral effects of atypical antipsychotic agents will provide a better understanding of how they differ from typical antipsychotics and aid in the development of future atypical antipsychotic drugs. Objectives: The present study was designed to provide information about the discriminative stimulus properties of the atypical antipsychotic olanzapine. Methods: Rats were trained to discriminate the atypical antipsychotic olanzapine (either 0.5 mg/kg OLZ or 0.25 mg/kg OLZ, i.p.) from vehicle in a two- lever drug discrimination procedure. The atypical antipsychotic clozapine fully substituted for olanzapine in both the 0.5-mg/kg OLZ group (99.3% drug lever responding [DLR]) and the 0.25-mg/kg OLZ group (99.9% DLR). The typical antipsychotic chlorpromazine also substituted for olanzapine in both the 0.5-mg/kg OLZ group (87.5% DLR) and in the 0.25-mg/kg OLZ group (98.9% DLR); whereas, haloperidol displayed partial substitution for olanzapine in the 0.5-mg/kg OLZ group (56.1% DLR) and in the 0.25-mg/kg OLZ group (76.4% DLR). The 5.0-mg/kg dose of thioridazine produced olanzapine-appropriate responding in the 0.5-mg/kg OLZ group (99.6% DLR), but only partial substitution was seen with the 0.25-mg/kg OLZ training dose (64.0% DLR). The atypical antipsychotics raclopride (53.9% DLR) and risperidone (60.1% DLR) displayed only partial substitution in the 0.5-mg/kg OLZ group. Both the muscarinic cholinergic antagonist scopolamine (90.0% DLR) and the 5-HT2A/2C serotonergic antagonist ritanserin (86.0% DLR) fully substituted for olanzapine in the 0.5-mg/kg OLZ group. Conclusions: In contrast to previous discrimination studies with clozapine-trained rats, the typical antipsychotic agents chlorpromazine and thioridazine and the serotonin antagonist ritanserin substituted for olanzapine. These results demonstrate that there are differences in the mechanisms underlying the discriminative stimulus properties of clozapine and olanzapine. Specifically, olanzapine’s discriminative stimulus properties appear to be meditated in part by both cholinergic and serotonergic mechanisms.
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  • 46
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    Psychopharmacology 148 (2000), S. 243-250 
    ISSN: 1432-2072
    Keywords: Key words Attention ; Scopolamine ; Mecamylamine ; Oxotremorine ; Physostigmine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: This study tried to determine the relative roles of muscarinic and nicotinic cholinergic receptors in attentional processing. Methods: The effects of cholinoceptor agonists and antagonists, and of an anticholinesterase, were studied on performance of rats in a five-choice serial reaction time task. Results: Scopolamine (0.1 mg/kg) and mecamylamine (5.0 mg/kg) produced deficits in accuracy and reaction time, respectively. This may suggest a differential role for the two types of cholinoceptors in information processing. Combinations of sub-threshold doses of scopolamine (0.01–0.03 mg/kg) and mecamylamine (0.5–1.6 mg/kg), which alone did not affect accuracy or reaction time, did not produce significant deficits in attention. However, the pattern of effects after combined treatment suggested that the differential deficits seen with these drugs alone remained. The anticholinesterase physostigmine (0.1 mg/kg) and the non- selective muscarinic agonist oxotremorine (0.03 mg/kg) induced severe behavioural disruption at doses that appeared to be relatively well tolerated in previous studies; this precluded the derivation of accuracy and response time data at these doses. At lower doses, neither physostigmine (0.05 mg/kg) nor oxotremorine (0.003 mg/kg) significantly affected any performance measure; this may reflect the ability of both drugs to indirectly or directly activate presynaptic muscarinic receptors that inhibit acetylcholine release, respectively. Conclusions: Both muscarinic and nicotinic cholinoceptors may be important in attention but they may serve different roles in information processing; this hypothesis could be tested using tasks that place different emphasis on different stages of information processing.
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  • 47
    ISSN: 1432-2072
    Keywords: Key words Benzodiazepine ; Operant ; Force ; Tolerance ; Chronic ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Several benzodiazepines (BZs) have been shown to increase the peak force of operant responses at doses that increased, decreased, or had no effect on response rate, suggesting that operant response force may be a sensitive index of BZs’ effects rather than solely a correlate of rate-dependent effects. In addition, contingent tolerance to the rate-dependent effects of BZs has been reported, but the degree of contingent tolerance that develops when the critical variable of the task is force of the response has not been explored. Objectives: These experiments examined the effects of acute and repeated oral administration of diazepam (DZ) and midazolam (MZ) on a force-differentiation task to explore the importance of task requirements on the development of contingent tolerance. Methods: Two groups of rats were trained to press a force-sensing operandum, and responses having peak forces falling within fixed lower and upper limits [low force (8–10 g) or high force (40–50 g)] were reinforced with water. Acute effects of the oral administration of DZ (0.3, 1.0, 3.0, 10.0, 30.0 mg/kg) and MZ (same doses) were determined for the discriminated-force task before and after a repeated-administration procedure. Results: When administered acutely, both drugs increased the peak force of responses in a dose-related manner and concomitantly reduced the proportion of reinforced responses, with MZ exhibiting greater potency. For the next 36 days, one group received drug before experimental sessions and the other group received drug after the experimental session. A second dose–effect determination demonstrated that rats chronically dosed with DZ or MZ pre-session displayed more contingent tolerance to alterations in peak force than rats that had received 36 drug injections post- session, where there was no opportunity to practice the force-discrimination response while under the drug state. Conclusions: These results suggest that perceptual motor difficulty of the task rather than effort may be an important variable in predicting the degree of contingent tolerance that develops. Additionally, these results suggest that both behavioral and pharmacological mechanisms are involved in the development of drug tolerance to the BZs.
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  • 48
    ISSN: 1432-2072
    Keywords: Key words ACTH ; Corticosterone ; GABA ; Noradrenaline ; Adrenaline ; Stress ; Rat ; Diazepam
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Gabolysat PC60 is a fish protein hydrolysate with anxiolytic properties commonly used as a nutritional supplement. Objective: The diazepam-like effects of PC60 on stress responsiveness of the rat pituitary-adrenal system and on sympathoadrenal activity were studied. Methods: The activity of the pituitary-adrenal axis, measured by plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (B) of the sympathoadrenal complex, measured by circulating levels of noradrenaline (NA) and adrenaline (A), and the gamma aminobutyric acid (GABA) content in the hippocampus and the hypothalamus were investigated in male rats which received daily, by an intragastric feeding tube, for 5 days running either diazepam (1 mg/kg) or PC60 (300 or 1200 mg/kg). Controls received only solvent (carboxymethylcellulose 1%). Six hours after the last force-feeding, the rats were subjected to 3 min ether inhalation or 30 min restraint and killed by decapitation 30 min after ether stress or at the end of restraint. Results: Baseline plasma levels of ACTH, B, NA and A were not affected by either diazepam or PC60. Both ether- and restraint-induced release of ACTH, but not B, were similarly and drastically reduced by diazepam and PC60 (1200 mg/kg). Both diazepam and PC60 (1200 mg/kg) deleted restraint-induced NA and A increases. Both treatments also reduced the ether-induced rise of A. Basal levels of GABA were significantly increased in both the hippocampus and the hypothalamus in PC60-treated rats and only in the hippocampus in diazepam-treated ones. In controls, ether inhalation as well as restraint increased GABA content of these two brain structures. In contrast, such stress procedures performed in PC60-treated rats reduced GABA content slightly in the hippocampus but significantly in the hypothalamus. In diazepam-treated rats, GABA content of the hypothalamus was unaffected by stresses but that of the hippocampus was slightly decreased. Conclusions: Present data suggest diazepam-like effects of PC60 on stress responsiveness of the rat pituitary adrenal axis and the sympathoadrenal activity as well as GABA content of the hippocampus and the hypothalamus under resting and stress conditions. These effects of PC60 agree with anxiolytic properties of this nutritional supplement, previously reported in both rats and humans.
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  • 49
    ISSN: 1432-2072
    Keywords: Key words 8-OH-DPAT ; WAY 100635 ; 5 ; 7-Dihydroxytryptamine ; Attention ; Impulsivity ; Pre- and postsynaptic 5-HT1A receptor ; Dorsal raphe ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Whilst several studies have investigated the role of serotonergic receptor subtypes in learning and memory, relatively few studies have examined their role in attentional processes. Objective: The present study investigated the role of pre- and postsynaptic 5-HT1A receptors on rats’ attentional performance in the five-choice serial reaction time task (5-CSRT). Methods: Hungry rats were trained in the 5-CSRT task to detect brief (0.5 s) flashes of light presented randomly in one of five locations with a fixed intertrial interval of 5 s paced by the rat. We studied the effects of 8-OH-DPAT, a 5-HT1A receptor agonist, at various subcutaneous (SC) doses (10–100 µg/kg) on measures of rats’ discriminative accuracy (the index of attentional functioning) and various behavioural indices of response control and motivation. Manipulations of basic task parameters, intracerebroventricular (ICV) injections of 5,7-dihydroxytryptamine (5,7-DHT) to deplete forebrain 5-HT and treatments with a selective 5-HT1A receptor antagonist WAY 100635 were made in order to determine the behavioural and neural specificity of the effects of 8-OH-DPAT. Results: A dose of 100 µg/kg, but not lower doses, significantly reduced choice accuracy and increased errors of omission, latencies to respond correctly and to collect food reward and premature responses. All these effects were completely blocked by WAY 100635, injected SC 5 min before 8-OH-DPAT at doses from 10–100 µg/kg. WAY 100635 by itself had no effect in the task. Dimming the visual stimuli to one-third of the usual brightness did not modify the effect of 8-OH-DPAT on choice accuracy. Prolonging the stimuli from 0.5 to 1.0 s reversed 8-OH-DPAT’s effect on choice accuracy but did not modify the other effects on rats’ performance. An ICV injection of 150 µg 5,7-DHT, which depleted forebrain serotonin by 90%, reversed 8-OH-DPAT’s effect on choice accuracy but did not modify the effects on errors of omission and latency to make correct responses. Similar effects were found by infusing 1.0 µg/0.5 µl WAY 100635 in the dorsal raphe 5 min before 8-OH-DPAT. 8-OH-DPAT increased the latency to collect the reinforcement; this effect was attenuated by ICV 5,7-DHT and completely antagonized by WAY 100635 in the dorsal raphe. Rats treated with 5,7-DHT or 8-OH-DPAT showed more premature responses and these effects were markedly reduced by the combined treatment. Conclusions: The results suggest that stimulation of presynaptic 5-HT1A receptors is involved in the ability of 8-OH-DPAT to cause attentional dysfunction and enhance impulsivity while slowing of responding and increase in errors of omission mainly depend on stimulation of postsynaptic 5-HT1A receptors.
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  • 50
    ISSN: 1432-2277
    Keywords: Key words Kidney transplantation ; Rat ; Chronic rejection ; Cytomegalovirus ; Adhesion molecules
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous studies have demonstrated that both cytomegalovirus (CMV) infection and prolonged cold ischemia of the allograft (CI) are associated with chronic rejection of renal transplants. The purpose of this study is to investigate the effect of CMV infection, of CI and of the combination of both, on the progression of chronic rejection, and to obtain a more detailed insight in their effects on the expression of adhesion molecules. Therefore, a rat transplantation model was used. Lewis recipients of renal allografts (with and without CI) from MHC-incompatible Brown Norway rats were inoculated with rat CMV or left uninfected. CMV infection alone resulted in an increased influx of CD4+ cells and macrophages early after infection, and in an increase in glomerular sclerosis and intima proliferation. CI caused an increase in infiltrating NK cells and an effect on intimal proliferation, glomerular sclerosis, and tubular atrophy. When CMV infection and CI were combined, an additive effect could be measured. This was however not the case for the function of the kidney. The creatinin showed a synergistic effect of the two influencing factors. Due to the CMV infection, an increase in CD49 d cells was detected. CI resulted in an increase in CD18 cells and an increase in the expression of CD62P on vessels, and CD54 and CD44 on tubules. When CMV infection and CI were combined, all the effects caused by CMV and CI alone were present in an additional way.¶The results of the present study suggest that special attention should be paid to the recipient of an ischemically injured graft when either the donor or the recipient is CMV-infected. The patterns seen in histology, the infiltration of leukocytes and the expression of adhesion molecules, suggest that CI and CMV infection both have an effect on rejection, but act by different mechanisms.
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  • 51
    ISSN: 1432-2277
    Keywords: Key words Small bowel transplantation ; Monoclonal antibody ; Rat ; Rejection ; Flow cytometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study assessed the effect of an anti-rat CD4 monoclonal antibody (OX38) on heterotopic small bowel allograft rejection. Fully allogeneic small bowel transplants were performed in the PVG-to-DA-rat strain combination. Animals received either i) short course (days –1, 0 and 1) of 1 mg/kg per day OX38, ii) short course of 5 mg/kg per day or iii) extended course (days –2, –1, 0, 1, 2 and twice weekly thereafter) of 1 mg/kg per day. Both the high dose (13 days) and extended low-dose (12 days) courses prolonged graft survival compared to untreated control animals (7 days). The low-dose, short-course treatment had no effect. Similar regimens were given to animals that did not receive transplants and in which peripheral blood CD4+ cell counts fell to between 20 and 55 % of pretreatment levels and 20–30 % of binding sites were blocked. In summary, anti-CD4 monoclonal antibody therapy delayed rejection of rat small bowel allografts; however, long-term survival was not achieved.
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  • 52
    ISSN: 1615-3146
    Keywords: Key Words Spinal cord compression ; Autoradiography ; Blood flow ; ATP ; Glucose ; Lactate ; Bioluminescence ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Many data are available concerning spinal cord blood flow (SCBF) and metabolism on various models and timing after spinal cord injury, however, detailed information on their exact relationship in the same injury model is lacking. This relationship is a crucial factor in the understanding of the pathophysiology of spinal cord trauma. Rats were subjected to lumbar laminectomy or lumbar spinal cord compression trauma. 3 hours later, changes in SCBF were evaluated autoradiographically and changes in ATP, glucose and lactate levels were analyzed using substrate-specific bioluminescence techniques. Measurements were performed at the lesion site (segment L4), adjacent segments (L3 and L5) and at remote thoracic segments (Th8 to Th9). Laminectomy alone did not change SCBF, both in thoracic and lumbar segments. In contrast, ATP levels were significantly reduced and lactate levels were increased at the lesion site and in adjacent lumbar segments at 3 hours after laminectomy, whereas glucose levels were not significantly changed. In animal subjected to additional compression trauma, SCBF was significantly reduced in segments L3, L4 and L5 paralleled by a significant ATP reduction and lactate increase. Glucose levels did not differ significantly from controls 3 hours after compression injury. This metabolic profile was also reflected in the remote thoracic segments. In contrast, SCBF was not reduced in thoracic segments of traumatized animals. The observation that ATP was already significantly reduced and lactate increased in laminectomized segments and in remote thoracic regions after trauma signals that metabolic changes are sensitive indicators to spinal stress. The fact that posttraumatic metabolic profile differs from the pattern of hemodynamic and metabolic changes induced by ischemia, suggests posttraumatic mediators may be involved in the different regulation of the energy producing machinery.
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  • 53
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    European journal of applied physiology 83 (2000), S. 310-319 
    ISSN: 1439-6327
    Keywords: Key words Motor unit ; Mechanomyography ; Evoked contraction ; Medial gastrocnemius muscle ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Acoustic phenomena accompanying contractions of single motor units (MUs) have previously received little attention. Therefore, in the present study, the mechanomyographic (MMG) signals during evoked contractions of single MUs have been recorded from the medial gastrocnemius muscle of the rat. A piezoelectric transducer immersed in a paraffin-oil pool was used for the measurement of these signals. Muscle fibre action potentials, tension and MMG were recorded in parallel during twitch (the weakest) and fused tetanic (the strongest) MU contractions. It was observed that the onset of the MMG signals was coincident with the beginning of the increase in tension for both the twitch and tetanus. Weaker MMG signals than those accompanying the beginning of the first phase of the fused tetanus were seen during the beginning of the relaxation after tetanic contraction. During contraction and relaxation, MMG signals were characterised by the reverse-direction of the first extreme phase, positive and negative, respectively. No MMG signals were observed when the tension was constant during the fused tetanus. The amplitude of MMG signals was correlated with both the tension increase and the velocity of tension increase during both the twitch and the fused tetanus. The strongest MUs (fast fatiguable) generated MMG signals of the highest amplitude. MMG signals were not detected for some of the weakest slow MUs (with tension increases of ≤2 mN). These results indicate a strong correlation between the MMG and the change of tension. Therefore, we believe that MMG signals are generated by muscle deformation that occurs during the contraction of MU muscle fibres. We conclude that the number of active muscle fibres, their topography, and their localisation in relation to the muscle surface (which is variable for different types of MUs) influence these MMG phenomena.
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  • 54
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    Annals of biomedical engineering 28 (2000), S. 128-134 
    ISSN: 1573-9686
    Keywords: Hippocampus ; Vigilance states ; Paired-pulse ; Dentate gyrus ; Dentate granule cells ; Evoked response ; Rat ; In vivo studies ; Perforant path ; Maturation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract This study examined the effect of normal development and vigilance state on the modulation of dentate granule cell activity in the freely moving rat at 15, 30, and 90 days of age across three vigilance states: quiet waking, slow-wave sleep, and rapid eye movement sleep. Using paired-pulse stimulation, the paired-pulse index (PPI) was obtained for the dentate evoked field potentials elicited by the stimulation of the medial perforant path. Although significant differences in PPI values were observed during development, no significant vigilance state related changes were obtained. Preweaning infant rats, i.e., 15-day old, exhibited significantly less early (interpulse intervals, IPI= 20–50 ms) and late (IPI = 300–1000 ms) inhibition, and less facilitation (IPI = 50–150 ms) when compared to the 90-day old adult rats during all three vigilance states. PPI values obtained from the 30-day old group fell intermediate between the 15- and 90-day old animals. These changes in PPI values provide a quantitative measure of changes in the modulation of dentate granule cell excitability during normal maturation. They can now can be used to evaluate the impact of various insults, such as prenatal protein malnutrition or neonatal stress, on hippocampal development. © 2000 Biomedical Engineering Society. PAC00: 8717Nn, 8719La, 8719Nn
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  • 55
    ISSN: 1573-9686
    Keywords: Heart ; Left ventricle ; LV contractility ; ESPVR ; Pig ; Rat ; Magnetic resonance imaging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract The end systolic pressure–volume relation (ESPVR) has been shown to be a relatively load independent measure of left ventricular (LV) contractility. Recently, several single-beat ESPVR computation methods have been developed, enabling the quantification of LV contractility without the need to alter vascular loading conditions on the heart. Using a single-beat ESPVR method, which has been validated previously in humans and assumes that normalized elastance is constant between individuals of a species, we studied the effects of myocardial infarction on LV contractility in two species, the rat and the pig. In our studies, LV pressure was acquired invasively and LV volume determined noninvasively with magnetic resonance imaging, at one week postinfarction in pigs and at 12 weeks postinfarction in rats. Normalized systolic elastance curves in both animal species were not statistically different from that of humans. Also, the slope of the ESPVR $$\left( {E_{es} } \right)$$ decreased significantly following infarction in both species, while the volume-axis intercept $$\left( {V_0 } \right)$$ was unaffected. These results indicate that a single-beat ESPVR method can be used to measure the inotropic response of the heart to myocardial infarction, and that the basis for this method (i.e., constant normalized elastance) is applicable to a variety of mammalian species. © 2000 Biomedical Engineering Society. PAC00: 8719Uv, 8761Lh, 8719Hh, 8719Rr, 8719Ff
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  • 56
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    Annals of biomedical engineering 28 (2000), S. 1101-1115 
    ISSN: 1573-9686
    Keywords: Time–frequency analysis ; Coherence ; Cross correlation ; Nonstationary persistent signals ; Central pattern generator ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract We present a novel time-varying phase spectrum (TVPS) method to quantify the dynamics of coevolution of two persistent nonstationary coupled signals. Based on the TVPS, an instantaneous intersignal phase shift is defined within the primary frequency range in which the two signals are highly correlated. The TVPS is estimated using a fixed-window method or an adaptive-window method. In the latter method, the window length changes dynamically and automatically as a function of change in frequency of the signals. The effects of altering window types and lengths on the accuracy of the estimation of the primary phase shift is assessed by analyzing synthesized linear chirp signals with decaying amplitude and constant relative phase shift or decaying amplitude and changing relative phase shifts. The methods developed are also used for determining the evolution of the primary phase shift among ventral root activities during fictive locomotion in an in vitro rat spinal cord preparation. The analyses indicate that the TVPS method in conjunction with the determination of the primary frequency range, allows determination of both the evolution of the coupling strength and the evolution of the phase shift between two persistent nonstationary rhythmic signals in the joint time–frequency domain. An adaptive window reduces the estimation bias and the estimation variability. © 2000 Biomedical Engineering Society. PAC00: 0230-f, 8780Tq
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  • 57
    ISSN: 1438-8359
    Keywords: Key words: Halothane ; Dopamine release ; Dopamine uptake ; Microdialysis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose. In our previous microdialysis study, sevoflurane or isoflurane anesthesia significantly decreased the extracellular level of dopamine in rat striatum in vivo. On the other hand, other investigators demonstrated that halothane anesthesia either increased or did not affect the extracellular dopamine level. To explore the differences among these volatile anesthetics, the effects of halothane and nitrous oxide on the striatal dopamine level were reinvestigated. Methods. Halothane alone, nitrous oxide with or without halothane, or drugs known to affect the dopaminergic pathway were administered to rats. Microdialysates were collected every 20 min and directly applied to an on-line high-performance liquid chromatograph without any pretreatment. The effects of halothane on respiratory and cardiovascular variables were monitored. Results. General anesthesia with halothane alone de-creased the dialysate (extracellular) concentration of dopamine but increased that of dopamine metabolites. Nitrous oxide alone slightly increased dopamine metabolites in dialysates but did not affect the halothane-induced decrease in extracellular dopamine. Apomorphine and haloperidol reproduced reported results, confirming the adequacy of our methodology. Nomifensine- or methamphetamine-induced increase in extracellular dopamine was augmented by halothane. Conclusion. These results suggest that halothane po-tently enhances striatal dopamine release and activates the reuptake or metabolic process, which is consistent with our previous results for sevoflurane or isoflurane. Volatile anesthetics interfere with dopamine regulation, at least in the rat striatum.
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  • 58
    ISSN: 0219-1032
    Keywords: c-Fos ; Dopamine ; D1 ; Hippocampus ; Rat ; Synaptic Plasticity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract While dopamine is likely to modulate hippocampal synaptic plasticity, there has been little information about how dopamine affects synaptic transmission in the hippocampus. The expression of IEGs including c-fos has been associated with late phase LTP in the CA1 region of the hippocampus. The induction of c-fos by dopaminergic receptor activation in the rat hippocampus was investigated by using semiquantitative RT-PCR and immuno-cytochemistry. The hippocampal slices which were not treated with dopamine showed little expression of c-fos mRNA. However, the induction of c-fos mRNA was detected as early as 5 min after dopamine treatment, peaked at 60 min, and remained elevated 5 h after treatment. Temporal profiles of increases in c-fos mRNA by R(+)-SKF-38393 (50 μM) and forskolin (50 μM) were similar to that of dopamine. An increase in [cAMP] was observed in dopamine-, SKF-, or forskolin-treated hippocampal slices. By immunocytochemical studies, control hippocampal cells showed little expression of c-Fos immunoreactivity. However, when cells were treated with dopamine, an increase in the expression of c-Fos immunoreactivity was observed after treatment for 2 h. The treatment of hippocampal neurons with R(+)-SKF38393 (50 μM) or forskolin (50 μM) also induced a significant increase in c-Fos expression. These results indicate that the dopamine D1 receptor-mediated cAMP dependant pathway is associated with the expression of c-Fos in the hippocampal neurons. These data are consistent with the possible role of endogenous dopamine on synaptic plasticity via the regulation of gene expression. Furthermore, these results imply that dopamine might control the process of memory storage in the hippocampus through gene expression.
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  • 59
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    Medical & biological engineering & computing 38 (2000), S. 42-48 
    ISSN: 1741-0444
    Keywords: Bowel sounds ; Rat ; Motility ; Body acoustics ; Signal detection ; Signal characterisation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract This study is aimed at detecting gastrointestinal sounds (GIS) and correlating their characteristics with gastrointestinal (GI) conditions. The central hypotheses are that GIS generation depends on the motility patterns and the mechanical properties of the gut, and that changes in those result in measurable differences in GIS. An animal model which included both healthy rats and those with small bowel obstruction (SBO) was developed. The acoustic bursts, of GIS were detected by amplitude thresholding the signal envelope. Three methods of envelope estimation were proposed and evaluated. Envelope estimation using a Hilbert transform was found to produce the best results in the current application. The duration and dominant frequency of each detected GIS event was estimated and clear differences between healthy and diseased rats were discovered. In the control state, GIS events were found to consistently be of relatively short duration (3–65ms). Although the majority of events in the SBO state had similar short duration, infrequent longer events were also detected and appeared to be pathognomonic. Long duration events (〉100 ms) occurred in each of seven obstructed, but in none of 14 non-obstructed, cases (p〈0.001). It is concluded that GIS analysis may prove useful in the non-invasive, rapid, and accurate diagnosis of SBO.
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  • 60
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    Experimental brain research 31 (1978), S. 433-443 
    ISSN: 1432-1106
    Keywords: Rat ; Soleus ; Fusimotor innervation ; Skeletofusimotor innervation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the small segmental tail muscles of the rat beta fibres provide exclusively the dynamic fusimotor control, while gamma fibres provide exclusively the static fusimor control. The present experiments were made to investigate the fusimotor innervation of spindles in a large muscle of the rat, the soleus, and thus to determine the occurrence and significance of beta innervation in this muscle. Our results have revealed no case of beta innervation in the rat soleus. As a consequence of our experimental method, however, we would not claim that beta innervation does not exist in the soleus, only that it must play an insignificant role relative to that seen in the tail segmental muscles. Investigations of the fusimotor innervation of eight spindles were sufficiently complete to warrant detailed illustration. The number of gamma fibres ranged from two to four. In every case the slowest conducting gamma fibre was dynamic. However, the conduction velocity spectra for the static and dynamic gamma fibres to rat soleus overlap to such an extent that it is impossible to use conduction velocity as the sole guide to functional gamma fibre classification. The pooled results from the eight spindles fully investigated provide a ratio of static to dynamic gamma fibres of approximately 1:1. Other evidence discussed in the paper suggests that in the muscle nerve the ratio is considerably higher. These differences are reconciled if the dynamic gamma fibres branch more profusely and innervate more spindles than do the static gamma fibres.
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  • 61
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    Experimental brain research 31 (1978), S. 573-590 
    ISSN: 1432-1106
    Keywords: Hippocampus ; Place units ; Unit recording ; Sensory cues ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Place units in the dorsal hippocampus of the freely-moving rat signal the animal's position in an environment (place field). In the present experiments, thirty four place units were recorded in two different environments: one, a small platform where the rat had received neither training nor reward; the other, an elevated T-maze inside a set of black curtains where the rat had been trained on a place discrimination. The places within the curtained enclosure were specified by four cues (a light, a card, a fan, and a buzzer) in addition to the food. Other cues were eliminated by rotating the maze and the four controlled cues relative to the external world from trial-to-trial. Some units had place fields in both environments while others only had a place field in one. No relationship could be seen between the place fields of units with fields in both environments. All twelve units tested extensively in the controlled enclosure had place fields related to the controlled cues. Probe experiments in which only some of the controlled cues were available showed that some of these units were being excited by one or two cues while others were influenced in a more complex way. The fields of these latter units were maintained by any two of the 4 cues and were due to inhibitory influences which suppressed the unit firing over the rest of the maze.
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  • 62
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    Experimental brain research 32 (1978), S. 365-375 
    ISSN: 1432-1106
    Keywords: Intraspecific aggression ; Lateral hypothalamus ; Electrical stimulation ; Specificity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of electrical stimulation of the lateral hypothalamus (LH) of rats on intraspecific aggressive behaviour were studied. In order to investigate the specificity of the stimulation effects, each experimental animal was stimulated in a number of different social situations. Stimulation of the LH in the presence of a subordinate male increased the amount of time spent on aggressive behaviour patterns and locomotion. In the presence of a dominant male, however, the stimulated animal never initiated a fight, whereas in the presence of an estrous female attack occurred in some rare occasions and sexual behaviour disappeared almost entirely. Stimulation of some sites also elicited mouse killing behaviour. Many of the electrodes that elicited intraspecific aggressive behaviour also supported intracranial self-stimulation. It is concluded that 1. electrical stimulation of this area of the LH predominantly potentiates intraspecific aggressive behaviour, 2. that this behaviour becomes overt depends on the external situation, including the behaviour of the opponent.
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    Experimental brain research 33 (1978), S. 213-225 
    ISSN: 1432-1106
    Keywords: Rat ; Hypoglossal nucleus ; Axotomy ; ATP-ase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The hypoglossal nuclei of adult male albino rats, either normal, or from 1 to 70 days after left hypoglossal nerve transection, were studied cytochemically with a lead method for sodium- and potassium-activated membrane ATP-ase, using light and electron microscopy. Reaction product was measured at the light microscopical level by microdensitometry, and significance determined statistically. Light microscopy revealed a brown reaction product in the neuropil, but none in cell bodies. Blood vessel walls were more strongly coloured. Reaction product was undiminished by ouabain pre-incubation, or by incubation without sodium or potassium, or by incubation with calcium instead of magnesium. Reaction product was diminished by absence of magnesium if calcium was also absent, and abolished if sections were boiled before incubation, or if substrate was absent. Axotomy caused a statistically significant increase in neuropil reaction product in injured nuclei, maximal at 35 days postoperatively, and subsequently decreasing to normal at 70 days. Electron microscopy showed a predominantly surface membrane reaction product, with occasional positive intracellular cisternae. Basal lamina and intra-endothelial vacuoles were also positive. Axotomy resulted in the arrival and disappearance of microglia (2 to 35 days), followed by astrocyte hypertrophy (35 days), and increase in thickness and homogeneity of surface membrane reaction product. The results suggest the presence of one or more calcium- or magnesium-dependent membrane ATP-ases. The peak of the increase after axotomy is probably partly attributable to hypertrophic astrocytes, and partly to the surfaces of neuronal processes. Increase of membrane movements might explain such enzyme activity.
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  • 64
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    Psychopharmacology 56 (1978), S. 211-215 
    ISSN: 1432-2072
    Keywords: Chlordiazepoxide ; d-Amphetamine ; Response force ; Punishment ; Stereotyped behavior ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats were reinforced with water on a continuous reinforcement schedule and were also punished with electric shock for every fifth response applied to a silent, isometric, force-sensing manipulandum. Oral doses of chlordiazepoxide (3.0, 9.0, 27.0 mg/kg) increased both conventional rate and force of punished responding. In contrast, d-amphetamine (0.8, 1.6, 3.2 mg/kg, by gavage) further decreased conventional rate and force of response, but this latter drug increased the rate of recorded responses that were lower than the 15-g force criterion for response consequences. The results for chlordiazepoxide are viewed in terms of its anxiolytic properties, while the d-amphetamine data appear to support a theory of amphetamine effects based on the concept of stereotyped behaviors.
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  • 65
    ISSN: 1432-2072
    Keywords: Ethanol ; Tolerance ; Behavioral augmentation ; Physical dependence ; Carry-over ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Adult male rats were subjected to 1–4 cycles of daily gastric intubation with ethanol (6 g/kg) for 16 days, separated by 17-day alcohol-free periods. Tolerance produced by this treatment (designated ‘physiological tolerance’) was measured by change in effect of a 2.2 g/kg i.p. dose of ethanol on the moving-belt test. It occurred in each cycle, disappeared completely in the drug-free periods, and developed more rapidly in the second and later cycles than in the first. Tolerance produced by the ‘behavioral augmentation’ technique (daily test practice under the influence of ethanol) also developed more rapidly on a second than on a first cycle. The progression from within-session to between-session tolerance was still evident, but accelerated. With 25-day alcohol cycles, separated by a one-month drug-free period, the ‘carry-over’ effect (i.e., more rapid acquisition of tolerance in the second cycle) applied equally, regardless of whether or not tolerance was produced by the same technique in both cycles, or by a crossover in either direction between the two techniques.
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  • 66
    ISSN: 1432-2072
    Keywords: Polyphloretin phosphate ; Prostaglandins ; Behaviour ; Temperature ; Bram biogenic amines ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The possibility that polyphloretin phosphate (PPP) antagonizes the central effects elicited by prostaglandin (PG) E2 and F2α was investigated. PPP was administered i.c.v. to male Wistar rats (10 or 25 μg) 10 or 30 min before i.c.v. injection of PGE2 or PGF2α (1 or 10 μg). The duration of several components of behavior, the degree of irritability, and the rectal temperature of rats were measured; the levels of noradrenaline, dopamine, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid were measured spectrophotofluorometrically in discrete brain areas. PPP antagonized temperature and behavioral changes induced in rats by PGF2α, but not those induced by PGE2. The magnitude of antagonism depended on the dose of PPP and on the time of the pretreatment before PGF2α administration. Changes in the level of biogenic amines in discrete brain areas evoked by PGs were not affected by PPP. We found that PPP antagonizes the central effects of PGF2α but not those of PGE2, and that changes of biogenic amines in discrete brain areas elicited by PGs are not specific.
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    Virchows Archiv 378 (1978), S. 45-53 
    ISSN: 1432-2307
    Keywords: Alcohol ; Myopathy ; Histochemistry ; Electrophysiology ; Human ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Muscles of the lower legs of rats given 25% ethanol in water ad libitum for up to 9.5 months were studied using histological, histochemical and electrophysiological techniques. Ethyl alcohol was substituted for about 20% of the total calorific input of the animals. The observations were compared with the structure of the gastrocnemius muscle of five alcoholics with clinical neuropathy. Fibrillation potentials and angulated atrophic fibers were observed in the muscles of animals on alcohol for 9.5 months. No fiber type grouping was present. There was also phagocytosis of the muscle fibers and changes in their internal structure, as reflected by the distribution of NADH-diaphorase. The observed muscle changes in the alcoholics and those in the experimental animals on alcohol differed mainly quantitatively, the only exception being the presence of fiber type grouping in the biopsies from the alcoholics.
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    Research in experimental medicine 173 (1978), S. 239-244 
    ISSN: 1433-8580
    Keywords: Experimental chronic uremia ; Rat ; Oxygen consumption ; Body weight ; Experimentelle chronische Urämie ; Ratte ; Sauerstoffverbrauch ; Körpergewicht
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die verminderte Gewichtszunahme bei experimenteller chronischer Urämie führte zu der Bestimmung des Sauerstoffverbrauches chronisch urämischer Ratten und eines normalen Vergleichskollektivs. Die Messung des Sauerstoffverbrauches wird als Hinweis auf den Energiebedarf des Gesamtstoffwechsels gewertet. Drei Gruppen von Versuchstieren wurden untersucht: urämische Ratten (CU) von geringerem Gewicht (403,66 ± 9,9 g) als deren gesunde Vergleichstiere (NA) (498,31 ± 26,13) und jüngere Normaltiere (NJ), welche ein annähernd ähnliches Körpergewicht wie die chronisch Niereninsuffizienten aufwiesen (376,0 ± 8,8). Signifikante Unterschiede des Sauerstoffverbrauches, bezogen auf das Körpergewicht, wurden zwischen den Gruppen NJ (0,927 ± 0,042 ml O2/mn/100 g Ratte) und beiden Gruppen CU und NA (0,788 ± 0,036 und 0,788 ± 0,028 jeweils) gefunden. Eine proportionale Verminderung der energetisch aktiven Körpermasse mag die Ursache der Sauerstoff-Meßergebnisse bei chronischer experimenteller Urämie sein.
    Notes: Summary Impaired weight gain, a common feature in experimental chronic uremia, led to compare oxygen consumption values of chronic uremic rats and their controls. Oxygen consumption measurement may allow an approach to the evaluation of total energy requirement. Three groups of animals were considered: uremic rats (CU) of less weight (402.66 ± 9.9 g) than their control group (NA) (498.31 ± 26.13) and younger normal animals (NJ), showing a similar weight (376.0 ± 8.8) to that of the uremics. Significant differences in oxygen consumption values/body weight were found between group NJ (0.927 ± 0.042 ml O2/mn/100 g rat) and both groups CU and NA (0.788 ± 0.036 and 0.788 ± 0.028 respectively). Proportional decrease of energetically active body mass in chronic uremic animals may be the reason of the findings.
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    Research in experimental medicine 174 (1978), S. 57-65 
    ISSN: 1433-8580
    Keywords: Complement system ; Sodium taurocholate ; Acute experimental pancreatitis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The role of the complement system was studied in Na-taurocholate pancreatitis in rats. Complement activity (CH 50) was determined at various times in the course of pancreatitis. Immediately after induction of acute pancreatitis, serum complement activity declined and massive C 3 deposits could be detected in the vicinity of acinar necroses and necrobioses. After a phase of recovery three to six hours postoperatively a second complement consumption occurred. Lethality rate increased as serum complement activity fell below 50% of preoperative values. The degree of C 3 deposition increased up to six hours. Decline of serum complement activity and deposition within the pancreas seemed to be correlated with histologically demonstrable tissue lesion. The first decline of complement activity in serum is thought to be caused by liberation of complement activating substances within the pancreas due to the detergent action of Na-taurocholate itself. The second decline, however, may be due to the liberation of complement activating and/or destroying enzymes into the blood stream.
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    Research in experimental medicine 172 (1978), S. 247-253 
    ISSN: 1433-8580
    Keywords: Rat ; Parotid saliva
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A method is described, which is suitable to collect continuously and quantitatively saliva from both parotid glands in rats under in vivo conditions and which allows to investigate salivary electrolyte composition in relation to flow rate during several hours. This might be of expanding scientific interest in disturbances of transepithelial electrolyte transport in various pathophysiological situations (for instance different forms of experimental hypertension, endstage renal failure and so on).
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    Anatomy and embryology 154 (1978), S. 27-37 
    ISSN: 1432-0568
    Keywords: Capillarization ; Cortex ; Rat ; 6-Aminonicotinamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary During different embryonic and postnatal stages, 6-aminonicotinamide (6-AN) was administered to Wistar albino rats. The capillarization of the occipital cortex has been examined morphometrically. A 6-AN-vulnerable stage of prenatal development was found, which lasted to the 19th prenatal day and which only partly corresponds to the so-called ‘critical stage’ of capillary sprouting (Kapillarsprossung). Capillary sprouting was not impaired by 6-AN during postnatal stages. Impairment of capillarization by 6-AN might be the result of glial lesion. The importance of glia for capillarization is discussed.
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    Anatomy and embryology 153 (1978), S. 1-8 
    ISSN: 1432-0568
    Keywords: Ileal epithelial cell ; Suckling period ; Rat ; Scanning electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ileal epithelial cells containing the tubulo-vacuolar systems and supranuclear vacuoles in suckling rats were investigated with scanning electron microscopy, using specimens treated with osmium-thiocarbohydrazide-osmium staining methods, and critical point drying and cracking. The cracked surface of the apical cytoplasm is seen as irregular and small hollows and pores of the anastomosing and branching tubulo-vacuolar system. The cracked surface of the supranuclear vacuoles shows the ellipsoidal structures. Numerous pores of various size and irregular shape are present on the apical inner surface of the supranuclear vacuole. These pores are clearly the openings from the tubulo-vacuolar system to the supranuclear vacuole. Some small pores are visible on the inner lateral surface of the supranuclear vacuole, especially near the nucleus. They are probably the pathways of the absorbed materials from the supranuclear vacuole into the lateral cytoplasm. Usually, the inclusions of the supranuclear vacuole reveal the globes or coarse and sponge-like networks.
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  • 73
    ISSN: 1432-0568
    Keywords: Rat ; Iris ; Cornea ; Catecholamine fluorescence ; Cholinesterase ; Histochemistry ; Ontogenesis ; Catecholamines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Glyoxylic acid-induced fluorescence technique and a copper thiocholine method were used to investigate the ontogenesis of the catecholamine-containing and cholinesterase-positive nerves of the rat iris and cornea. First fluorescent nerve fibres appeared in the iris on the 18th gestation day and in the cornea on the 19th day. A rapid increase in the density of the adrenergic nerve fibres of the iris continued to the age of three weeks, while the number of such fibres were small in the cornea. Acetylcholinesterase-positive fibres appeared both in the cornea and in the iris on the 19th gestation day. Their density increased more rapidly in the iris, especially in the sphincter muscle, than in the cornea. Non-specific cholinesterase activity was localized in the Schwann cells and the reaction was more intense during development than in the nerves of the cornea of adult rats.
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  • 74
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    Anatomy and embryology 154 (1978), S. 241-251 
    ISSN: 1432-0568
    Keywords: Nervous system ; Serotonin ; Raphe nuclei ; Development ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pre- and early postnatal development of serotonin neurons in the rat brainstem was studied using the fluorescence histochemical method. The technique utilized does not require drug pretreatment to visualize an intense serotonin fluorophore localized in neuronal perikarya, dendrites, and axons. All the serotonin neuron groups develop as bilateral nuclei which extend from the midbrain through the medulla. Six of the nine groups undergo a midline fusion from embryonic day 18 (E 18) through postnatal day 6 (P 6) in a rostrocaudal gradient. Cells of the nucleus raphe dorsalis fuse first (by P1), whereas the serotonin neurons located in nucleus raphe pallidus do not fuse until P 6. This gradient is comparable to the one described for the first observable fluorescence in the serotonin neurons groups. After final cell division, the serotonin neurons undergo a primary migration from the ventricular zone along the midline, where they are situated during embryogenesis, and a secondary migration extending into postnatal life which concludes with fusion in the midline. The bilateral origins of the serotonin cell groups are maintained in the adult. This is expressed by the apparent ipsilateral projections of some of the raphe neurons determined recently in our laboratory utilizing autoradiographic and horseradish peroxidase techniques.
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  • 75
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    Annals of hematology 37 (1978), S. 295-306 
    ISSN: 1432-0584
    Keywords: Β-adrenerge Rezeptoren ; (3H) (−) Dihydroalprenolol ; Erythrozyten ; Ratte ; Β-Adrenoceptors ; (3H) (−) Dihydroalprenolol ; Erythrocytes ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary By means of the radioactive antagonist ligand (3H) (−) dihydroalprenolol (DHAP) specific binding sites were identified in membrane preparations from red blood cells from rats. These specific sites were characterized asΒ-adrenoceptors because of the following reasons: Specific binding of DHAP (in contrast to unspecific binding) was dependent on temparature and time of incubation. Furthermore, specific binding of DHAP showed saturability, temperature-dependent reversibility and high affinity (KD-value of DHAP = 6.51 nM). Specific binding of DHAP was competitively inhibited byΒ-adrenergic antagonists (pindolol 〉 alprenolol ≧ propranolol 〉 practolol) and agonists (isoprenaline 〉 adrenaline). The (−) enantiomers of pindolol and isoprenaline showed pronounced higher affinities for the receptor sites than the respective (+) enantiomers. The receptor density in the membrane preparations (pmoles/mg protein) was strongly dependent on the degree of reticulocytosis: The Bmax-values increased more than 4 to 5 fold without alteration of the respective KD-values when reticulocyte counts were enhanced from 3 to 80 % treatment of the animals with increasing doses of acetyl phenylhydrazine.
    Notes: Zusammenfassung Mittels des radioaktiv markierten Antagonist-Liganden (3H) (−) Dihydroalprenolol (DHAP) wurden spezifische Bindungsstellen in Membran-PrÄparationen von Erythrozyten der Ratte identifiziert, die aus folgenden Gründen alsΒ-adrenerge Rezeptoren angesprochen werden können: Im Gegensatz zur unspezifischen Bindung von DHAP war die spezifische Bindung abhÄngig von der Inkubationszeit und der Temperatur. Sie folgte einer SÄttigungskinetik, war — in AbhÄngigkeit von der Temperatur — reversibel und wies eine hohe AffinitÄt auf (KD für DHAP = 6,51 nM). Die rezeptorspezifische Bindung von DHAP wurde durchΒ-Rezeptorenblocker (Pindolol 〉 Alprenolol ≧ Propranolol 〉 Practolol) oderΒ-Sympathomimetika (Isoprenalin 〉 Adrenalin) kompetitiv gehemmt. Die (−) Enantiomeren von Pindolol und Isoprenalin hatten eine wesentlich höhere AffinitÄt als die antsprechenden (+) Enantiomeren. Die Dichte Β-adrenerger Rezeptoren (pmole/mg Eiwei\) nahm mit steigendem Retikulozytosegrad zu: Sie stieg auf das 4-bis 5fache an, wenn die Retikulozytenwerte durch Vorbehandlung der Tiere mit Azetylphenylhydrazin von 3 auf 80 % gesteigert wurden.
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  • 76
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    Archives of dermatological research 262 (1978), S. 167-172 
    ISSN: 1432-069X
    Keywords: Rat ; Oxygen uptake ; Induced skincycle ; Spontaneous skincycle ; Diurnal rhythm ; Ratte ; Sauerstoffverbrauch ; Induzierter Hautcyclus ; Spontaner Hautcyclus ; Tagesschwankung
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung In der vom Panniculus carnosus gereinigten “glatten” Rattenhaut wurde der Sauerstoffverbrauch des spontanen und induzierten Hautcyclus zu verschiedenen Tageszeiten ermittelt. Das Niveau des Sauerstoffverbrauches korrelierte mit den Tag-Nacht-Zeiten. Der Sauerstoffverbrauch zeigte während des Hautcyclus Schwankungen. Ferner fanden sich Anhaltspunkte, daß der frühanagene Wert des Sauerstoffverbrauches von der Cyclusphase mit beeinflußt wird, während welcher der neue Cyclus künstlich induziert wird. Weiter wurde festgestellt, daß eine gewisse Abnahme des Sauerstoffverbrauches die ruhenden Haarfollikel zur spontanen Proliferation anregt. Während des Katagen schien der Maximalwert des Sauerstoffverbrauches mit speziellen morphofunktionellen perifollikulären Veränderungen in Beziehung zu stehen. Die Übertragung dieser Befunde auf die Pathophysiologie menschlicher Haarwachstumsstörungen wird erwogen.
    Notes: Summary In the “clean” rat skin purified from the panniculus carnosus the oxygen consumption of the spontaneous and artificially induced skincycle was measured at different times of day. The level of oxygen consumption correlated to diurnal and nocturnal periods. During the skincycle the oxygen consumption showed fluctuations. There were indications that the value of oxygen consumption of the early anagen is influenced by that phase of the cycle at which the new cycle is artificially induced. Furthermore, it was found that a certain decrease of oxygen consumption stimulates the quiescent hair follicles to spontaneous proliferation. During the katagen the peak value of the oxygen consumption seemed to be correlated with specially morphofunctional perifollicular changes. The application of these findings to the pathophysiology of human hair growth disturbances is discussed.
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  • 77
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    Acta neuropathologica 42 (1978), S. 159-164 
    ISSN: 1432-0533
    Keywords: Perhexiline maleate ; Pexid ; Abnormal inclusion ; Rat ; CNS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The basic cellular lesion in CNS of suckling rats treated with Pexid was studied by light and electron microscopy. The most pronounced abnormality, the formation of various intracytoplasmic inclusions, was found in neurons, astrocytes, oligodendrocytes, ependymal cells, endothelial cells and fibroblasts. These abnormal inclusions were generally membrane-bound, although clearly non-membrane-bound inclusions were occasionally found. The several internal patterns of the inclusions were (1) lamellar, both concentric and parallel, (2) reticular and (3) crystalloid. These alterations were completely resersed following withdrawal of the drug. The structural characteristics of the abnormal inclusions in Pexid-treated animals were similar to those found with certain hypocholesterolemic, neuroleptic, anorectic, and antimalarial drugs. This suggests that the inclusions occurring within the cells of animals treated with any of these drugs may develop in a similar manner, and that the formation of such inclusions is likely to be a form of cellular reaction common to certain metabolic disturbances.
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  • 78
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    Acta neuropathologica 44 (1978), S. 53-56 
    ISSN: 1432-0533
    Keywords: Blood-brain barrier ; Air embolism ; Horseradish peroxidase ; Cerebral cortex ; Electron microscopy ; Carotid artery ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Male albino rats were anaesthetized with diazepam, injected with horseradish peroxidase and Evans blue-labeled albumin and given an embolus of 0.01 ml air in the right common carotid artery after ligation of the external carotid branch. The pial arteries of the right cerebral hemisphere were stained blue, particularly the middle cerebral artery and its main arterial branchlets. Ultrastructurally, some endothelial cells in the right middle cerebral artery, small arteries and arterioles showed a diffuse distribution of horseradish peroxidase in their cytoplasm, although these vessels only occasionally showed peroxidase in their basement membranes. Other endothelial cells in these arterial branchlets showed few if any signs of a diffuse distribution of peroxidase but displayed several pinocytotic vesicles and occasionally trans-endothelial channels filled with peroxidase, sometimes with a slight leakage of peroxidase into adjacent basement membranes and neuropil. Scattered pinocytotic vesicles were observed in capillaries and venules, but there was usually no extravasation of peroxidase around these vessels.
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  • 79
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    Acta neuropathologica 44 (1978), S. 147-149 
    ISSN: 1432-0533
    Keywords: Cadmium ; Endothelial cell ; Capillary ; Fetal brain ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Pregnant rats received a single administration of 0.5, 1.0, or 2.0 mg/kg of cadmium on day 18 or 20 or gestation Maternal animals were killed on day 21 and samples of the caudate nucleus from fetal brains were examined using the transmission electron microscope. A 2.0 mg/kg dose of cadmium administered to maternal rats on day 20 of gestation caused the formation of vacuoles in the endothelial cells of capilaries in the fetal brain. Significant endothelial cell vacuolization was not observed in the brain of fetuses from other treatment groups. The vacuoles occurred singly, were spherical in shape, were located adjacent to the intercellular junctions and caused focal distortion of the endothelial cell. Vacuoles were the only ultrastructural alteration observed in the caudate nucleus of fetal brains.
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  • 80
    ISSN: 1432-0533
    Keywords: Protein-calorie malnutrition ; Rat ; Spinal root ; Sciatic nerve ; Internodal length
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The current investigation comprised normal young rats as well as rats submitted to a 50% food reduction or severe protein restriction. Isolated nerve fibres from lumbar spinal roots and sciatic nerves were investigated with reference to the relation between length and diameter of internodes as well as variation of internodal length along single nerve fibres. The present results do not support the view that protein-calorie malnutrition should cause neuropathy. Internodal segments were, on an average, shorter in relation to their thickness in young rats submitted to severe protein restriction or a 50% food reduction. The deviation was most marked in low-protein animals and particularly among coarser internodal segments. An inhibition of longitudinal growth was considered to be the main factor behind the difference between malnourished and normal rats.
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  • 81
    ISSN: 1432-0533
    Keywords: Experimental brain gliomas ; Chemically induced ; Rat ; Cell cultures ; Humoral antibodies ; Immunofluorescence staining ; Microcytotoxicity assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Brain tumors were induced in Sprague-Dawley and Long-Evans rats by administration of N-methyl-N-nitrosourea in the drinking water. Of these tumors, a grade 2 mixed glioma, a grade 2 to 3 astrocytoma and a grade 1 to 2 oligodendroglioma were established in vitro, maintained in culture and designated 75SD-G-376, 75SD-G-420 and 77LE-G-180, respectively. Of these mass cultures, two were successfully cloned and are currently available as 75SD-G-376C and 75SD-420C cell lines. Clonal lines produce S-100 protein and grow as tumors when isografted in young rats. Using the cultured cells as target cells, specific antibodies were searched for in the sera of the rats with the primary tumors by means of an indirect fluorescent antibody staining method and a complement-dependent antibody-mediated microcytotoxicity assay. Fluorescent and cytotoxic antibodies were demonstrated in the sera of the mixed glioma- and astrocytoma-bearing animals. However, a variable proportion of cells of the 75SD-G-376 and 75SD-G-420 lines showed no reaction with the corresponding sera. Furthermore, cytotoxic anfibodies had a lytic effect on the autologous glioma cells only in the presence of rabbit complement.
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  • 82
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    Acta neuropathologica 44 (1978), S. 245-247 
    ISSN: 1432-0533
    Keywords: Schwann cells ; PNS myelin ; Retina ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Within the retinal nerve fiber layer of a 6-week-old Sprague-Dawley rat, scattered aggregates of PNS myelinated axons have been found and described. We believe this is likely to represent a normal but rare phenomenon in the rat.
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  • 83
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    Calcified tissue international 25 (1978), S. 75-83 
    ISSN: 1432-0827
    Keywords: Rat ; Fluorosis ; Enamel ; Scanning electron microscopy ; Low temperature incineration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Sixteen 58-day-old male rats of Wistar strain, with a mean body weight of 179 g, were divided into two equal groups. Each group of eight animals was maintained for 70 days on drinking water, ad lib., containing no fluorine (control group) and 100 ppm of fluorine (experimental group). All specimens examined were obtained from the incisal portions of the incisors. The following types of enamel specimens were prepared for scanning electron microscopy: (1) acid-etched specimens; (2) acid-etched specimens followed by low temperature microincineration; and (3) fractured specimens. The enamel formed during high fluoride exposure showed marked hypocalcification, that is, the crystallite density in the prism core and interprismatic region was lower than that of control animals. The organic substances appeared to increase in these regions. These changes were prominent in the outer and middle enamel layers. Such changes following fluoride administration appear to indicate an inhibition of enamel maturation, that is, an inhibition of the mineral deposition and/or an inhibition of organic matrix withdrawal.
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  • 84
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    Naunyn-Schmiedeberg's archives of pharmacology 303 (1978), S. 165-170 
    ISSN: 1432-1912
    Keywords: Striatum ; Evoked potentials ; Neuroleptics ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The interaction of cortico- and nigrofugal inputs to the striatum of the rat was investigated using the technique of evoked potentials. Repetitive, unilateral stimulation of the substantia nigra inhibited potentials which were evoked from the ipsilateral rostral cortex and recorded from the ipsilateral striatum. The inhibition was antagonized by low doses of various intraperitoneally administered neuroleptics such as: pimozide (0.1–0.2 mg/kg), haloperidol (0.1–0.5 mg/kg), chlorpromazine (0.5–2.0 mg/kg) and thioridazine azine (0.5–4.0 mg/kg). These findings are discussed in view of the existing controversy regarding the mode of action of dopamine in the striatum.
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  • 85
    ISSN: 1432-2013
    Keywords: Oxygen dissociation curve ; Oxygen transport ; Cardiac output ; Coronary blood flow ; Blood flow to organs ; Hypoxia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A major displacement of the blood O2 dissociation curve (ODC) was achieved in rats by chronic administration of sodium cyanate (NaOCN). Control animals with a normal position of the ODC received NaCl instead. Arterial and mixed-venous O2 content ( $${\text{C}}_{{\text{O}}_{\text{2}} }$$ ) and O2 consumption were measured during breathing room air, 14.9, 8.0, or 5.6% O2 in N2. Cardiac output was obtained by the Fick principle.86RbCl was administered i.v., the rats were killed and the activity of86Rb in heart, spleen, stomach and intestines, liver, kidney, skeletal muscle, and skin was measured. According to Sapirstein (1956, 1958) the fractional uptake of86Rb in these organs corresponds to the fractions of cardiac output supplying these organs, and from the fractional uptake and cardiac output the nutritional blood flow may be calculated. Arterial and mixed-venous $${\text{C}}_{{\text{O}}_{\text{2}} }$$ was larger in the NaOCN than in the NaCl rats at all levels of oxygenation. At normoxia and 14.9% O2 the venous $${\text{C}}_{{\text{O}}_{\text{2}} }$$ was enlarged more than the arterial one, and so the arterio-venous O2 difference [ $$\left( {{\text{a}} - {\text{v}}} \right)_{{\text{O}}_{\text{2}} }$$ ] as an index of the O2 extraction in the body was smaller in the rats with a left-shifted ODC. However, at more severe hypoxia (8.0 and 5.6% O2) the arterial $${\text{C}}_{{\text{O}}_{\text{2}} }$$ in the NaOCN rats was enlarged more than the mixed-venous one, resulting in a larger $$\left( {{\text{a}} - {\text{v}}} \right)_{{\text{O}}_{\text{2}} }$$ (and therefore O2 extraction) when compared with the NaCl animals. Cardiac output was larger in the NaOCN than in the NaCl rats at 14.9 and 5.6% O2, when expressed per kg body weight. At 14.9% O2 the augmented cardiac output compensated for the lower O2 extraction when compared with the NaCl animals. At 5.6% O2 the NaOCN rats had both a larger ( $$\left( {{\text{a}} - {\text{v}}} \right)_{{\text{O}}_{\text{2}} }$$ ) and cardiac output than the NaCl animals. In the NaCl rats the decreased O2 extraction was not compensated for by an augmented cardiac output and therefore their O2 consumption was not only lower than that of the NaOCN rats but decreased even below the normoxic value of the NaCl rats. Coronary blood flow was increased in both NaOCN and NaCl animals at deep hypoxia to about the same extent, but due to a much lower arterial $${\text{C}}_{{\text{O}}_{\text{2}} }$$ of the NaCl animals, their O2 supply to the heart was lower than that of the NaOCN rats. The nutritional blood flow to spleen, kidney, liver, stomach and intestines, and skin in ml/min · g was lower in the rats with a normal position of the ODC than in those with a left-shifted ODC. This, together with the low arterial $${\text{C}}_{{\text{O}}_{\text{2}} }$$ of the NaCl rats, suggests a serious compromising of the O2 supply to these organs. Results of this study support the conclusion of our theoretical studies (Turek et al., 1973; Turek and Kreuzer, 1976) that a shift of the ODC to the left might be disadvantageous for the O2 transport to tissues at mild hypoxia, but advantageous at severe hypoxia.
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  • 86
    ISSN: 1432-2013
    Keywords: Blood gases ; Cardiac hypertrophy ; Intercapillary distance ; Myocardial infarction ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In rats with a myocardial infarction due to ligation of the left coronary artery a marked right ventricular hypertrophy developed after 41/2 weeks. At this time no difference against control animals was observed in arterial $$P_{{\text{O}}_2 }$$ , $$P_{{\text{CO}}_2 }$$ , pH, ideal alveolar $$P_{{\text{O}}_2 }$$ , and alveolar-arterial O2 pressure difference, as measured in unanesthetized animals at normoxia. In histological sections of the heart stained by PAS reaction capillaries and muscle fibers were counted, and the mean intercapillary distance and muscle fiber diameter were estimated. In the right ventricle of the rats with myocardial infarction both increased when compared with control animals or with sham-operated rats. Fibercapillary ratio was the same in all three groups. Similar results were obtained in the remaining undamaged tissue of the left ventricle of rats with a myocardial infarction when compared with the left ventricle of control or sham-operated rats. Findings concerning intercapillary distance suggest that also in the myocardium which remains intact during the development of the infarction and later hypertrophies, tissue oxygen transport might be impaired, particularly during a stress situation. Results in the right ventricle of rats with myocardial infarction show an opposite trend against rats exposed chronically to simulated high altitude, where in the hypertrophied right ventricle a shorter intercapillary distance occurs and therefore an improvement of tissue oxygen transport might be expected.
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  • 87
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    Pflügers Archiv 376 (1978), S. 245-249 
    ISSN: 1432-2013
    Keywords: Colon ; Amino acid uptake ; Basolateral membrane ; Active transport ; Sheep ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Uptake of the nonmetabolizable model amino acid 2-aminoisobutyric acid (=AIB) through the basolateral membrane into epithelial cells was studied in sheep colon stripped of serosa and muscle layers. Only the antiluminal surface of the mucosa was exposed to the incubation medium. Thus AIB entry into epithelial cells could only occur through the basolateral membrane. AIB was taken up by a saturable process against a high concentration gradient. AIB uptake was inhibited by other neutral amino acids but not by sugars. In a low Na+ medium AIB uptake was impaired, indicating that active transport of amino acids through the basolateral membrane of colon epithelial cells is Na+-dependent. In the rat a saturable concentrative uptake of AIB through the basolateral membrane of colon epithelial cells has also been demonstrated. Concentrative uptake of amino acids through the basolateral membranes is probably important for the supply of colon epithelium with amino acids.
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  • 88
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    Pflügers Archiv 373 (1978), S. 133-138 
    ISSN: 1432-2013
    Keywords: Deoxycholate ; Intestinal perfusion ; Rat ; Enzymatic release ; Localization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The release of proteins, sucrase (SA), maltase (MA), leucine aminopeptidase (LA) and alkaline phosphatase (AP) activity from rat jejunum by sodium deoxycholate (DOC) was studied by an in vivo perfusion technique. In our experimental conditions, a 2 mmol/l DOC perfusion for 30 min induced a marked and reversible release of proteins and hydrolases. When specific activities were considered, each enzyme showed a distinct release pattern. Significantly, the SA release was largely increased, the AP release was decreased and there was no correlation between the releases of SA and AP. Furthermore, the various enzymes recovered into the lumen were solubilized at different extents. SA was chiefly present in a soluble and AP in a particular form. The microscopical appearances showed a slight exfoliation of the epithelial cells from the villous tips but no specific changes when compared to the control group. The results are discussed in terms of enzymic localization in the brush border membrane; SA would be located very superficially in the surface membrane and AP buried in the membrane and less accessible than the other enzymes.
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    Pflügers Archiv 374 (1978), S. 229-234 
    ISSN: 1432-2013
    Keywords: Cyclic AMP ; ADH ; Vasopressin ; Isoproterenol ; 3-isobutyl-1-methylxanthin ; Rat ; Water diuresis ; Antidiuresis ; Dehydration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In vivo experiments were performed in male Wistar rats to elucidate the probable relation between renal concentrating ability and medullary cyclic AMP content as influenced by changes of hydration and by administration of antidiuretic hormone (ADH). Cyclic AMP levels were 37% lower in water diuretic than in control animals (P〈0.01), but were not significantly changed during prolonged antidiuresis induced by dehydration or ADH administration. Nor could any change of cyclic AMP levels be demonstrated between 2 and 20 min after ADH injection. Significant increases of medullary cyclic AMP content occurred following stress, anesthesia, and administration of isoproterenol and 3-isobutyl-1-methylxanthin. The results suggest that the level of cyclic AMP in the renal medulla may not be an important determinant of the antidiuretic response produced by ADH in rats.
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  • 90
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    Pflügers Archiv 374 (1978), S. 285-288 
    ISSN: 1432-2013
    Keywords: High altitude ; Blood volume ; Red cell volume ; Plasma volume ; Body haematocrit ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Circulating blood volume (BV) as the sum of circulating red cell volume (RCV) and plasma volume (PV) was estimated in rats native to a simulated altitude of 3500 m (“natives”), in rats born at sea level and later in life transferred to the simulated high altitude (“newcomers”), and in control sea-level rats. RCV per kg body weight (b.w.) was significantly larger in both “newcomers” and “natives” than in controls. PV per kg b.w. was in the “newcomers” insignificantly and in the “natives” significantly smaller than in the controls. BV per kg b.w. in both high altitude groups tended to be larger than in controls but the difference was not significant. Arterial haematocrit (Ahct) in the “newcomers” was significantly higher than in the controls, and in the “natives” significantly higher than in both other groups. Body haematocrit (the ratio of RCV and BV in per cent) was smaller than Ahct in all groups; this was more pronounced in the “newcomers” than in the controls and even more so in the “natives”. Apparently the haematocrit in the minute vessels of the organs of animals exposed to chronic hypoxic hypoxia increases much less than might be expected from changes of the Ahct. An attempt was made to evaluate the possible error of the more commonly used method of estimating BV, when only RCV, or only PV, is measured, and BV and its complementary fraction are calculated from arterial or venous haematocrit. When, in our results, BV was calculated from RCV and Ahct, the absolute values and also the differences between groups were somewhat underestimated. When BV was calculated from PV and Ahct, the BV itself, and particularly the differences between groups, were overestimated quite considerably. It is suggested that the only safe way to estimate BV is to measure RCV and PV separately.
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  • 91
    ISSN: 1432-2013
    Keywords: PAH clearance ; PAH extraction ; Glomerular filtration rate ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PAH secretion (TPAH) was studied in rats at spontaneously occurring glomerular filtration rate (GFR). At saturated transport, TPAH was found to be correlated to GFR. This relationship was also observed at unsaturated transport where TPAH depends upon the PAH concentration in arterial plasma. However, no significant correlation between TPAH and renal PAH load or renal plasma flow rate was found when the effects of GFR were removed by partial correlation analysis. A dependency of TPAH on GFR explains the correlations found between filtration fraction (FF) and renal PAH extraction (EPAH) or renal tubular PAH extraction fraction (EPAH-FFPAH). Thus, even at low PAH concentration in a. plasma, renal PAH extraction may only be assumed to be constant if the filtration fraction is constant.
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  • 92
    ISSN: 1432-2013
    Keywords: Oxygen dissociation curve ; Oxygen transport ; Blood gases ; Hypoxia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Theoretical deductions have shown that a shift of the blood O2 dissociation curve (ODC) to the right might improve O2 transport to tissues at normoxia and at mild hypoxia whereas at severe hypoxia the organism should be better off with an ODC shifted to the left (Turek et al., 1973b; Turek and Kreuzer, 1976). The present study was performed in order to ascertain this ambiguous effect of an ODC shift depending on the degree of hypoxia in intact animals. A major displacement of the ODC to the left was achieved in rats by chronic administration of sodium cyanate (NaOCN). Control animals received sodium chloride (NaCl) instead. Arterial and mixed-venous $$P_{{\text{O}}_{\text{2}} }$$ , $$P_{{\text{CO}}_{\text{2}} }$$ , and pH were measured at normoxia and during breathing 14.9, 8.0, or 5.6% O2 in N2 in both groups. From $$P_{{\text{O}}_{\text{2}} }$$ , pH, ODC and arterial hematocrit, arterial and mixed-venous O2 contents were estimated and $$({\text{a}} - {\text{v)}}_{{\text{O}}_{\text{2}} }$$ as an index of blood O2 extraction was obtained. At normoxia and during breathing 14.9% O2 the NaOCN rats had a lower mixed-venous $$P_{{\text{O}}_{\text{2}} }$$ than the NaCl rats without any difference in pH. Arterio-venous O2 difference did not differ at normoxia but was lower in NaOCN rats at 14.9% O2. However, at 8.0 and 5.6% O2 the NaOCN rats had a higher mixed-venous $$P_{{\text{O}}_{\text{2}} }$$ , an increased $$({\text{a}} - {\text{v)}}_{{\text{O}}_{\text{2}} }$$ , and a higher pH (arterial and mixed-venous). At 5.6% O2 the NaCl rats developed a severe acidosis concomitant with pronounced hypocapnia. These findings confirm that rats with a left-shifted ODC have an impaired O2 transport to tissues at normoxia and mild hypoxia but a more efficient O2 transport at severe hypoxia as compared with rats with an unshifted ODC, in agreement with our previous theoretical studies.
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  • 93
    ISSN: 1432-0738
    Keywords: Cadmium ; Drug Metabolism ; Metallothionein ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of acute and chronic cadmium administration on hepatic drug metabolism was investigated in the male rat. 3 days after the acute administration of cadmium by either the intraperitoneal (0.84 mg Cd/kg) or the oral (〉 80 mg Cd/kg) route, there was a significant potentiation in duration of hexobarbital hypnosis and inhibition of hepatic microsomal metabolism of hexobarbital and aniline. Administration of cadmium in the drinking water at levels of 100 or 200 ppm Cd for periods of 2–12 weeks or at levels of 5 or 20 ppm Cd for 50 weeks did not produce alterations in either drug response or hepatic drug metabolism. Significant levels of metallothionein, a cadmium binding protein, found in the liver of the rats receiving cadmium chronically may offer an explanation for the observed differences in drug metabolism between the acute and chronic administration of cadmium. In additional studies, pretreatment of the rats with subthreshold doses of cadmium (0.21 or 0.42 mg Cd/kg) intraperitoneally produced a tolerance to the alterations in drug metabolism induced by the previous cadmium dose (0.84 mg Cd/kg, i.p.). However, chronic cadmium treatment (5 or 20 ppm Cd for 50 weeks) did not impart any such tolerance to subsequently administered Cd (0.84 mg/kg) by the intraperitoneal route. The hepatic levels of metallothionein induced by the chronic cadmium treatment were only 30–60% of those induced by the subthreshold cadmium and thus may not have bound enough of the large challenge cadmium dose to produce the tolerance phenomenon.
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  • 94
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    Archives of toxicology 39 (1978), S. 267-287 
    ISSN: 1432-0738
    Keywords: Rat ; Plasma ; Alkaline phosphatase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This report describes the application of a test system which applies different substrates, inhibitors and acrylamide electrophoresis to the study of the alkaline phosphatase activity of rats. The system, which was specifically devised to characterise the alkaline phosphatase activity of small quantities of plasma from rats in toxicological studies, was also used to examine the plasma from rats under several physiological conditions, e.g. time of day, age, diet, etc. These physiological factors can influence the measurement of plasma alkaline phosphatase activity and should be taken into account when designing toxicological studies. Different experimental regimes were used to produce increases in liver, bone and intestinal alkaline phosphatase isoenzymes in the plasma of rats and these were reflected in the characterisations by the system. Although much remains unknown, a few concepts of rat plasma alkaline phosphatase activity emerged under our conditions. There is a ‘tidal’ intestinal component which arises from feeding and is approximately 60% of the total activity of the fed rat. In the fasted rat this ‘tidal’ component has largely disappeared and the ‘core’ activity which remains is composed of approximately equal proportions of bone isoenzyme and another as yet ill-defined component. The liver isoenzyme which appears in the plasma of the cholestatic rat appears to be either a very minor component or absent from the plasma of our normal CFE derived rat.
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  • 95
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    Archives of toxicology 40 (1978), S. 7-16 
    ISSN: 1432-0738
    Keywords: Thallium ; Furosemide ; Acetazolamide ; Renal elimination ; Oral absorption ; 204Tl ; Kidney ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Im Rahmen einer Untersuchung über das Schicksal von Thallium im Organismus und über den Einfluß von Diuretika auf die Eliminationsgeschwindigkeit dieses Giftes wurde Tl2SO4 (48.9 μmol = 10 mg/kg) an wachen Ratten oral verabreicht. Die Blutspiegel von Tl+ wurden anschließend als Funktion der Zeit ermittelt, sie konnten mit einer klassischen Bateman-Funktion nicht richtig beschrieben werden. Etwa l Std nach oraler Verabreichung war die Blutkonzentration maximal. Die Behandlung mit Furosemid (30 mg/kg) beschleunigte die Entfernung von Thallium aus dem Organismus auf signifikante Weise. Etwa 35% der zugeführten Menge Thallium wurde während einer Woche nach der Injektion dieses Diuretikums mit dem Urin ausgeschieden. Auch die Ausscheidung von Natriumionen und Wasser war signifikant erhöht, die von Kaliumionen blieb jedoch fast unverändert. Thallium selbst verursachte eine schwache diuretische Wirkung. Nach fortgesetzter Behandlung mit Furosemid (bis 2 Wochen) blieb die Eliminationsgeschwindigkeit von Thallium, Wasser und Natrium beschleunigt, während die Ausscheidung von Kaliumionen im Vergleich zu Kontrolltieren etwas herabgesetzt war. Ethacrynsäure verursachte nach wiederholter Gabe in diuretisch wirksamen Dosen eine retroperitoneale Fibrose. Dieses wirksame Diuretikum konnte daher nicht in die Untersuchung einbezogen werden. Acetazolamid (30 mg/kg) erhöhte ebenfalls die Ausscheidung von Thallium, vor allem innerhalb der anfänglichen 24 Std. Die Wirkung war weniger intensiv als die von Furosemid, sie war außerdem bald erschöpft. Die Ergebnisse legen den Schluß nahe, Furosemid in hohen Dosen sei eine wirksame Maßnahme zur Beschleunigung der Thalliumentfernung aus dem Organismus, zumindest im vorliegenden Tiermodell. Acetazolamid ist zu diesem Zwecke wahrscheinlich nicht geeignet.
    Notes: Abstract In connection with a programme of investigations concerning the disposition of thallium in the rat and the influence of diuretic agents on the rate of elimination of thallium from the body, Tl2SO4 (48.9 μmol = 10 mg/kg) was given by mouth to conscious rats. Blood levels were studied as a function of time. They could not be described adequately by means of a classical Bateman function. The maximum blood level was achieved approximately 1 h following oral ingestion. Treatment with furosemide for 11 days (30 mg/kg twice daily) significantly accelerated the removal of thallium from the body with the urine. Approximately 35% of the administered thallium was excreted within one week following the injection of this diuretic agent. The excretion of sodium and water was also considerably enhanced, that of potassium hardly changed. Thallium itself displayed weak diuretic activity. Upon prolonged treatment (1–2 weeks) with furosemide the elimination of thallium, water and Na+ was still accelerated, although that of potassium proved diminished with respect to controls. Ethacrynic acid when administered repeatedly in appropriate doses caused retroperitoneal fibrosis. Therefore, this potent diuretic agent was not included in the investigations. Acetazolamide (30 mg/kg) also enhanced the excretion of thallium, especially within the initial 24 h of treatment. The effect was less pronounced than that of furosemide and rapidly exhausted. The results suggest that furosemide in a high dose is effective in accelerating thallium elimination from the body in the present animal model. Acetazolamide is probably not suitable for this purpose.
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  • 96
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    Archives of toxicology 41 (1978), S. 99-105 
    ISSN: 1432-0738
    Keywords: Rat ; Method ; Gastric ulceration ; Distention of stomach ; Stress ; Anti-inflammatory drugs ; Ulcerogenic side effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Das sog. „distention“-Ulkus wurde an Albinoratten untersucht und als neue Möglichkeit für die Feststellung ulzerogener Nebenwirkungen von Substanzen beschrieben. Die Dehnung des Magens in sich war nicht ausreichend um ulzerogene Läsionen auszulösen, denn die Dehnung des Magens mit physiologischer Kochsalzlösung führte nicht zur Ulzeration. Die Säure ist ein entscheidender Faktor in der Bildung des „distention“-Ulkus. Große Volumina von 0,1 N Salzsäure riefen innerhalb von 1 Std massive Ulzeration hervor. Kleine Mengen von dieser Säurelösung verursachten keine Ulzeration im Magen. Entzündungshemmer, die in noch von ulzerogenen Nebenwirkungen freien therapeutischen Dosen verabreicht wurden, erhöhten die Empfindlichkeit der gastralen Mukosa dem aggressiven Faktor, der Säure, gegenüber. Bei den mit bekanntlich ulzerogen wirkenden Dosen von Entzündungshemmern vorbehandelten Ratten wurde eine schnellere Bildung von Ulzera durch die Dehnung des Magens mit Säure beobachtet. Auch die Stressvorbehandlung beschleunigte und verstärkte die Bildung der durch Dehnung hervorgerufenen ulzerogenen Veränderungen im Magen.
    Notes: Abstract A modification of the distention ulcer was studied in albino rats and a new possibility of testing ulcerogenic side effects of drugs was described. The distention alone was not sufficient to produce lesions. The severity of ulcer lesions was highly dependent on the volume of the acid solution. Large volumes of 0.1 N HCl evoked severe ulcers within 1 h. Small amounts of weak acid solution did not cause any ulceration. Anti-inflammatory drugs administered in therapeutic doses, which did not yet produce any ulcers in animals, increased the sensitivity of the gastric mucosa against the aggresive factor, the acid. In animals pretreated by anti-inflammatory drugs in toxic doses an earlier development of ulceration was observed by distention with acid. Stress also accelerated and aggravated the formation of distention ulcers.
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  • 97
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    Archives of toxicology 39 (1978), S. 249-266 
    ISSN: 1432-0738
    Keywords: Rat ; Alkaline phosphatase ; Plasma ; Organs ; Toxicity testing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A manual system of various estimations of rat plasma alkaline phosphatase activity has been devised for small volumes of plasma which uses different inhibitors, compares the utilisation of two substrates and includes acrylamide gel electrophoresis. The different inhibitors etc. allow a degree of discrimination between alkaline phosphatase extracts of rat organs. The properties of isoenzymes, e.g. intestinal alkaline phosphatase, differ depending upon the environment in which they are studied. In conjunction, if necessary, with the methods described for the estimation of liver and intestinal alkaline phosphatase activity, it is hoped to use the system to discriminate between the isoenzymes present in the plasma alkaline phosphatase of rats in toxicological studies.
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  • 98
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    Journal of cancer research and clinical oncology 91 (1978), S. 157-164 
    ISSN: 1432-1335
    Keywords: MNU ; DNA Repair ; Rat ; Age
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary DNA repair time-course was studied after injury by N-methyl-N-nitrosourea (MNU) in rat liver cells of animals of different ages and in fetuses using hydroxyurea (HU) as inhibitor of scheduled DNA synthesis. DNA repair was a rapid phenomenon, more so in young adults than in newborns, and was not detectable in fetuses. A correlation seems to exist among organ sensitivity to carcinogen, age of animal and DNA repair.
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  • 99
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    Journal of molecular medicine 56 (1978), S. 309-310 
    ISSN: 1432-1440
    Keywords: Perhexilin-Maleat ; generalisierte Lipidose ; Ratte ; Perhexiline maleate ; Generalized lipidosis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Administration of perhexiline (Pexide®) to rats causes generalized occurrence of lamellated and crystalloid cytoplasmic inclusions which resemble those described in patients with perhexiline-induced polyneuropathy. It is concluded that perhexiline being an amphiphilic cationic compound is a potent inducer of generalized lipidosis.
    Notes: Zusammenfassung Perhexilin (Pexid®) verursacht bei der Ratte das generalisierte Auftreten von lamellären und kristalloiden zytoplasmatischen Einschlußkörpern, die denjenigen gleichen, die bei Patienten mit Perhexilin-induzierter Polyneuropathie beschrieben worden sind. Aus den vorgelegten Befunden wird geschlossen, daß Perhexilin, eine amphiphile kationische Verbindung, ein starker Induktor einer generalisierten Lipidose ist.
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  • 100
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    Naunyn-Schmiedeberg's archives of pharmacology 302 (1978), S. 239-254 
    ISSN: 1432-1912
    Keywords: Myocardial α-adrenoceptors ; Rat ; Guinea pig ; Cat ; Hypothyroidism ; Single adrenoceptor type
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The presence and distribution of myocardial α-adrenoceptors in different parts of the heart of various mammalian species was investigated. For this reason experiments were performed in isolated cardiac preparations of rats, guinea pigs and cats. In order to obtain more information about the nature of the cardiac α-adrenoceptors additional experiments were undertaken at different temperatures. These studies were aimed to show whether or not a conversion of β-to α-adrenoceptors or vice versa takes place. Moreover, we analyzed the influence of hypothyroidism on the sensitivity of α- and β-adrenoceptors of preparations from rats fed with propylthiouracil. Finally, we tried to find out whether stimulation of these α-adrenoceptors leads to the formation of the cyclic nucleotides cAMP and cGMP. The following results were obtained: 1. In right ventricular strips of rats, guinea pigs and cats phenylephrine stimulated α-adrenoceptors. After blockade of β-adrenoceptors the respective pD2-values of phenylephrine were 5.32, 5.99 and 5.33. The doseresponse curves obtained in the presence of α-adrenolytic drugs were shifted to the right without depression of the maximum. In the rat, in addition, the pA2-values for the α-adrenolytic drugs yohimbine (5.79) and phentolamine (7.85) were determined. They were at least 0.5 log units higher than those found in the rat for other α-adrenoceptors (Van Rossum, 1965) thus supporting the view that the population of cardiac α-adrenoceptors is different from that of other organs. In left ventricular strips of guinea pigs the pD2-value for the α-mimetic effect of phenylephrine was of the same order of magnitude as that obtained in the right ventricle. 2. In the papillary muscle of the right ventricle of guinea pigs and cats phenylephrine stimulated α-adrenoceptors. 3. In the left atrium of the rat, phenylephrine stimulated myocardial α-adrenoceptors (pD2: 5.58). Also in this preparation the pA2-values for yohimbine (6.36) and phentolamine (8.21) were different from those found for other α-adrenoceptors in the rat (Van Rossum, 1965). Likewise in strips from the left atrium of the cat myocardial α-adrenoceptors are present. 4. In spontaneously beating right atria of the rat a clear-cut positive chronotropic effect mediated by stimulation of α-adrenoceptors could not be demonstrated although in 6 out of 15 preparations a small positive chronotropic effect became evident. No positive chronotropic effect at all was obtained by stimulation of α-adrenoceptors in the cat right atrium. 5. In ventricular strips as well as in left atria from hypothyroid rats the pD2-value for the α-effect of phenylephrine was increased, in the atrium more than in the ventricle, while the pA2-values for yohimbine and phentolamine were not significantly different from the controls. Under these conditions a distinct positive chronotropic effect mediated by stimulation of α-receptors was found in the spontaneously beating rat atrium. 6. After stimulation of α-adrenoceptors in atria and ventricular strips of normal and propylthiouraciltreated rats, as well as in strips of guinea-pig ventricles or cat atria no elevation of cAMP and cGMP was observed. 7. The concept of a single adrenoceptor convertible from α- to β-type or vice versa was not supported by our experiments. These were carried out at different temperatures on left atria and on ventricular strips of rat hearts using the irreversible α-adrenoceptor blocking agent phenoxybenzamine. 8. The present experiments provide evidence for the existence of α-adrenoceptors in the myocardium of various mammalian species. Their stimulation produces positive inotropic effects without increases in heart rate.
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