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  • 101
    ISSN: 1432-2072
    Keywords: A 68930 ; NNC-756 ; BW 737C ; SCH 23390 ; Dopamine D-1 and D-2 receptors ; Grooming ; Vacuous chewing ; D-1:D-2 interactions ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The full efficacy, high potency isochroman D-1 agonist A 68930 demonstrated greater than 220-fold selectivity for D-1 over D-2 receptors. A 68930 (0.06 and 0.25 mg/kg) readily induced intense grooming, together with vacuous chewing; these responses became less evident following higher doses (1.0 and 4.0 mg/kg) and sniffing became prominent. Intense grooming was blocked by three D-1 antagonists, the benzazepines SCH 23390 (0.01–1.0 mg/kg) and NNC-756 (0.01–1.0 mg/kg), and the isoquinoline BW 737C (0.2–5.0 mg/kg); however, vacuous chewing was not antagonised by SCH 23390 and NNC-756, but was blocked by BW 737C. Intense grooming was attenuated by the D-2 antagonist YM 09151 (0.005–0.5 mg/kg) while vacuous chewing was enhanced. These data suggest that intense grooming is mediated by a “D-1 like” receptor that recognises all known chemical classes of D-1-selective compounds, while vacuous chewing may be mediated by a pharmacologically distinct subtype of “D-1-like” receptor that recognises preferentially the isochromans and isoquinolines.
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  • 102
    ISSN: 1432-2072
    Keywords: Schedule-induced polydipsia ; SIP ; Clozapine ; Raclopride ; SCH 23390 ; Dopamine D1 antagonist ; Dopamine D2 antagonist ; Major tranquilizers ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of clozapine (CLOZ) upon acquired schedule-induced polydipsia in rats were compared to the effects of the dopamine (DA) D1 antagonist SCH 23390 (SCH) and the DA D2 antagonist raclopride (RAC). All three compounds suppressed water consumption, but only SCH and RAC decreased drinking efficiency. SCH was the only compound with an effect on panel pressing (PP), causing suppression even at a dose without effect upon water intake. SCH also affected the temporal pattern of licking (TPL) at all doses, while clozapine, 10 mg/kg, only affected the pattern acutely, and raclopride was without effect. In conclusion, PP and the TPL are more sensitive to D1 than D2 blockade. While PP and the TPL are more sensitive than water intake to D1 blockade, the opposite is true for D2 blockade. It is possible to differentiate between DA D1/D2 antagonists and CLOZ in this model, focusing upon reduction in water consumption, with and without reduction in drinking efficiency. Furthermore, it is possible to differentiate between D1 and D2 blockade by analyzing water consumption, PP and the TPL.
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  • 103
    ISSN: 1432-2072
    Keywords: Haloperidol ; Cocaine ; Apomorphine ; Stereotypy ; Locomotor activity ; Sensitization ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This experiment investigated the possibility that rats maintained on chronic haloperidol treatment would show increased behavioral responsiveness to cocaine, similar to that observed in human stimulant abusers who are chronically treated with neuroleptics. Thus, the effects on locomotion and stereotyped behavior of intermittent injections of cocaine were investigated in female rats receiving chronic haloperidol treatment. Daily injections of haloperidol (0.2 mg/kg, IP) or vehicle were administered for 6, 12 or 18 days prior to the start of testing with cocaine and were then continued throughout cocaine testing. All rats received four doses of cocaine (0.0, 3.0, 7.5, or 15.0 mg/kg, IP) in random order with an intervening vehicle day between successive drug days. The four dose sequence of cocaine was repeated a total of four times. Initial cocaine administration produced dose dependent increases in locomotion and stereotyped behavior. When the sequence of cocaine doses was repeated, differences among treatment groups emerged. Groups treated with haloperidol exhibited heightened locomotion in response to cocaine and with repeated injections, showed a higher rate of behavioral sensitization than control animals. These differences in the behavioral response to cocaine were maintained for at least 2 months following termination of daily haloperidol treatment. In order to examine the mechanisms underlying this heightened responsiveness to cocaine, apomorphine-induced locomotion (dose range, 0–250 µg/kg, SC) was determined. Regardless of dose, rats treated with haloperidol showed different temporal patterns of locomotion in response to apomorphine suggesting that the increased response to cocaine was related to changes in dopaminergic receptor sensitivity.
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  • 104
    ISSN: 1432-2072
    Keywords: Ultrasonic vocalizations ; Defense ; Pain ; Fear ; Aversion ; Social interactions ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study was carried out to determine whether 22–28 kHz vocalizations emitted during intermale interactions in adult rats were related with a state of fear, aversion or resulted from painful stimulation. Vocalizations in the 22–28 kHz range were measured in male rats during non-aggressive and aggressive social interactions; when given foot shock with a partner; during non-aggressive social interactions after an injection of (i) acetic acid (1%, IP); (ii) pentylenetetrazol (20–30 mg/kg, IP) and (iii) lithium chloride (63.8 mg/kg, IP). Ultrasonic vocalizations were consistantly detected in all rats while the animals displayed defensive or submissive postures when tested as intruders confronted with offensive residents or when administered foot shocks. Only occasional vocalizations were emitted, even in the presence of a partner, when the animals had received other painful or aversive treatments. These data support the hypothesis that 22–28 kHz vocalizations during intermale interactions are associated with defensive postures and are not the consequence of a state of fear or aversion.
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  • 105
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 111 (1993), S. 207-214 
    ISSN: 1432-2072
    Keywords: Feeding ; Striatum ; Nucleus accumbens ; Morphine ; Opiates ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Both systemic and intracranial administration of morphine can result in spontaneous feeding in nondeprived rats. The present investigation was conducted to examine the involvement of the striatum in this phenomenon. Morphine sulfate (0, 0.5, 1.0, 5.0, 10.0, and 20.0 µg/0.5 µl) was microinjected into five discrete striatal subregions in non-deprived rats: the nucleus accumbens, the ventromedial striatum, the ventrolateral striatum, the anterior dorsal striatum, and the posterior dorsal striatum. Feeding, drinking, locomotion, rearing, and food intake were measured over 4 h after infusion. Results indicate that the striatum is a heterogeneous structure with regard to the regulation of opiate-induced feeding behavior and locomotor activity. Morphine infusion into anteroventromedial regions including the nucleus accumbens resulted in a marked hyperphagia that was generally delayed in onset; much smaller increases or no change in feeding occurred after administration into more dorsal, lateral and posterior areas. It is hypothesized that there may exist within the striatum an anatomical gradient that is most sensitive to opiate-induced feeding within the anteroventromedial sector. Since this area has extensive connections with other brain sites sensitive to opiate-induced feeding, it may be a critical part of an opiatergic feeding system within the brain. In addition, a possible role for the anteroventromedial striatum in compulsive feeding and bulimia is discussed.
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  • 106
    ISSN: 1432-2072
    Keywords: Radial maze ; Spatial memory ; Scopolamine ; Cholinomimetics ; ACE inhibitors ; Angiotensin II antagonists ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of cholinomimetic and non-cholinomimetic agents on spatial memory using a novel task in the 12-arm radial maze were investigated. The task was designed to reduce the tendency to use non-spatial strategies. Animals were repeatedly trained to retrieve food rewards from three arms, until a criterion level of performance was reached. Scopolamine (0.03 and 0.1 mg/kg SC), but not N-methylscopolamine (0.1 mg/kg SC) disrupted performance of this task. Physostigmine (0.3 mg/kg SC) and pilocarpine (30 mg/kg SC) completely reversed the deficit of performance produced by scopolamine. Furthermore, the ACE inhibitor Hoe 288 (10 nmol ICV) and the angiotensin AT1 receptor antagonist losartan (10 mg/kg SC) also significantly attenuated the scopolamine-induced deficit. These results show that this novel task in the radial maze is sensitive to the disruptive effects of scopolamine and can identify cognitive enhancing effects of both cholinomimetic and non-cholinomimetic drugs. Thus, this maze task provides a useful model for the evaluation of novel cognitive enhancing agents.
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  • 107
    ISSN: 1432-2072
    Keywords: Spatial learning ; Rat ; Muscarinic ; Nicotinic ; Receptors ; Chronic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Nicotine, scopolamine, oxotremorine, diisopropyl-fluorophosphate (DFP) and tetrahydroaminoacridine (THA) were administered chronically to different groups of rats in doses reported to alter central muscarinic and/or nicotinic receptro numbers. Beginning 24 h after final drug injection, the groups were compared to a vehicle control group on acquisition of a hidden platform position in the Morris water maze over 20 trials with a 30-min inter-trial interval. Chronic treatment with either nicotine or scopolamine significantly improved the rate of learning, but oxotremorine and DFP retarded learning and THA had no effect on learning. The chronic drug effects on behaviour were consistent with known effects of the injected drugs on muscarinic and nicotinic binding in the forebrain and on the sensitivity of frontal cortex neurones to iontophoretically applied cholinoceptor agonists. However, alternative explanations for the observed changes cannot be ruled out, since the drugs used are known to have a wide range of effects on other neurotransmitters.
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  • 108
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 113 (1993), S. 177-186 
    ISSN: 1432-2072
    Keywords: Rat ; Behavior ; Microstructure ; Scaling measures
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous studies demonstrated that drug effects on the movement sequences of rats in unconditioned motor activity paradigms can be quantified by scaling measures that describe the average relationship between a variable of interest and an experimental parameter. However, rats engage in a wide variety of geometrically distinct movements that can be influenced differentially by drugs. In this investigation, the extended scaling approach is presented to capture quantitatively the relative contributions of geometrically distinct movement sequences to the overall path structure. The calculation of the spectrum of local spatial scaling exponents,f(d), is based on ensemble methods used in statistical physics. Results of thef(d) analysis confirm that the amount of motor activity is not correlated with the geometrical structure of movement sequences. Changes in the average spatial scaling exponent,d, correspond to shifting the entiref(d) function, and indicate overall changes in path structure. With the extended scaling approach, straight movement sequences are assessed independently from highly circumscribed movements. Thus, thef(d) function identifies drug effects on particular ranges of movement sequences as defined by the geometrical structure of movements. More generally, thef(d) function quantifies the relationship between microscopically recorded variables, in this paradigm consecutive (x, y) locations, and the macroscopic behavioral patterns that constitute the animal's response topography.
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  • 109
    ISSN: 1432-2072
    Keywords: Diisopropylfluorophosphate ; Atropine ; Somatostatin receptors ; Brain ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The acute and chronic administration of diisopropylfluorophosphate (DFP), an inhibitor of acetylcholinesterase (AChE), and of atropine, a blocker of muscarinic cholinergic receptors, did not affect somatostatin-like immunoreactivity (SLI) content in the frontoparietal cortex and hippocampus of rats. Acute and chronic DFP administration increased the number of specific125I-Tyr11-somatostatin (125I-Tyr11-SS) receptors in synaptosomes from the frontoparietal cortex but not in those from the hippocampus and did not change the affinity constant. This increase in125I-Tyr11-SS binding was not due to a direct effect of DFP on somatostatin (SS) receptors since no rise of binding was produced by high concentrations of DFP (10−5 M) when added in vitro. The increase could be blocked by pretreatment with atropine. The acute administration of atropine alone had no observable effect on the number of SS receptors. However, repeated atropine administration produced a significant decrease in the125I-Tyr11-SS binding in synaptosomes from the frontoparietal cortex but not in those from the hippocampus although the affinity constant was unchanged. The results suggest that interactions between somatostatinergic and cholinergic receptors may be important in the rat frontoparietal cortex.
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  • 110
    ISSN: 1432-2072
    Keywords: Cocaine ; Amphetamine ; Drug discrimination ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats with different behavioral histories, defined by rearing and housing in either an enriched condition (EC) or an isolation condition (IC), were trained in a two-lever operant procedure to discriminate 5.0 mg/kg cocaine from saline. In cocaine dose-generalization tests, the IC rats exhibited an ED50 (1.01 mg/kg) significantly lower than the EC rats (ED50:1.55 mg/kg). The cocaine-appropriate responding was emitted when the rats were treated withd-amphetamine, and for thed-amphetamine test doses the ED50 (0.19 mg/kg) was again significantly lower for the IC rats compared to the ECs (ED50:0.33 mg/kg). These data suggest that IC rats are more sensitive to the stimulus properties of indirect dopaminergic agonists than EC rats and highlight the importance of environmental variables in governing an organism's response to the stimulus properties of abused drugs.
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  • 111
    Electronic Resource
    Electronic Resource
    Springer
    Pflügers Archiv 422 (1993), S. 523-529 
    ISSN: 1432-2013
    Keywords: Confocal microscopy ; Fluorescence microscopy ; Proximal tubule ; 2′,7′-Bis(carboxyethyl)-5(6)-carboxyfluorescein ; Intracellular pH ; Viability ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Confocal laserscan microscopy with a dual-excitation device was used to record intracellular pH (pHi) regulation in rat proximal convoluted tubules microperfused in vivo. Cells were loaded with the pH-sensitive, fluorescent dye 2′,7′-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF). Single cells could be distinguished within the tubules and separate measurements were possible. Application of an NH4Cl pulse by peritubular perfusion caused an immediate increase in intracellular pH. Intraluminal injection of NH4Cl led to a slower increase in intracellular pH. In both cases, cessation of perfusion led to an immediate acidification. Peritubular perfusion with 300 μM 4,4′-diisothiocanatodihydrostilbene-2, 2′-disulphonic acid (H2DIDS) caused an intracellular alkalinisation. Microperfusion, pH-sensitive dyes and confocal laserscan microscopy provide a new non-invasive method to measure intracellular pH effectively in individual cells of near-surface structures of the intact kidney.
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  • 112
    Electronic Resource
    Electronic Resource
    Springer
    Archives of toxicology 67 (1993), S. 510-513 
    ISSN: 1432-0738
    Keywords: Pyrethroids ; Acute toxicity ; Drug metabolism inhibitors ; Neonatal ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The present study aims specifically at obtaining a comparison of the acute toxicity of cypermethrin (CY), a type I pyrethroid, and permethrin (PERM), a type II pyrethroid, administered orally as a single dose to neonatal and adult rats, and at assessing the importance of pyrethroid biotransformation in CY and PERM toxicity through use of drug metabolism inhibitors. Our experiments show that CY is more toxic than PERM to adult and neonatal rats. The sensitivity of neonatal rats both to CY and to PERM toxicity is higher, the younger the animals. CY is much more toxic than PERM in the neonatal rat, compared with the adult. In rats aged 8, 16, and 21 days, pretreatment with piperonil butoxide (PB), a monooxygenase inhibitor, or with tri-o-tolyl phosphate (TOTP), an esterase inhibitor, does not produce significant variations in the lethal effects of CY and PERM. Instead, in the adult rats, a significant increase in CY (X2=5.97;p〈0.05) and PERM (X2=4.37;p〈0.05) mortality occurred in rats pretreated with esterase inhibitors, whereas no increase in CY and PERM toxicity was found in adult animals pretreated with monooxygenase inhibitor. It was concluded that the higher level of sensitivity of the neonate rat to pyrethroid toxicity is probably due to incomplete development of the enzymes which catalyze the metabolism of pyrethroids in the liver of young animals. It is suggested that ester hydrolysis is an important pyrethroids detoxification reaction in the adult rat.
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  • 113
    ISSN: 1432-0738
    Keywords: Rat ; Hamster ; Microsomes ; Scoparone ; Cytochrome P450 ; Species differences ; Induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The hamster is known to display very high rates of monooxygenase-mediated biotransformation. In comparison with other species little knowledge has been gathered with respect to the nature of its cytochrome P450 enzymes and their respective inducibility. We studied the consequences of induction of P450 enzymes in rats and Syrian golden hamsters using the regioselective oxidative O-demethylation of the coumarin derivative scoparone. This metabolic conversion indicates differential effects of P450 inducers in the rat, in which various types of inducers cause different shifts in the isoscopoletin/scopoletin metabolite ratio (I/S-ratio). Liver microsomes from hamster not treated with P450 inducers oxidized scoparone much more efficiently than liver microsomes of untreated rats. In rat liver microsomes total demethylation rates of scoparone increased upon in vivo treatment with phenobarbital or ß-naphthoflavone. Phenobarbital reduced the I/S-ratio whereas ß-naphthoflavone caused an increase in this ratio. In hamster liver microsomes both phenobarbital and β-naphthoflavone treatments resulted in a decrease in the I/S ratio. In this species the total scoparone demethylation rate was not much affected by phenobarbital, but β-naphthoflavone caused a huge increase in over-all scoparone biotransformation. In both species, dexamethasone, isoniazid and clofibrate were much less effective. In contrast to the rat, in the hamster the scoparone biotransformation profile cannot be used to differentiate between phenobarbital- or β-naphthoflavone-treated animals.
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  • 114
    Electronic Resource
    Electronic Resource
    Springer
    Archives of toxicology 67 (1993), S. 120-125 
    ISSN: 1432-0738
    Keywords: Amoscanate ; Retinal degeneration ; Rat ; Electroretinography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Amoscanate, a substance which damages photoreceptors, was administered orally to Wistar rats in doses of 10, 40, and 125 mg/kg body weight once daily for 3 or 10 days. At both times electroretinographic, ophthalmological, and histopathological examinations of the retina were carried out to compare the sensitivity of conventional methods and to test electroretinography (ERG) for suitability for use in toxicity studies. Time-dependent and dose-dependent effects were found by electroretinography and light microscopy. However, signs of retinal changes appeared earlier and more distinctly in the electroretinogram. Ophthalmological fundus examination in albino rats yielded no characteristic correlate. In conclusion, electroretinography constitutes a valuable supplement to histopathology and is suitable for use in toxicity studies.
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  • 115
    ISSN: 1432-0738
    Keywords: Alkaline elution ; 1,3-Butadiene ; Lung ; Liver ; Mouse ; Rat ; Single-strand breaks ; DNA-DNA cross-links ; DNA-protein cross-links
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The alkaline filter elution technique was used to evaluate single strand breaks (SSB), DNA-DNA (DDCL) and DNA-protein cross-links (DPCL) in liver and lung of male rats (Sprague-Dawley) and male mice (B6C3F1) after exposure to 2000 ppm 1,3-butadiene (BD) for 7 days (7 h/day and/or to 100, 250, 500, 1000) 2000 ppm BD for 7 h. SSB were detected in liver DNA of both species at 2000 ppm. Cross-links are more pronounced in mouse lung than in mouse liver. Elution rates of lung DNA from mice exposed for 7 h to different concentrations of BD revealed an increase in cross-links between 250 and 500 ppm, and a further increase in cross-links up to 2000 ppm. No such signs of genotoxicity could be observed for the lung of rats. Our data support the involvement of reactive metabolites (epoxybutene and especially diepoxybutane) in butadieneinduced carcinogenesis in the mouse but not to that extent in the rat.
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  • 116
    ISSN: 1432-0738
    Keywords: C(±)P(±)-Soman ; Toxicokinetics ; 2-(o-cresyl)-4H-1∶3∶2-benzodioxaphosphorin-2-oxide ; CBDP ; Carboxylesterase ; Rat ; Guinea pig ; Marmoset
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Pretreatment of rats and guinea pigs with the specific carboxylesterase inhibitor 2-(o-cresyl)-4H-1 ∶ 3 ∶ 2-benzodioxaphosphorin-2-oxide (CBDP) reduces the LD50 of the nerve agent C(±)P(±)-soman in these species to the same range as in primates. This suggests that such CBDP-pretreated animals can be used in investigations that are relevant for prophylaxis and therapy of intoxication with C(±)P(±)-soman in primates including humans. In order to test this hypothesis we have studied the toxicokinetics of the toxic C(±)P(−)-isomers of soman in artificially respirated and CBDP-pretreated rats and guinea pigs at intravenous doses corresponding to 6 × LD50. A comparison of the areas under the curve (AUCs) of the blood levels of C(±)P(−)-soman in pretreated and non-pretreated animals at the same absolute dose shows extreme nonlinearity with dose, indicating that CBDP occupies highly reactive binding sites which are no longer available for sequestration of the soman isomers. The AUCs of C(±)P(−)-soman at equitoxic doses of 6× LD50 are reduced by pretreatment with CBDP from 1683 to 464 ng.min.ml−1 in rats and from 978 to 176 ng.min.ml−1 in guinea pigs, which is in the range of the AUC in non-pretreated marmosets at an equitoxic dose (419 ng.min.ml−1). The blood levels of the C(±)P(−)-isomers in marmosets and CBDP rats are rather similar during the first 7 min, but persist in CBDP rats for 2 h longer at toxicologically relevant levels than in marmosets. The levels of C(±)P(−)-soman in CBDP-pretreated guinea pigs are substantially lower than in marmosets for an initial period of 80 min. Nevertheless, they drop below toxicologically relevant levels approximately 50 min later than in marmosets. Evidently, one should be cautious in considering CBDP, pretreated rats and guinea pigs as substitute primates.
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  • 117
    Electronic Resource
    Electronic Resource
    Springer
    Archives of toxicology 67 (1993), S. 107-112 
    ISSN: 1432-0738
    Keywords: Toluene ; Ethanol ; Metabolism ; Hepatocytes ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Hepatocytes isolated from control, acetone- and phenobarbital-pretreated rats were used to study the metabolic conversion of toluene to benzyl alcohol, benzaldehyde, benzoic acid and hippuric acid at low (〈100 μM) and high (100–500 μM) toluene concentrations. The baseline formation rates of toluene metabolites (benzyl alcohol, benzoic acid and hippuric acid) were 2.9±01.7 and 10.0±2.3 nmol/mg cell protein/60 min at low and high toluene concentrations, respectively. In vivo pretreatment of rats with acetone and phenobarbital increased the formation of metabolites: at low toluene concentrations 3- and 5-fold, respectively; at high toluene concentrations no significant increase (acetone) and 8-fold increase (phenobarbital). Apparent inhibition by ethanol, 7 and 60 mM, was most prominent at low toluene concentrations: 63% and 69%, respectively, in control cells; 84% and 91% in acetone-pretreated cells, and 32% (not significant) and 51% in phenobarbital-pretreated cells. Ethanol also caused accumulation of benzyl alcohol. The apparent inhibition by isoniazid was similar to that of ethanol at low toluene concentrations. Control and acetone-pretreated cells were apparently resistant towards metyrapone; the decrease was 49% and 64% in phenobarbital-pretreated cells at low and high toluene concentrations, respectively. In these cells, the decrease in presence of combined ethanol and metyrapone was 95% (low toluene concentrations). 4-Methylpyrazole decreased metabolite formation extensively in all groups. Benzaldehyde was only found in the presence of an aldehyde dehydrogenase inhibitor. Increased ratio benzoic/hippuric acid was observed at high toluene concentrations. These results demonstrate that toluene oxidation may be studied by product formation in isolated hepatocytes. However, the influence of various enzymes in the overall metabolism could not be ascertained due to lack of inhibitor specificity.
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  • 118
    ISSN: 1432-0738
    Keywords: 1,3-Butadiene ; Closed-chamber technique ; 1,2-Epoxybutene-3 ; Glutathione ; Glutathione turnover ; Inhalation ; Mouse ; Pharmacokinetics ; Physiological model ; Ping-pong mechanism ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The gas 1,3-butadiene (BU) is an important industrial chemical and an environmental air pollutant. BU has been shown to be a weak carcinogen in the rat but a potent carcinogen in the B6C3F1 mouse. This species difference makes risk extrapolation to humans difficult and the underlying mechanism should be clarified before meaningful risk extrapolation to humans can be made. One possible explanation for the species differences in cancer response is that there are quantitative species differences in the formation of genotoxic epoxides. To investigate this possibility a physiologically based pharmacokinetic (pbpk) model for BU together with its first reactive metabolite l,2-epoxybutene-3 (butadiene monoxide, BMO) was developed. Previously reported values on hepatic glutathione (GSH) turnover, depletion of hepatic GSH in rodents exposed to BU, and in vitro metabolic data of BU and BMO were included in the model, which incorporates intrahepatic first-pass hydrolysis of BMO and the ordered sequential, ping-pong mechanism to describe the enzyme kinetics of BMO-GSH conjugation. In vitro studies were carried out to obtain tissue: air partition coefficients of BU and BMO in rat tissue homogenates. The simulated pharmacokinetics of BU, BMO, and GSH agreed with previously published experimental observations in rat and mouse obtained in closed and open chamber experiments. According to the model, the internal dose of BMO (expressed either as the concentration in mixed venous blood or as the area under the concentration-time curve) is approximately 1.6 times higher in the mouse than in the rat for exposure to BU below 1000 ppm. At higher exposure levels, GSH depletion occurs in the mouse, but not in the rat, after about 6–9 h. This GSH depletion results in up to 2–3 times higher internal doses in the mouse than in the rat. The clear but relatively small species difference in body burdens of BMO indicated from our model can only partly explain the marked species difference in cancer response between mice and rats exposed to BU.
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  • 119
    ISSN: 1432-0738
    Keywords: Bis(tri-n-butyltin)oxide ; TBTO ; Thymus ; Epithelium ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bis(tri-n-butyltin)oxide (TBTO) induces cortical atrophy in the rat thymus. We studied the potential involvement of the cortical epithelium in TBTO-induced thymotoxicity by (immuno) histology and electron microscopy. Juvenile male Wistar rats were orally intubated once with either 30 or 90 mg/kg TBTO and sacrificed 4 or 10 days later. A dose-dependent thymic atrophy occurred. Anti-keratin labelling showed epithelial cell aggregation in some animals at 10 days after exposure to 90 mg/kg TBTO, when recovery of the thymus was apparent. At the ultrastructural level, a relative shift was observed from “pale” to darker epithelial cell subtypes at the 30 mg/kg dose level, both at day 4 and day 10 after intubation. This phenomenon was not observed after exposure to 90 mg/kg TBTO. Both the altered keratin distribution and the increased electron density of the epithelium probably represent non-specific phenomena. The present morphological observations support the concept that TBTO affects the thymus via its action on lymphoid cells rather than on the epithelial compartment.
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  • 120
    ISSN: 1432-0738
    Keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin ; TCDD ; Thymus ; Epithelium ; Ultrastructure ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known for inducing cortical atrophy in the rat thymus. The present study was conducted to provide ultrastructural evidence for the cortical epithelium to be a target for TCDD in vivo. Juvenile male Wistar rats were orally intubated once with either 50 or 150 μg/kg TCDD and killed 4 or 10 days thereafter. Major changes were found in the cortical thymic epithelium. First, a relative shift occurred from “pale” to darker cortical epithelial cell types, as judged by their nuclear and cytoplasmic electron density. This effect was most prominent at 10 days after exposure to 150 μg/kg TCDD. The increased electron density of the cortical epithelium indicates an altered state of cellular differentiation. Secondly, at the 150 μg/kg dose level focal epithelial cell aggregates were seen both at day 4 and day 10 after administration. This aggregation may either be compound induced or represent a secondary event to the collapse of the thymic stroma. Thirdly, increased vacuolation of cortical epithelial cells was apparent. This effect is interpreted as a consequence rather than a cause of thymocyte depletion from the cortex. This study indicates that TCDD exposure affects the cortical epithelium of the rat thymus at a high dose level. Electron microscopy reveals that the differentiation of epithelial cells is altered. In addition, epithelial cell aggregates are formed.
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  • 121
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    Archives of toxicology 67 (1993), S. 307-311 
    ISSN: 1432-0738
    Keywords: Aristolochic acid ; Nephrotoxicity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The nephrotoxic action of aristolochic acid (AA) was investigated in female Wistar rats given single doses of 10, 50 or 100 mg/kg by gastric tube. Renal lesions developed within 3 days, the effect being dose-dependent. Histologically, there was evidence of necrosis of the epithelium of the renal tubules, and functionally, there were rises in plasma creatinine and urea together with increases in urinary glucose, protein, N-acetyl-β-glucosaminidase, gammaglutamyl transferase and malate dehydrogenase. Taking AA as an example, the aim of the present study was to consider the suitability of this model, based on a combination of histology and laboratory investigations, as a short-term test for the detection of nephrotoxic agents.
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  • 122
    ISSN: 1432-0738
    Keywords: Pharmacokinetics ; Styrene ; Diethyl dithiocarbamate ; Species scaling ; Allometric extrapolation ; Mouse ; Rat ; Man ; Closed chamber technique
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of styrene were investigated in male Sprague-Dawley rats and male B6C3F1 mice using the closed chamber technique. Animals were exposed to styrene vapors of initial concentrations ranging from 550 to 5000 ppm, or received intraperitoneal (i.p.) doses of styrene from 20 to 340 mg/kg or oral (p.o.) doses of styrene in olive oil from 100 to 350 mg/kg. Concentration-time courses of styrene in the chamber atmosphere were monitored and analyzed by a pharmacokinetic two-compartment model. In both species, the rate of metabolism of inhaled styrene was concentration dependent. At steady state it increased linearly with exposure concentration up to about 300 ppm; more than 95% of inhaled styrene was metabolized and only small amounts were exhaled unchanged. At these low concentrations transport to the metabolizing enzymes and not their metabolic capacity was the rate limiting step for metabolism. Pharmacokinetic behaviour of styrene was strongly influenced by physiological parameters such as blood flow and especially the alveolar ventilation rate. At exposure concentrations of styrene above 300 ppm the rate of metabolism at steady state was progressively limited by biochemical parameters of the metabolizing enzymes. Saturation of metabolism (Vmax) was reached at atmospheric concentrations of about 700 ppm in rats and 800 ppm in mice, Vmax being 224 μmol/(h·kg) and 625 μmol/(h·kg), respectively. The atmospheric concentrations at Vmax/2 were 190 ppm in rats and 270 ppm in mice. Styrene accumulates preferentially in the fatty tissue as can be deduced from its partition coefficients in olive oil∶air and water∶air which have been determined in vitro at 37°C to be 5600 and 15. In rats and mice exposed to styrene vapors below 300 ppm, there was little accumulation since the uptake was rate limiting. The bioaccumulation factor body:air at steady state (K′st*) was rather low in comparison to the thermodynamic partition coefficient body:air (Keq) which was determined to be 420. K′st* increased from 2.7 at 10 ppm to 13 at 310 ppm in the rat and from 5.9 at 20 ppm to 13 at 310 ppm in the mouse. Above 300 ppm, K′st* increased considerably with increasing concentration since metabolism became saturated in both species. At levels above 2000 ppm K′st* reached its maximum of 420 being equivalent to Keq. Pretreatment with diethyldithiocarbamate, administered intraperitoneally (200 mg/kg in rats, 400 mg/kg in mice) 15 min prior to exposure of styrene vapours, resulted in effective inhibition of styrene metabolism, indicating that most of the styrene is metabolized by cytochrome P450-dependent monooxygenases. In order to simulate chronic exposure rats and mice were exposed to 150 and 500 ppm styrene on 5 consecutive days (6 h/day). On day 6, inhalation kinetics were studied. No change in the rate of styrene metabolism was detected compared to non-pretreated controls. Intraperitoneal administration of styrene to rats and mice led to concentration-time courses in the atmosphere of the closed chamber with agreed with those predicted by the applied pharmacokinetic model. After p.o. administration of styrene to rats and mice concentration time-courses showed considerable inter-animal variability. The pharmacokinetic model was extended by a first order absorption from the gastrointestinal tract with half-lives of 0.87 h (rat) and 0.41 h (mouse) to obtain reasonable fits through the measured data. The pharmacokinetic parameters of inhaled styrene were extrapolated allometrically from rat to mouse and from rat and mouse to man. A good agreement was obtained with experimentally determined values indicating similar pharmacokinetic behaviour of styrene in these species.
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  • 123
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    Archives of toxicology 67 (1993), S. 231-236 
    ISSN: 1432-0738
    Keywords: Tributyltin ; Thymic atrophy ; Immunotoxicity ; Apoptosis ; In vivo ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tributyltin (TBT) immunotoxicity in rodent species is primarily characterised by T-lymphocyte deficiency resulting from a depletion of cortical thymocytes. In this study, bis(tri-n-butyltin) oxide (TBTO) was administered to male rats as a single oral dose of 30 or 60 mg/kg, and assessments were made of thymic cytopathology and the integrity of cellular DNA. TBTO treatment did not cause severe toxicity or overt clinical signs; however, by 48 h post-dosing relative thymus weights at 30 and 60 mg/kg were reduced to 66 and 43%, respectively, of control values. Increased DNA fragmentation was evident in thymic cell isolates (principally thymocytes) obtained from treated animals during the period of thymic involution. When DNA purified from these cells was visualised by agarose gel electrophoresis a multimeric internucleosomal fragmentation pattern, indicative of supra-physiological levels of apoptosis, was detected. Although unassociated apoptotic or necrotic thymocytes were essentially absent in cell preparations from TBTO-treated rats, significantly increased numbers of mononuclear phagocytic cells were observed. Many of these cells contained either apoptotic thymocytes, with nuclear morphologies exhibiting chromatin condensation, or cell remnants which were characterised as apoptotic bodies. Dibutyltin, which is a major metabolic dealkylation product of tributyltin, failed to significantly stimulate apoptosis when added to isolated thymocytes in vitro. Collectively, these findings suggest that activation of apoptosis contributes to TBT-induced thymocyte depletion in vivo, and indicate that it is unlikely that the metabolite dibutyltin is responsible for this effect.
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  • 124
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    European journal of pediatrics 152 (1993), S. S47 
    ISSN: 1432-1076
    Keywords: Rat ; Rabbit ; Contralateral damage ; Fertility ; Microvascular patency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An experimental approach was designed to analyse the outcome of testicular autotransplantation after microsurgery of arteries with 0.3–0.6 mm diameter in two different animal species. In particular, the patency of the anastomosis of the vessels, as well as testicular histology and fertility, was studied. In rats as well in rabbits, we could not observe contralateral damage after testicular autotransplantation. With the rabbit model, we can achieve a fertility rate of 37.5%; but only when we have a good patent anastomosis. Whereas, the rat model is good for surgical training of microvascular anastomosis; the quality of the microanastomosis shows no correlation to the testicular histology of the transplanted testis.
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  • 125
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    Current genetics 23 (1993), S. 15-18 
    ISSN: 1432-0983
    Keywords: Yeast ; Rat ; Ribosomal protein ; 60S Ribosomal subunit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary This communication reports on a single-copy gene of Saccharomyces cerevisiae which is homologous to the rat ribosomal protein gene L21. The yeast and the rat genes show 59% identity in DNA sequences and in the predicted protein sequences. This yeast gene is, therefore, assumed to code for an as yet unassigned ribosomal protein (URP1). The URP1 open reading frame is 480 nucleotides long and can encode a protein of about Mr 18 200. Like most of the other known ribosomal protein genes, URP1 is interrupted by an intron in its 5′ terminal part and it is preceeded by upstream sequence elements which usually regulate transcription of these genes. Northern blot analysis reveals that the URP1 gene is actually expressed in vivo.
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  • 126
    ISSN: 1432-1335
    Keywords: Differentiation ; Leukemia cell ; Stromal cell ; Colony-stimulating factor ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Differentiation of the rat myelomonocytic leukemia cell line (c-WRT-7) was investigated, by co-culture with a rat embryonic bone marrow preadipose cell line (REC A16). Co-cultivation with REC A16, or with conditioned medium from REC A16 cultures (REC-CM), induced differentiation of c-WRT-7 cells to macrophages. A soluble factor(s) produced by REC A16 appeared to be responsible for the differentiation of c-WRT-7. Because REC-CM was associated with colony-stimulating activity on murine marrow progenitors, c-WRT-7 cells were cultured with various colony-stimulating factors (CSF) and it was found that macrophage CSF (M-CSF) significantly induced differentiation of c-WRT-7. We further demonstrated that both the colonystimulating and differentiation-inducing activities of REC-CM were significantly blocked by anti-M-CSF antiserum. These results suggest that the differentiation of c-WRT-7 is due to M-CSF produced by REC A16. Co-culture of these two cell lines should provide a useful model to study the mechanisms of interaction between leukemia cells and marrow stroma.
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  • 127
    ISSN: 1433-0350
    Keywords: Pineal gland ; Glucose metabolism ; Quantitative autoradiography ; Rat ; Development ; Aging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Employing quantitative autoradiography, pineal body glucose utilization (GU) was measured in daytime or at night in prepubertal (aged 1 month), adult (aged 3 months), and mature (over 12 months old) rats. In prepubertal and adult rats, in daytime, GU values within the pineal tissue were homogeneously distributed around 65 μmol glucose/100 g per min. In prepubertal animals no significant variations in GU were observed between daytime and nocturnal measurements. A circadian metabolic rhythmicity was evident in adult rats, with a GU peak measured at 2 a.m. In mature animals, GU also varied between day and night, with an increment in the relative difference between the two values. The present investigation is the first to demonstrate that circadian metabolic rhythmicity is absent before sexual maturation while it is enhanced in 12-month-old rats. These changes in pineal energy metabolism with advancing age are intriguing in view of the concept that the pineal gland may be involved in functional changes occurring during the process of aging.
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  • 128
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    Psychopharmacology 110 (1993), S. 280-286 
    ISSN: 1432-2072
    Keywords: Drug discrimination ; Generalization ; Antagonism ; DN ; 2327 ; Diazepam ; Buspirone ; Pentobarbital ; Pentylenetetrazol ; Benzodiazepine antagonist ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In an operant learning lever-pressing procedure on an FR10 schedule of milk reinforcement, male Wistar rats were trained to discriminate between saline and 3 mg/kg IP DN-2327, a new anxiolytic which acts on benzodiazepine receptors, 3 mg/kg IP diazepam or 15 mg/kg IP pentylenetetrazol (PTZ). More than 80% appropriate lever responding was established after 27, 38 and 44 daily training sessions with DN-2327, diazepam and PTZ, respectively, as the training drug. Although rats trained with DN-2327 dose-dependently generalized to various doses of DN-2327 and diazepam, the cue of DN-2327 was more potent than that of diazepam: ED50 values of DN-2327 and diazepam for stimulus generalization were 0.30 and 0.66 mg/kg, respectively. These animals partially generalized to pentobarbital (1–10 mg/kg) but did not generalize to buspirone (0.1–10 mg/kg). Rats trained with diazepam dose-dependently generalized to various doses of DN-2327, diazepam and pentobarbital with ED50 values of 0.51, 0.47 and 4.5 mg/kg, respectively, but did not generalize to buspirone. In rats trained with PTZ, DN-2327 and diazepam antagonized the discriminative stimulus produced by 15 mg/kg PTZ in a dose-dependent manner with ED50 values of 0.27 and 0.83 mg/kg, respectively, but buspirone neither antagonized nor was able to substitute for the PTZ-induced stimulus. The cue of DN-2327 was antagonized by flumazenil dose-dependently as was that of diazepam. Diazepam and pentobarbital reduced the total number of responses in all animals at 10 mg/kg, and buspirone did so at more than 3 mg/kg, while DN-2327 did not affect the total number of responses from 0.1 to 10 mg/kg. In conclusion, the cue of DN-2327 is similar to and more effective than that of diazepam; moreover, it is quite different from that of buspirone. In addition, the similarity of the interoceptive stimuli of DN-2327 and diazepam may suggest that they are not related to muscle relaxant and sedative properties, since the two drugs differ in this respect.
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  • 129
    ISSN: 1432-2072
    Keywords: Conditioned place preference ; Hedonia ; Food ; Dopamine ; Neuroleptics ; Autoreceptors ; Incentive learning ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Numerous data support the hypothesis that dopamine (DA) plays a crucial role in reward-related processes and in incentive learning in animals and man. The possibility that various neuroleptics exhibiting a high affinity for the dopaminergic D2 (and D3) receptors could reinforce DA transmission was studied using the conditioned place preference paradigm (CPP) in rats. This was done by examining the ability of these compounds to potentiate the reinforcing properties of food in hungry rats subjected to a version of the CPP paradigm which consisted of repeated pairings of food with a single environmental cue, the floor texture of an open field. During the test session when food was no longer available in the open field, the increase in the time spent by drug-free rats on the food-paired texture was assumed to indicate the perceived rewarding value of the food. This time was significantly lengthened when the specific D2 (D3)-receptor antagonists sulpiride (4 mg/kg), amisulpride (0.5, 1 mg/kg) or pimozide (0.03, 0.06 mg/kg) were administered before the food conditioning sessions. Larger doses of these compounds as well as haloperidol, metoclopramide and the non-specific D1-D2 antagonist, chlorpromazine, regardless of the doses tested, did not exhibit this effect, but rather reduced the food-induced CPP, an action usually associated with neuroleptics. The positive effects of amisulpride was reversed by a D1 receptor antagonist, SCH 23390 (0.01 mg/kg). These results suggest that, as with amphetamine (0.5 mg/kg), some D2-specific neuroleptics enhance the incentive value of food in a narrow range of low doses, an effect proposed to reflect a “prohedonic” property. The potentiation of the release of DA unconditionally evoked by food, through a selective blockade of the release-modulating D2-autoreceptors, could constitute the neurobiological substratum of this effect. A concomitant blockade of either D2 or D1 postsynaptic receptors, however, appeared to be sufficient to counteract such activity.
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    Psychopharmacology 111 (1993), S. 85-90 
    ISSN: 1432-2072
    Keywords: Phencyclidine ; Spatial learning test ; Memory disruption ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the first experiment rats with 1, 2, 3 or 4 mg/kg phencyclidine (PCP), or saline injections were tested for acquisition or retention of a cheese board spatial task (dry land version of a water maze). Results indicate that relative to controls or rats with injections of 1 and 2 mg/kg PCP, rats with 3 or 4 mg/kg PCP injections were impaired in acquisition and retention of the task as measured by increased distances traveled to find the correct food location. This impairment was primarily observed in between days but not within days performance. In the second experiment rats with 4 mg/kg PCP or saline injections were tested for memory performance of a delayed spatial matching-to-sample task. Results indicate that relative to controls rats with 4 mg/kg PCP injections were not impaired at either 1–5 or 30 s delays. It is suggested that PCP through its blocking action of the NMDA receptor mediates long- but not short-term memory for spatial location information as well as the ability to retrieve previously learned spatial location information.
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  • 131
    ISSN: 1432-2072
    Keywords: Cocaine ; Nucleus accumbens ; Sensitization ; Locomotor activity ; Conditioning ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of repeated systemic or intra-nucleus accumbens cocaine administration on locomotor activity were examined for environmental dependence. Repeated IP administration of cocaine (15 mg/kg) for 5 days in the context of a given environment increased the locomotor response to a subsequent IP cocaine challenge in that environment. However, there were no differences in the locomotor response to a subsequent IP cocaine challenge in the test chamber in subjects which had received prior repeated IP administration of cocaine in the home-cage. In a second experiment, cocaine (100 µg/side) was infused into the nucleus accumbens (NACC) daily for 5 days. This repeated administration produced increases in locomotor activity to subsequent intra-NACC cocaine infusions that were environmentally independent. In contrast to the effects of repeated IP cocaine administration, subjects which received administration of vehicle, acute cocaine, or repeated cocaine in the NACC did not differ following an IP cocaine challenge. The results from these experiments indicate that increases in the response to IP cocaine following repeated IP administration are in part environmentally dependent. Moreover, repeated intra-NACC cocaine infusions increase the responsiveness of the NACC to subsequent intra-NACC cocaine. However, local activation of the NACC alone does not appear to be adequate to produce sensitization to systemically administered cocaine.
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  • 132
    ISSN: 1432-2072
    Keywords: Methamphetamine ; Cocaine ; Opioids ; Antihistamines ; Place preference ; Drug interaction ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We previously reported that the reinforcing effects of opioids are enhanced in combination with antihistamines. In the present study, effects of opioids and antihistamines on the reinforcing effects of psychostimulants such as methamphetamine and cocaine were investigated by utilizing the conditioned place preference procedure in rats. The place preference induced by methamphetamine was enhanced in combination with either morphine or chlorpheniramine, which produced additive and potentiative effects, respectively. In contrast, although the preference for cocaine was also enhanced by combination with these two drugs, morphine caused a potentiative effect and chlorpheniramine an additive one. In other words, the reinforcing effect of methamphetamine was differentially enhanced by opioids and antihistamines as compared to that of cocaine. These results suggest that the mechanism of reinforcing effect of methamphetamine is different from that of cocaine, resembling rather those of opioids.
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  • 133
    ISSN: 1432-2072
    Keywords: Adenosine A2 receptor ; Apomorphine ; Dopamine-denervation ; Striatum ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The ipsilateral intrastriatal administration of the specific adenosine A2a receptor agonist, 2-[p-(2-carboxyethyl)phenethylamino]-5′-N-ethylcarboxamido adenosine (CGS 21680), produced a dose related decrease in apomorphine-induced rotation in the unilaterally 6-hydroxydopamine-lesioned rat. This effect could be reversed by intrastriatal infusions of the A2a antagonist, 4-amino-l-phenyl[1,2,4]triazolo[4,3-a]quinoxaline (CP 66,713). However, CP 66,713 had no significant effect when infused alone, neither did it influence the response to apomorphine in the absence of CGS 21680. The possible behavioural interactions between A2a receptors and striatal ACh activity were also investigated using this model. Atropine administered intrastriatally in a dose that had no effect on the response to apomorphine reduced the inhibitory effects of CGS 21680 on apomorphine-induced turning. Naloxone also reduced the effects of apomorphine, an effect which could be prevented by the co-administration of atropine, or CP 66,713. These results indicate that adenosine agonists can modulate apomorphine-induced turning by an interaction with both cholinergic and opioidergic mechanisms in the striatum.
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    Psychopharmacology 111 (1993), S. 427-434 
    ISSN: 1432-2072
    Keywords: NMDA antagonist ; MK-801 ; D1/D2 dopamine receptors ; Locomotor activity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Blocking glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptor complex with MK-801 (0.15–0.5 mg/kg, IP) was found to induce a robust, dose-dependent increase in locomotor activity. This behavioural activation was similar in intensity to that observed afterd-amphetamine (1 mg/kg, SC). The locomotor stimulation induced by MK-801 at 0.3 mg/kg was significantly inhibited by the D2 dopamine receptor antagonist raclopride (0.1–0.3 mg/kg, SC) and by the D1 receptor antagonist SCH 23390 (0.04 mg/kg, SC). The locomotor activity induced by a higher dose of MK-801 (0.5 mg/kg) was reduced by higher doses of raclopride or SCH 23390 administered alone (0.3 and 0.08 mg/kg, respectively), and was inhibited by simultaneous administration of ineffective doses. Raclopride significantly reducedd-amphetamine-induced locomotor activity at a dose (0.2 mg/kg) that also blocked the effects of a low dose of MK-801. In contrast, SCH 23390 blocked the effects ofd-amphetamine at a dose (i.e. 0.01 mg/kg) lower than that needed to block MK-801. These results suggest that the dopaminergic system may in part mediate the locomotor effects induced by the NMDA antagonist, MK-801, in rats. However, the locomotor activity induced by MK-801 appears to be less sensitive to dopaminergic receptor blockade than that induced byd-amphetamine, suggesting that the underlying mechanisms, although similar, are not identical.
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  • 135
    ISSN: 1432-2072
    Keywords: Delayed matching to position ; Competitive NMDA antagonist ; Non-competitive NMDA antagonist ; Short term memory ; MK 801 ; CPP ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 (dizolcipine) on short term working memory in the rat were investigated. The behavioural paradigm used was discrete trial, operant delayed matching to position, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. These delays generated an orderly “forgetting” curve in control rats, with matching accuracy decreasing from approximately 100% at 0-s delay to approximately 75% at 30-s delay. Intraperitoneal (IP) administration of CPP (10 mg/kg) produced a markeddelay dependent impairment in performance, suggesting a specific effect on short term working memory. This effect was accompanied by a minor decrease in the speed of responding, and a slight increase in the number of missed trials. Lower doses of CPP had no significant effects on either matching accuracy or sedation. In contrast, IP administration of MK 801 (0.1 and 0.2 mg/kg) caused a markeddelay independent impairment in the accuracy of delayed matching performance, suggesting a non-specific disruption of performance. A lower dose (0.05 mg/kg) of MK 801 had no significant effect on matching accuracy. The two lower doses of MK 801 increased the number of nose pokes made during the delays and tended to increase the speed of responding, suggesting a stimulant-like action. The highest dose of MK 801 had the opposite effects and also decreased the number of trials completed. The results with CPP therefore support the hypothesized role of NMDA receptors in learning and memory, and the contrasting effects of these two NMDA antagonists support previous suggestions of different behavioural effects resulting from administration of competitive and non-competitive NMDA antagonists.
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  • 136
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    Psychopharmacology 111 (1993), S. 495-498 
    ISSN: 1432-2072
    Keywords: Seizure threshold ; Electroconvulsive shock ; ECS ; Lidocaine ; GABA-ergic system ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Seizure susceptibility to lidocaine was investigated in rats which had received repeated ECS (electroconvulsive shock). In the first experiment three groups of rats received an ECS daily for 18 days, an ECS weekly for 18 weeks, and 18 sham treatments, respectively. Twelve weeks after the last ECS all rats received a lidocaine challenge (LC) in the form of an intraperitoneal (IP) injection of lidocaine (65 mg/kg). After the injection the animals were observed for occurrence of motor seizures. A total of 67% (10/15), 47% (7/15), and 0% (0/18) of the daily, weekly, and sham groups, respectively, had motor seizures in response to the LC. In the second experiment five groups of rats received an ECS daily for 0, 1, 6, 18, and 36 days, respectively. Eighteen weeks after the last ECS all rats received an LC and 0% (0/15), 13% (2/15), 20% (3/15), 53% (8/15), and 58% (7/12), respectively, developed seizures in response to the LC. In the third experiment two groups of rats received daily ECS and sham-ECS, respectively. Twenty-four hours after the last ECS all rats received an LC. A total of 60% (9/15) of the ECS group and 0% (0/10) of the sham-ECS group had seizures in response to the LC. The study demonstrates a decrease in seizure threshold to lidocaine in ECS-pretreated rats as early as 1 day and as late as 18 weeks following the last ECS, and a positive correlation between the number of ECS administered and the proportion of animals having seizures in response to the LC was found. The convulsant effect of lidocaine has been proposed to be mediated through binding on the GABA receptor-ionophore complex. Therefore this study suggests that ECS causes long-lasting, possibly permanent, changes within the GABA-ergic system.
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    Psychopharmacology 112 (1993), S. 86-92 
    ISSN: 1432-2072
    Keywords: 5-Hydroxytryptamine ; Lesion ; Operant behaviour ; Temporal differentiation ; IRT〉t schedule ; Deprivation level ; Reinforcer magnitude ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In a previous experiment we found that destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways by microinjection of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei resulted in impaired acquisition of temporal differentiation under an interresponse-time-greater-than-15-s (IRT〉15 s) schedule of sucrose reinforcement. This paper reports three experiments, the results of which bear on the interpretation of that finding. In Experiment 1, 32 rats were trained for 120 sessions under the IRT〉15 s schedule; then 16 received lesions of the 5HTergic pathways and 16 received sham lesions. Comparisons of the IRT frequency distributions of the two groups showed that the lesion produced a significant reduction of the mean IRT and an increase in the dispersion of IRTs, as expressed by the coefficient of variation. Obtained reinforcement rates were significantly reduced in the lesioned group, but response rates were not significantly altered. Levels of 5HT and 5-hydroxyindoleacetic acid were markedly reduced in all forebrain areas examined, without significant change in noradrenaline and dopamine levels. The results indicate that destruction of the 5HTergic pathways disrupts performance as well as acquisition of temporal differentiation. Experiments 2 and 3 examined whether changes in deprivation level and reinforcer magnitude, which are known to affect reinforcer value, would influence temporal differentiation in a similar fashion to destruction of the 5HTergic pathways. In experiment 2, 20 rats were trained under the IRT〉15 s schedule while maintained at 80% or 90% of free-feeding body weight; the more severe deprivation condition was associated with alonger mean IRT and alower coefficient of variation. In experiment 3, 16 rats were trained under the IRT〉15 s schedule using 100 µl or 20 µl of a 0.6 M sucrose solution as the reinforcer; indices of temporal differentiation did not differ between the two conditions. These results indicate that the deleterious effect of destruction of the 5HTergic pathways upon timing behaviour is unlikely to be secondary to the motivation enhancing effect of the lesion.
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  • 138
    ISSN: 1432-2072
    Keywords: Dopamine receptors ; Neuroleptics ; SCH 23 390 ; Raclopride ; Jumping ; Learned behavior ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to explore further the putative differential behavioral consequences of D1 dopamine and D2 dopamine receptor antagonism, SCH 23 390 (0.01–0.12 mg/kg) and raclopride (0.12–1.0 mg/kg) were administered to two separate groups of rats that had been trained in an eight-trial-per-day format to run down an alleyway, climb a vertical rope, and run across a horizontal board to access sweetened milk. Although both drugs dose-dependently reduced the speed of task completion, only raclopride produced vigorous, maldirected jumping behavior in the floor segment of the apparatus. The number of such jumps increased with dose. This raclopride-specific jumping phenomenon may provide a new behavioral arena for investigating the functional differences between D1 and D2 receptor antagonism.
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  • 139
    ISSN: 1432-2072
    Keywords: Rat ; Behavior ; Microstructure ; Dopamine releasers ; Dopamine uptake inhibitors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of four indirect dopamine agonists,d-amphetamine (0.25–4.0 mg/kg), cocaine (2.5–40.0 mg/kg), GBR 12909 (10.0–30.0 mg/kg), and nomifensine (5.0–20.0 mg/kg), on the behavioral organization of movements in an unconditioned motor paradigm were investigated in rats. The extended scaling hypothesis using the fluctuation spectrum of local spatial scaling exponents was used to quantify the geometrical characteristics of movements. The results reveal a qualitatively similar disruption of behavioral organization by lower doses of these drugs. Specifically, rats treated withd-amphetamine (〈2.0 mg/kg), cocaine (〈20.0 mg/kg), GBR 12909 (〈20.0 mg/kg), or nomifensine (〈10.0 mg/kg) exhibited a reduced range in the fluctuation spectrum, reflecting a predominance of meandering movements with local spatial scaling exponents between 1.3 and 1.7. This reduction was accompanied dynamically by a reduced predictability of movement sequences as measured by the dynamical entropy,h. By contrast, higher doses of these drugs produced distinctly different changes in behavioral organization. In particular, 4.0 mg/kgd-amphetamine and 40.0 mg/kg cocaine increased the fluctuation range, reflecting relative increases in both straight and circumscribed movements that are interpreted as a combination of spatially extended and local perseveration. In contrast, high doses of 30.0 mg/kg GBR 12909 and 20.0 mg/kg nomifensine induced only local perseveration. High doses ofd-amphetamine, cocaine, GBR 12909 and nomifensine reduced the dynamical entropy,h, indicating an increased predictability of the movement sequences. These results suggest that the generic behavioral change induced by low doses of dopamine agonists is characterized by a reduced variety of path patterns coupled with an increased variability in sequential movement sequences. The differential effects of higher doses of these drugs may be due to their influences on other neurotransmitter systems or differential affinities for different dopamine subsystems.
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  • 140
    ISSN: 1432-2072
    Keywords: Opiates ; Discrimination learning ; Conditioned taste aversion ; Parabrachial nucleus ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Morphine is known to act centrally to produce discriminative stimulus effects, but the specific neuroanatomical sites mediating this action have not been identified. We used morphine as a discriminative stimulus in a taste aversion paradigm to elucidate the neural basis of morphine's cueing properties. Rats were injected subcutaneously with 5 mg/kg morphine 15 min prior to the presentation of a 0.1% saccharin solution. After 20 min of exposure to the flavor, lithium chloride (130 mg/kg, IP) was injected. On alternate days, an injection of 0.9% physiological saline both preceded and followed the presentation of saccharin. Animals learned to consume significantly less saccharin after morphine than after saline injections. Unilateral guide cannulae were then implanted into brain areas containing relatively high densities of opiate binding sites, comprising the medial prefrontal cortex, the nucleus accumbens, the anterior dorsolateral striatum, the medial thalamus, the basolateral amygdaloid nucleus, the dorsal hippocampus, the caudal periaqueductal grey and the parabrachial nucleus. Generalization to central routes of administration was then evaluated by microinjecting morphine (2.5, 5, 10 and 20 µg) into these brain areas. Dose-dependent decreases in saccharin consumption similar to those of systemic morphine were produced by the administration of morphine into the parabrachial nucleus and the nucleus accumbens. Control data showed that only in the parabrachial nucleus could these effects be attributed to the cueing properties of morphine; in the nucleus accumbens, morphine administration induced unconditioned decreases in saccharin consumption. In the remaining brain areas, morphine generalized to the systemic saline condition. The data point to ascending visceral pathways (parabrachial nucleus), but not dopamine terminal fields (nucleus accumbens), as possible substrates for opiate discriminative effects. These putative discriminative substrates are distinct from the medial forebrain bundle pathways mediating the positive reinforcing effects of opiates.
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  • 141
    ISSN: 1432-2072
    Keywords: 5-Hydroxytryptamine ; 5,7-Dihydroxytryptamine ; Operant behaviour ; Timing ; Intervalbisection procedure ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Seventeen rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei: 12 rats received sham injections. The rats were trained in a series of discrete trials to press lever A following a 2-s presentation of a light stimulus and to press lever B following an 8-s presentation of the same stimulus. Both groups learnt the task rapidly and maintained 〉90% accuracy throughout the experiment. When stable performance had been attained, “probe” trials were introduced in which the light was presented for intermediate durations. Both groups showed sigmoid functions relating percent choice of lever B to log stimulus duration. The bisection point (duration corresponding to 50% choice of lever B) was significantly shorter in the lesioned group than in the control group. There was no significant difference between the slopes of the psychophysical functions or the Weber fractions derived for the two groups. The levels of 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid in the parietal cortex, hippocampus, amygdala, nucleus accumbens and hypothalamus were markedly reduced in the lesioned group, but the levels of noradrenaline and dopamine were not significantly affected by the lesion. The results confirm the involvement of 5HTergic function in timing behaviour, but suggest that destruction of these pathways does not disrupt the capacity for temporal discrimination.
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  • 142
    ISSN: 1432-2072
    Keywords: Morphine drug discrimination ; Rat ; 5-HT3 receptor antagonists ; Opioid ; Naloxone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 5-HT3 receptor antagonists, e.g. MDL72222, ondansetron and ICS205-930, have been previously reported to block a morphine (1.5 mg/kg)-induced conditioned place preference in rats. This finding suggests that these drugs may modify the morphine discriminative stimulus which underlies place conditioning. To study this further we have examined the effects of MDL72222, ondansetron and ICS205-930 against a morphine discriminative stimulus using a two-choice, food reinforced, operant paradigm. In an attempt to provide consistency with previous place conditioning studies, a morphine training dose of 1.5 mg/kg was used in addition to a higher 3 mg/kg dose which was studied in separate animals. Stimulus control of behaviour was attained at both morphine training doses, the characteristics of each being consistent with an effect at the mu opioid receptor. Ondansetron (0.001–1 mg/kg), MDL72222 (0.1–3 mg/kg), and ICS205-930 (0.001–1 mg/kg) all failed to consistently antagonise the morphine cue at both training doses, although a mild attenuation was seen in the 1.5 mg/kg group following pretreatment with an intermediate dose of ondansetron and ICS205-930 (both 0.01 mg/kg). The present results therefore suggest hat 5-HT3 antagonists do not block a morphine discriminative state, at least in rats.
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  • 143
    ISSN: 1432-2072
    Keywords: Peptides ; Tachykinins ; Substance P fragments ; Inhibitory avoidance learning ; Conditioned place preference ; Nucleus basalis magnocellularis ; Dopamine ; Neostriatum ; Nucleus accumbens ; In vivo microdialysis ; Neurodegeneration ; Alzheimer's disease ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract There is ample evidence that the neurokinin substance P (SP) can have neurotrophic as well as memory-promoting effects. This paper outlines a recent series of experiments dealing with the effects of SP and its N- and C-terminal fragments on memory, reinforcement, and brain monoamine metabolism. It was shown that SP, when applied peripherally (IP), promotes memory (inhibitory avoidance learning) and is reinforcing (place preference task) at the same dose of 37 nmol/kg. Most important, however, is the finding that these effects seemed to be encoded by different SP sequences, since the N-terminal SP1-7 (185 nmol/kg) enhanced memory, whereas C-terminal hepta- and hexapeptide sequences of SP proved to be reinforcing in a dose equimolar to SP. These differential behavioral effects were paralleled by selective and site-specific changes in dopamine (DA) activity, as both SP and its C-, but not N-terminus, increased extracellular DA in the nucleus accumbens (NAc), but not in the neostriatum. The neurochemical changes lasted at least 2 h after injection. These results show that the reinforcing action of peripheral administered SP may be mediated by its C-terminal sequence, and that this effect could be related to DA activity in the NAc. Direct application of SP (0.74 pmol) into the region of the nucleus basalis magnocellularis (NBM) was also memory-promoting and reinforcing, and again, these effects were differentially produced by the N-terminus and C-terminus, supporting the proposed structure-activity relationship for SP's effects on memory and reinforcement. These results may provide a hypothetical link between the memory-modulating and reinforcing effects of SP and the impairment in associative functioning accompanying certain neurodegenerative processes.
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  • 144
    ISSN: 1432-2072
    Keywords: Morphine ; Behavioral activity ; Analgesia ; Rat ; Self-administration ; Genetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The purpose of the current study was to investigate genetic differences between two inbred strains of rats, Fisher-344 (F344/N) and Wistar Albino Glaxo (WAG/GSto), in a number of drug-naive and drug-related behaviors, including oral and intravenous morphine self-administration. F344/N and WAG/GSto rats differed in drug-naive behaviors such as nociception, rearing and sensitivity to lick suppression tests but did not differ in locomotor activity, ambulation or grooming behavior. F344/N rats were less sensitive to thermal stimuli as measured via tail-flick response, and more sensitive to the suppressive effects of intermittent shock in a lick suppression test. The F344/N rats demonstrated a significantly greater amount of rearing in open field tests but did not differ from WAG/GSto rats in locomotor activity, ambulation or grooming behavior. In addition to the behavioral results, naive F344/N and WAG/GSto rats were found to differ in μ and α2 receptor concentrations (F344/N〉WAG/GSto) and in 5HT2 and D2 affinity constants (WAG/GSto〉F344/N). These two inbred rat strains also differed in drug-related behaviors. F344/N rats showed significantly greater depression of locomotor activity at morphine 3 mg/kg than WAG/GSto rats. In addition, F344/N rats consumed significantly greater amounts of morphine in a two-bottle choice procedure and morphine maintained significantly greater amounts of behavior during intravenous self-administration sessions. Importantly, drug maintained behavior was significantly greater than with vehicle only in the F344/N rats during operant self-administration sessions.
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  • 145
    ISSN: 1432-2072
    Keywords: Amphetamine ; cis-Flupenthixol ; Nucleus accumbens ; Feeding ; Sugar ; Baseline dependent ; Circadian ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Evidence indicates that amphetamine (AMP) affects feeding in a baseline-dependent fashion and that the nucleus accumbens (Acc) is an important site of action for AMP's effects on feeding. Experiment 1 examined the contribution of Acc-dopamine (DA) mechanisms to the baseline-dependent feeding effects of a 0.125 mg/kg dose of AMP using intra-Acc administrations of cis-flupenthixol (FLU). Results showed that there was an inverse relation beetween baseline sugar intake and the feeding response to AMP, such that AMP stimulated feeding in animals with low baseline intake and inhibited feeding in animals with high baseline intake. Intra-Acc FLU administration reversed the stimulatory but not the inhibitory effect of AMP. Further, intra-Acc FLU attenuated baseline feeding in high but not low baseline feeders. Experiment 2 sought to determine whether AMP would affect feeding in a baseline-dependent manner when administered in the dark photoperiod of the rat circadian cycle, when rats do most of their feeding. To this end, rats were administered three doses (0.05, 0.1, and 0.25 mg/kg) of AMP in the dark photoperiod and the intake of sugar monitored. Results showed that in low baseline feeders, AMP stimulated intake at lowest dose and had no effect at higher doses. In high baseline feeders, AMP inhibited intake in a dose-dependent manner. Taken together, these results further establish that AMP affects feeding in a baseline-dependent fashion. Moreover, the similar effects of AMP across the light and dark photoperiods suggest that a straightforward rate-dependency interpretation is not adequate. Finally, it is speculated that Acc-DAergic activity may play a role in the observed differences in baseline intake levels and in the response to AMP.
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  • 146
    ISSN: 1432-2072
    Keywords: Dopamine ; SKF 38393 ; Quinpirole ; d-Amphetamine ; Nucleus accumbens ; Localization ; Locomotor activity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of local injections of dopamine receptor agonists into various areas within the nucleus accumbens or the medial caudate-putamen on the generation of locomotor activity were examined. Combinations of 0.32 µg/side of the dopamine receptor agonists SKF 38393 (D1) and quinpirole (D2) produced increases in locomotor activity that varied according to the rostral-caudal placement of the cannulae within the nucleus accumbens. The greatest levels of locomotion were generated by injections into a region in the caudal-central nucleus accumbens, with lower levels of activity elicited by injections into more rostral or caudal regions. A similar pattern of responses was produced by administration of the indirect dopamine agonistd-amphetamine. These results indicate that there is marked heterogeneity in the response of discrete sub-regions of the nucleus accumbens to dopamine receptor stimulation and that this heterogeneity is functionally expressed in the mediation of the locomotor effects of dopaminergic agonists.
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  • 147
    ISSN: 1432-2013
    Keywords: β-Adrenergic receptors ; Muscarinic receptors ; Cardiac hypertrophy ; Cardiac myocyte ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The beta adrenergic (βAR) and muscarinic (MR) receptors have been quantitated in parallel, using 125I-pindolol and 3H-quinuclidinylbenzilate, in a model of compensatory left ventricular (LV) hypertrophy (LVH), which developed in rats 4–6 weeks after an abdominal aortic stenosis. Since aortic banding resulted in a pronounced LVH of 62%, the results were expressed both in terms of density (fmol/mg protein) and quantity (fmol per LV). In addition, competition curves using either a specific β1-antagonist or isoproterenol or carbachol allowed the determination of the two βAR subtypes and of the low and high affinity sites (defined by the inhibitory constant K i) for both β1AR and MR. In LVH, receptor density decreased for each of total βAR, β1AR subtype, high affinity (K i 6–8nM) β1AR sites (from 26±2 to 19±3 fmol/mg protein, P〈0.05), total MR and high affinity (K i 12 nM) MR sites (from 63±6 to 40±4 fmol/mg protein, P〈0.001). The βAR and MR densities dropped in parallel so that the MR/βAR ratio remained unchanged. In sharp contrast (because the LVs were bigger) the quantities of total βAR, β1 AR subtype, β1AR high affinity sites, total MR and MR high affinity sites per LV were unmodified. Thus, in compensatory LVH the total quantity of receptors per LV was unchanged, suggesting that either both synthesis and degradation were augmented in parallel or that during the process of cardiac hypertrophy they are not regulated, i. e., that the genes encoding for the two receptors were not activated, as it has been suggested for other membrane proteins. Assuming that the high affinity sites represent the receptors coupled to the adenylyl cyclase, we also propose that the overall regulatory systems were modified beyond the level of the receptors.
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  • 148
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    Pflügers Archiv 423 (1993), S. 356-364 
    ISSN: 1432-2013
    Keywords: Erythropoietin ; Hepatocytes ; Rat ; In vitro ; Hypoxia ; Signalling ; mRNA ; RNase protection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Since in juvenile rats the liver is the predominant site of erythropoietin (EPO) gene expression, we have used primary cultures of juvenile rat hepatocytes to establish an in vitro system for investigation of oxygen-dependent EPO formation. When isolated hepatocytes were incubated at reduced oxygen tensions for 18–48 h, we found increased secretion of EPO protein and elevated levels of EPO mRNA, as determined by RNase protection. This increase was maximal at 3% O2, where EPO mRNA levels after 18 h were approximately 15fold higher than at 20% O2. The increase in EPO mRNA at low oxygen tensions was specific insofar as [3H]uridine incorporation, as a measure of total RNA synthesis, was reduced by approximately 50% at 3% O2, and it appeared to involve gene transcription since it was abolished in the presence of actinomycin D (35 μM). Significant increases in EPO mRNA were also observed in cells kept at 20% oxygen in the presence of cobalt chloride (50 μM) and nickel chloride (400 μM), but EPO mRNA levels achieved under these conditions were less than 7% of those in cells incubated at 3% oxygen. No increase in EPO mRNA levels was observed in cultures incubated at 20% O2 in the presence of cyclic dibutyrylAMP (10 μM-3 mM), cyclic 8-bromoGMP (10 μM1 mM), cyclohexyladenosine (1 μM), 5′-N-ethylcarboxamidoadenosine (1 μM) and phorbol 12-myristate 13acetate (3 nM). In the presence of 10% carbon monoxide, used to block haem proteins in their oxy conformation, EPO mRNA levels in hepatocytes incubated at low oxygen tensions were reduced to 63%. Taken together, these findings indicate that oxygen-dependent control of the EPO gene in hepatocytes operates via intrinsic cellular oxygen-sensing mechanisms. Their signal transduction does not seem to occur via classical “second-messenger” pathways. A haem protein may be involved in oxygen sensing, but no conclusive evidence was obtained as to whether it is essential.
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  • 149
    ISSN: 1432-2013
    Keywords: Rat ; Renal function ; Micropuncture ; Blood gases ; Anaesthesia ; Thiopentone ; Thiobutabarbitone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The thiobutabarbitone(TB, Inactin)-anaesthetised rat is an extremely widely used preparation for the study of renal function at the whole-organ and nephron levels. The recent withdrawal of TB from the market has made it essential to find an anaesthetic producing experimental conditions as similar as possible to TB to allow comparison of past and future data. Blood gas analysis, clearance and micropuncture studies were therefore performed in rats anaesthetised with TB or the related thiobarbiturate thiopentone (TP) (both 100 mg/ kg body weight) to establish whether the latter meets this requirement. Both barbiturates caused similar transient respiratory depression and acidosis. Mean values (TP versus TB) over the total 8-h observation period for glomerular filtration rate (0.94 versus 1.05 ml/min), urine flow (3.8 versus 4.4 μl/min) and K+ excretion (0.98 versus 1.18 μmol/min) were slightly lower (P〈0.05) in TP rats, whereas renal blood flow (6.26 versus 6.24 ml/min), filtration fraction (0.31 versus 0.34) and Na+ excretion (0.11 versus 0.098 μmol/min) did not differ. The single-nephron filtration rate (SNGFR) (42.1 versus 41.1 nl/min) and fractional reabsorption (42% versus 47%), both measured in the proximal tubule, did not differ, although in the TP group SNGFR rose with time (4.4%/h) whereas the fractional reabsorption did not change significantly; in the TB group SNGFR was constant but fractional reabsorption declined with time (1.5%/h). Fractional reabsorption up to the distal convoluted tubule declined with time, this was more pronounced in the TP group. SNGFR measured at this site did not differ between TP and TB (30.3 versus 30.1 nl/min) but increased with time with TP (2.7%/h). Although renal function under TP is somewhat less stable than under TB, the differences are minor and, given that the latter is also characterised by non-steady-state conditions, it is concluded that TP is a reasonable replacement for TB.
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  • 150
    ISSN: 1432-2013
    Keywords: Ryanodine ; Rat ; Fetus ; Adult ; Skinned myocardial fibers ; Caffeine ; Calcium ; Magnesium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Ryanodine causes depression of the caffeine-induced tension transient (ryanodine depression) in skinned muscle fibers, because it blocks the sarcoplasmic reticulum (SR) Ca2+-release channels [Su, J. Y. (1988) Pflügers Arch 411:132–136, 371–377; (1992) Pflügers Arch 421:1–6]. This study was performed to examine the sensitivity of SR Ca2+-release channels to ryanodine in fetal compared to adult myocardium and to investigate the influence of Ca2+, caffeine, and Mg2+ on ryanodine depression in skinned fibers. Ryanodine (0.3 nM–1 μM) caused a dose-dependent depression in skinned myocardial fibers of the rat, and the fetal fibers (IC50≈74 nM) were 26-fold less sensitive than those of the adult (IC50≈2.9 nM). The depression induced by 0.1 μM or 1 μM ryanodine was a function of [caffeine], or [Ca2+] (pCa〈6.0), which was potentiated by caffeine, and an inverse function of [Mg2+]. At pCa〉8.0 plus 25 mM caffeine, a 20% ryanodine depression was observed in both the fetal and adult fibers, indicating independence from Ca2+. Ryanodine depression in skinned fibers of the fetus was less affected than that seen in the adult by pCai, [caffeine]i, or 25 mM caffeine plus pCai or plus pMgi (IC50≈pCa 4.5 versus 5.1; caffeine 12.7 mM versus 2 mM; pCa 6.7 versus 7.3; and pMg 3.9 versus 3.3 respectively). The results show that the SR Ca2+-release channel in both fetal and adult myocardium is modulated by Ca2+, caffeine, and Mg2+. It is concluded that less ryanodine depression seen in the skinned fibers of the fetus, indicating a relatively insensitive SR Ca2+-release channel, could contribute to the resistance of intact myocardium to ryanodine.
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  • 151
    ISSN: 1432-2072
    Keywords: Animal model ; Rat ; Antipsychotic ; Schizophrenia ; Latent inhibition ; Attention ; Selective attention ; Conditioned emotional response
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Latent inhibition (LI) of a conditioned emotional response (CER) has been proposed as a quantitative measure of selective attention. We have assessed the parallels of the pharmacology of LI in rats with the clinical pharmacology of schizophrenia. Drug and vehicle treated rats were divided into groups and preexposed 20 times to cage illumination as a CS, or not preexposed. All groups were conditioned with 2 CS-footshock pairings. The following day CER, as measured by interruption of drinking in response to CS presentation, was recorded. LI was observed as a decreased CER in preexposed relative to non-preexposed animals. LI was enhanced by haloperidol 0.3 mg/kg after 7 or 14 daily treatments, but not after a single acute dose. Haloperidol doses of 0.3 and 0.03 mg/kg enhanced LI, while doses of 0.003 and 3.0 mg/kg had no effect. Haloperidol enhancement of LI was unaffected by the coadministration of the anticholinergic agent trihexyphenidyl. Enhancement of LI is exhibited by the antipsychotic drugs fluphenazine, chlorpromazine, thiothixene, thioridazine, mesoridazine, and metoclopramide but not clozapine. The non-antipsychotic drugs pentobarbital, imipramine, chlordiazepoxide, trihexyphenidyl, and promethazine failed to enhance LI. LI exhibits striking parallels to the clinical pharmacology of schizophrenia.
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  • 152
    ISSN: 1432-2072
    Keywords: Nicotine ; Withdrawal ; Discrimination ; Activity ; Startle ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Three different behavioral measures were used to assess the effects of abrupt cessation of chronic nicotine treatment. Nicotine (0, 3, or 6 mg/kg per day) was continuously administered for 12 days in rats by surgically implanting Alzet osmotic mini-pumps subcutaneously. Experiment 1 employed a light/dark discrimination task. There were no significant effects on number of responses or percent correct responding either during nicotine administration, or following cessation of nicotine. Experiment 2 examined ambulatory (locomotor) and nonambulatory activity. Chronic nicotine administration produced significant dose-dependent increases in both ambulatory and nonambulatory activity during the first 3 days of exposure. However, no significant alterations were seen in activity levels following nicotine cessation. Experiment 3 examined sensorimotor reactivity using the auditory startle response. During nicotine withdrawal, significant increases were seen in startle amplitude in both nicotine groups for 4 days. Nicotine (0.4 mg/kg, IP) administered before startle testing during the withdrawal phase attenuated the increased reactivity seen during nicotine cessation. These studies indicate that 1) rats display increased sensorimotor reactivity after cessation of chronic nicotine exposure, and 2) the expression of nicotine dependence and withdrawal is dependent on the behavioral task employed.
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  • 153
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    Naunyn-Schmiedeberg's archives of pharmacology 348 (1993), S. 77-81 
    ISSN: 1432-1912
    Keywords: Amthamine ; Histamine H2 receptors ; Gastric acid secretion ; Conscious cat ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The new histamine H2 receptor agonist amthamine, [2-amino-5-(2-aminoethyl)-4-methylthiazole], was tested for its activity on gastric acid secretion in different in vivo and in vitro experimental models. Amthamine induced a dose-related increase in acid secretion both in conscious cats with a gastric fistula (ED50 = 0.069 μmol/kg/h) and in anaesthetized rats with a lumen-perfused stomach (ED50 = 11.69 gmol/kg i.v.). In this last preparation the efficacy of amthamine was significantly higher than that of histamine and dimaprit. Amthamine was an effective secretagogue also in the rat isolated gastric fundus, behaving as a full agonist (EC50 = 18.9 μmol/l). In all the experimental models amthamine was more potent than dimaprit (from 3 to 10 fold) and approximately equipotent with histamine, and its effect was competitively antagonized by the histamine H2 receptor antagonists famotidine or ranitidine. Experiments with H1 and H3 receptor antagonists indicated that Amhamine is devoid of stimulatory activity at H1 and H3 receptors. The present data indicate that amthamine is a full agonist at histamine H2 receptors and, being more effective and selective than the other compounds of the family, it may represent a good alternative to the other available histamine H2 receptor agonists for the study of gastric acid secretion.
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  • 154
    ISSN: 1432-1912
    Keywords: CCK-A receptor ; Food intake ; Locomotor activity ; cGMP levels ; Dopaminergic cells ; Rat ; Mouse ; CCK antagonist
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The activity of SR 27897, a potent and selective CCK-A vs CCK-B receptor antagonist (Ki = 0.2 nM on guinea-pig pancreas vs 2000 nM on rat brain) was studied on behavioural, electrophysiological and biochemical effects induced by peripheral or central injection of CCK-8S. For comparative purposes, devazepide, a reference CCK-A receptor antagonist, was investigated in these same models. CCK-induced hypophagia and CCK-induced hypolocomotion in rats, two behavioural changes associated with the stimulation of peripheral CCK-A receptors, were dose-dependently antagonized by SR 27897 (ED50 = 0.003 and 0.002 mg/kg i.p., respectively) and devazepide (ED50 = 0.02 and 0.1 mg/kg i.p., respectively). CCK-induced decrease of cerebellar cGMP levels in mice was also reduced by SR 27897 (ED50 = 0.013 mg/kg) and by devazepide (0.084 mg/kg). The CCK-induced turning behaviour after intrastriatal injection in mice, and the potentiation of the rate suppressant activity of apomorphine on rat DA neurons, were blocked by higher doses of SR 27897 and devazepide, consistent with the probable central origin of these effects. The respective ED50s were 0.2 mg/kg i.p. for SR 27897 and 4.9 mg/kg i.p. for devazepide in the former model, while the respective minimal effective doses were 1.25 and 5 mg/kg i.p. in the latter test. In most tests the i.p./p.o. ratio for SR 27897 was near unity, suggesting a high oral bioavailability of the compound. Taken together, these findings support the notion that SR 27897 behaves as a potent CCK-A antagonist able to cross the blood brain barrier.
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  • 155
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    Naunyn-Schmiedeberg's archives of pharmacology 348 (1993), S. 638-642 
    ISSN: 1432-1912
    Keywords: Guanethidine ; Rat ; Capsaicin ; Primary afferent nerves ; Nippostrongylus brasiliensis ; Ruthenium red
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Superfusion of capsaicin onto the serosal surface of jejunum of Nippostrongylus brasiliensis-sensitized rats induces a short-lasting (1–3 min), dose-dependent (2 to 20 μg) decrease in blood pressure which ranges from −5.3±1.40% to −22.6±2.20%. The hypotension evoked by capsaicin was more marked in sensitized rats than in unsensitized animals, which responded only to the highest dose (20 mg) of capsaicin tested. The hypotensive effects of capsaicin were not affected by intravenous injections of mepyramine (10 mg/kg), a histamine receptor antagonist, or by the cycloxygenase inhibitor indomethacin (10 mg/kg). However, an intravenous injection of a platelet-activating factor (PAT) antagonist, BN 52021 (20 mg/kg), or an intraperitoneal injection of guanethidine (8 mg/kg) 18 h prior to experimentation, to functionally impair the sympathetic nerves, abolished the capsaicin-induced drop in blood pressure. Treatment of neonatal rats with capsaicin reduced by 75% the hypotensive effects of capsaicin, whereas the capsaicin antagonist, ruthenium red, reduced non-significantly the hypotensive action of capsaicin. It is concluded that the activation of jejunal sensory nerves in N. brasiliensis-sensitized rats by capsaicin induced a reflex hypotension that is dependent upon PAF release from mast cells and functional sympathetic nerves. In addition, the afferent function of the sensory nerves are not totally blocked by ruthenium red as capsaicin elicits the reflex hypotension in the presence of this blocker of sensory nerve efferent function.
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  • 156
    ISSN: 1432-1912
    Keywords: WAY-100135 ; 5-HT1A receptor antagonists ; Enantiomers ; Rat ; Superior cervical ganglion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A grease-gap extracellular recording technique was used to detect 5-HT1A receptor-mediated hyper-polarizing responses to 5-hydroxytryptamine (5-HT) in the rat isolated superior cervical ganglion. In the presence of the novel 5-HT1A receptor antagonist, WAY 100135 [N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropanamide], the responses to 5-HT were antagonised in a competitive manner with a pA2 value of 7.2 (6.9–8.5) and Schild plot slope of 1.0 (0.4–1.6), n = 20. The antagonist activity was greater in the (+) than the (−)enantiomer of WAY-100135. The pA2 value of the (+)enantiomer was 7.5 (7.2–8.0), Schild plot slope 1.2 (0.8–1.6), n = 17. In contrast the (−)enantiomer had weak antagonist activity (pA2 6.3±0.25, n = 3). No agonist activity of WAY-100135 or its enantiomers were observed in this study.
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  • 157
    ISSN: 1432-0878
    Keywords: Spinal cord ; Motoneurones ; Dorsal horn ; Neurofilament ; Phosphorylation ; Immunocytochemistry ; Rat ; Cat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Neurofilament immunoreactivity was examined in spinal cords of rats and cats with antibodies to all three subunits (68 kD, 155 kD and 200 kD) and to different phosphorylation states of 200 kD. NFHP-, an antibody against non-phosphorylated 200 kD, labelled all rat neuronal perikarya but failed to labet cat neurofilaments. In both species, the perikarya and processes of motoneurones were immunoreactive for all three subunits but most dorsal horn neuronal perikarya were not immunoreactive for 68 kD and 155 kD. Motoneuronal perikarya and proximal processes showed filamentous labelling for 68 kD but not for 155 kD in the rat, while in neither species did these show labelling with RT97, an antibody against a highly phosphorylated form of 200 kD; immunoreactivity for 200 kD was present in both filamentous (probably partially phosphorylated) and non-filamentous (non-phosphorylated) forms, but in dorsal horn neurones only the latter was present. Interpretations consistent with this data are: in rat and possibly also cat, motoneuronal neurofilaments consist of a 68 kD backbone with partially phosphorylated 200 kD sidearms, with both 155 kD and 200 kD (non-phosphorylated) subunits in a non-filamentous form; this neurofilament becomes more highly phosphorylated along the proximal processes. The dorsal horn neurones probably contain 200 kD in a non-filamentous form but may lack the other subunits.
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  • 158
    ISSN: 1432-0878
    Keywords: Gap junction ; Cell junction ; Immunocytochemistry ; Biochemistry ; Heliothis virescens (Insecta)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Subcellular fractions enriched in gap junctions with an ultrastructure similar to those in intact insect tissue have been obtained by extracting crude membranes from the tobacco budworm Heliothis virescens (Lepidoptera: Noctuidae) with 2.5 mM NaOH. n-Octyl-β-d-glucopyranoside (OG) was used to further purify integral membrane proteins in the NaOH-extracted fractions. A polyclonal antibody (R16) is described that specifically labels nonextracted and NaOH-extracted gap junctions in cell fractions by electron microscope immunocytochemistry. R16 immunostaining of sectioned Heliothis testis at the light-microscope level yields a pattern of immunoreactivity consistent with the distribution of gap junctions in the tissue. R16 identifies a 40-kDa protein as a candidate gap junction protein on immunoblots of crude membrane, NaOH-extracted and NaOH/OG-extracted fractions.
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  • 159
    ISSN: 1432-0878
    Keywords: Endocrine pancreas ; IGF-1 ; IGF-2 ; Insulin ; Glucagon ; Somatostatin ; Pancreatic polypeptide ; Man ; Dog ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Immunohistochemical techniques were used to study the occurrence and distribution of insulin-like growth factor 1 (IGF-1) and IGF-2 in the pancreas of man, dog, and rat and their possible coexistence with insulin (INS), glucagon (GLUC), somatostatin (SOM) and pancreatic polypeptide (PP). All control experiments, including pre-absorption of the antisera with synthetic peptide hormones, indicated the specificity of the immunoreactions obtained. In all species investigated, IGF-2-immunoreactivity occurred exclusively in INS-immunoreactive cells as was found by the use of consecutive sections and double immunofluorescence on identical sections. In contrast, IGF-1-immunoreactivity co-existed with GLUC-immunoreactivity. In man, singular SOM-immunoreactive cells also contained IGF-1-immunoreactivity. Thus, IGF-1 and IGF-2 can be localized by means of immunohistochemistry in the mammalian pancreas, and can be shown to occur in different islet cell populations. It is presumed that IGF-1 derived from A-cells and/or D-cells acts on the B-cells in a paracrine manner. The co-existence of IGF-2-immunoreactivity and INS-immunoreactivity in the human, rat, and dog endocrine pancreas indicates that mammalian IGF-2 and INS genes are regulated simultaneously.
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  • 160
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    Cell & tissue research 272 (1993), S. 391-394 
    ISSN: 1432-0878
    Keywords: ANP binding ; Yolk sac ; Decidua ; Maternal placental vessels ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Using in vitro autoradiography, binding sites of 125I-ANP (atrial natriuretic peptide) were localized in the rat placenta, visceral yolk sac, and decidua at 16, 18, and 20 days of gestation. There was diffuse binding over the labyrinthine region of the placenta and an intense binding over the decidual gland and visceral yolk sac. In the yolk sac, ANP localized over the cores of the villi where it may be involved with the regulation of transport across the membranes or the flow of blood through the vitelline vessels. Of particular interest was binding over the maternal blood vessels supplying the decidual region and placenta. Receptors were located on the endothelial cells and smooth muscle cells of the arteries and veins, indicating that ANP may be involved with regional regulation of blood flow to the placenta.
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  • 161
    ISSN: 1432-0878
    Keywords: Ascites hepatoma ; Adhesive factor ; Monoclonal antibody ; Cell membrane polarity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract A cell surface-associated adhesive factor (AF) separated from differentiated rat ascites hepatoma AH136B cells (forming cell islands in vivo) has been highly purified by chromatography. AF is assumed to mediate the cell-cell adhesion essential to island formation of the hepatoma cells. A substance, immunologically crossreactive with AF, is present in the ascites fluid or culture medium of the AH136B cells. Because the substance is almost identical to AF in molecular weight and aggregation-promoting activity, it has been concluded that AF is released into the ascites fluid where it is concentrated. Monoclonal antibodies have been raised against AF purified from ascites fluid of AH136B cells. We have obtained a monoclonal antibody, coded MoAF-6D6, that strongly abolishes the aggregation-promoting activity of AF. When AH136B cell islands are incubated in the presence of Fab fragments of MoAF-6D6, cell detachment from the islands is evident within 24 h. Cell islands following 36-h culture show a distinct dissociation and islands completely lose their organization 48 h after culture. The dissociating effect of MoAF-6D6 is neutralized by the addition of AF. These results suggest that AF plays a significant role in the maintenance of cell islands.
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  • 162
    ISSN: 1439-6327
    Keywords: Successive selection ; Selection response ; Selection differential ; Realized heritability ; Percentage of slow twitch fibres ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The extent to which muscle fibre composition was determined by the genes transmitted from parents was estimated by using successive selections of rats. A foundation population (GO) was established to carry out the selections; it consisted of 100 albino rats which were randomly chosen from heterogeneous stock. The heterogeneous stock was produced by random-mating of three strains, Wistar-Imamichi, Fischer 344 and Donryu. Successive selection for a high percentage of slow twitch fibres (% ST) was made from GO to the fourth generation (G4). The mean values of % ST changed from 50.0% in G0 to 55.6% in G4. The mean value in G4 was significantly higher than that in GO. The realized heritability in G0–G4 was calculated from the regression of selection response on the cumulated selection differential. The regression coefficient was 0.17 (SEM 0.04). The realized heritability was significantly different from 0 at the 0.05 level. We concluded that in rats about 17% of the variation of muscle fibre composition was determined by the genes transmitted from parents.
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  • 163
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    European journal of applied physiology 66 (1993), S. 445-450 
    ISSN: 1439-6327
    Keywords: High-carbohydrate diet ; Oxygen consumption ; Prolonged exercise ; Glycogen ; Liver ; Muscle ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Whether or not a high intake of carbohydrate increases postprandial energy expenditure during exercise was studied in rats. The rats were meal-fed regularly twice a day (0800–0900 hours and 1800–1900 hours) on either a high carbohydrate (CHO) (carbohydrate/fat/protein = 70/5/25, % of energy) or high fat (FAT) (35/40/25) diet for 12 days. On the final day of the experiment, all of the rats in each dietary group were fed an evening meal containing equal amounts of energy (420 kJ · kg−1 body mass). After the meal, they were divided into three subgroups: pre-exercise control (PC), exercise (EX), and resting control (RC). The PC-CHO and PC-FAT groups were sacrificed at 2030 hours. The EX-CHO and EX-FAT groups were given a period of 3-h swimming, and then sacrificed at 2330 hours. The RC-CHO and RC-FAT groups rested after the meal and were sacrificed at 2330 hours. Total energy expenditure during the period 1.5 h from the commencement of exercise was higher in EX-CHO than in EX-FAT. The respiratory exchange ratio was also higher in EX-CHO than in EX-FAT, suggesting enhanced carbohydrate oxidation in the former. Compared with both PC-FAT and RC-FAT, the liver glycogen content of EX-FAT rats was significantly decreased by exercise. On the other hand, the liver glycogen content of both EX-CHO and RC-CHO was higher than that of PC-CHO rats. The glycogen content of soleus muscle of EX-FAT was slightly decreased during exercise, however, that of EX-CHO increased significantly. Thus postprandial energy expenditure during exercise was higher in the rats fed the CHO diet than in those fed the FAT diet, which could have been related to the increase of both liver and muscle glycogen storage during exercise in the former.
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  • 164
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    European journal of applied physiology 66 (1993), S. 451-454 
    ISSN: 1439-6327
    Keywords: Hindlimb suspension ; Fibre type composition ; HC IId isoform ; Soleus muscle ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The relationship between the myosin heavy chain (HC) IId isoform and histochemically defined fibre types was investigated in the rat soleus muscle after hindlimb suspension. After 4 weeks of suspension, right and left muscles were removed and fibre type composition and total fibre number were examined by histochemical myosin adenosine triphosphatase staining sections. Myosin HC isoforms were analysed by sodium dodecyl sulphate polyacrylamide gel electrophoresis. After the suspension, there was a significant decrease in the percentage of type I fibres and a concomitant increase in that of type IIa fibres. However, the total number of fibres was not affected by suspension. The synthesis of HC IId isoform, which was not found in the control, and the decrease in the ratio of slow type myosin heavy chain isoform (HC I) were observed after suspension. These results would may suggest that the change of fibre type composition was caused by a shift from type I to IIa fibres after suspension. Furthermore, it could be suggested that the synthesis of HC IId isoform occurred during the stage of type shift from type I to IIa fibres.
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  • 165
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    Neurochemical research 18 (1993), S. 965-969 
    ISSN: 1573-6903
    Keywords: Rat ; dopamine ; immunocytochemistry ; HPLC-ED ; dorsal root ganglia ; sensory neurons ; blood vessels innervation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract It has been shown that in the chick dorsal root ganglion (DRG) about 8% of neurons, belonging to both the A and B classes of sensory neurons exhibit a clear dopamine immunoreactivity. In the present study are reported the results of measurements, by mean of HPLC-electrochemical detection (HPLC-ED), of DA and of the DA metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the rat DRG and their central nerves. Very low levels of DA, about 10 folds lower than the levels found in the dorsal horn of the spinal cord, were found in the DRG. However the levels of DOPAC and HVA were approximately equivalent to the levels found in the cord. The immunocytochemical study performed in parallel has shown that some dopaminergic-immunoreactive fibers in the DRG are located around the blood vessels. Few dopamine-immunoreactive sensory neurons were identified in the DRG and immunoreactive fibers, not linked to blood vessels, were identified in the dorsal root nerves. The present work indicates that there is a dopaminergic innervation of the blood vessels in the rat DRG but that dopamine may also be, as in the chick, a transmitter of primary afferent fibers.
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  • 166
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    Documenta ophthalmologica 83 (1993), S. 175-180 
    ISSN: 1573-2622
    Keywords: Corneal contact lens electrode ; Electroretinogram ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The corneal contact lens electrode, because of its convenience, has replaced the cotton-wick electrode for recording electroretinograms from patients and animals such as dogs, rabbits, and cats. The cotton-wick electrode, however, remains popular for rat electroretinogram measurements because small contact lens corneal electrodes that fit rat eyes are difficult to fabricate. We prepared corneal electrodes from disposable needles for use in recording electroretinograms from rats. The electrodes were readily prepared, were inexpensive, and were used successfully in six rats.
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  • 167
    ISSN: 1435-2451
    Keywords: Orthotopic liver transplantation ; Rat ; Suture technique
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die Lebertransplantation (LTX) bei der Ratte ist das am häufigsten untersuchte Transplantationsmodell. In der vorliegenden Studie wird die Technik der orthotopen LTX mit Nahttechnik und arteriellem Wiederanschluß über ein hepatoaortales Segment detailliert beschrieben. Die häufigste Todesursache in der Übungsphase war eine zu lange anhepatische Zeit (〉 20 min), danach beobachtete Komplikationen waren ausschließlich auf eine fehlerhafte Anastomosentechnik zurückzuführen. Der Vorteil der Nahtanastomosen liegt in der physiologischen Gefäßadaption und im Falle von einem arteriellen Wiederanschluß in dem geringeren Operationstrauma im Empfängertier. Trotz der komplizierteren Technik der Nahtanastomose im Vergleich zur Cuff-Technik können anhepatische Zeiten von weniger als 20 min erreicht werden.
    Notes: Abstract Liver transplantation (LTX) in the rat is a frequently used transplantation model. In the present study we give a detailed description of the suture technique for all anastomoses, except the bile duct, with arterialization of the transplanted liver over an aortoceliac segment to the recipient's aorta. Using this technique, we finally achieved survival rates of 80%. During the development stages, the main cause of death was an exceedingly long anhepatic time (〉 20 min); later on, complications occurred only from insufficient anastomoses. The advantage of the suture technique over the cuff technique is that a more physiological anastomosis is obtained with less trauma to the recipient when using rearterialization. Despite the complicated suture technique, the anhepatic time can be well reduced to below 20 min.
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  • 168
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    European archives of oto-rhino-laryngology and head & neck 250 (1993), S. 18-21 
    ISSN: 1434-4726
    Keywords: Inner ear ; Vestibular system ; Saccule ; Vascularization ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A scanning electron microscope study of corrosion cast preparations of the vessels of the saccule was carried out in adult rats. This method shows the microvasculature of the saccule in the three-dimensional model. As a result of this technique we have been able to demonstrate a particular microvasculature of the saccule in the rat's inner ear. The main blood supply of the saccule consists of the arterioles coming from the vestibulocochlear artery entering the anterior margin of the macula sacculi. A few branches of the anterior vestibular artery enter the macula sacculi from the superior margin. The saccular vein drains the venous blood from a dense capil lary area underneath the striola to the posterior vestibular vein which eventually ends in the vein of the cochlear aquaduct.
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  • 169
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    European archives of oto-rhino-laryngology and head & neck 249 (1993), S. 470-472 
    ISSN: 1434-4726
    Keywords: Otitis media ; Tympanic membrane ; Topical phenol anesthesia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the present study, local anesthetics were applied to the tympanic membrane (TM) of rats following experimentally evoked purulent otitis media (POM). The structure of the TM was evaluated 24 h, 2 weeks and 3 months after application of phenol to a discrete are of the right TM. The left ear was used as a control. POM induced swelling of all tissue layers of the pears tensa. The tissues were invaded by inflammatory cells and disintegrated. The fibrous layer also dissolved, leaving spontaneous perforations. However, phenol on inflamed TMs did not further alter the TM structure. These findings infer that the injurious effect of topical anesthesia on the intact TM is more or less negligible when applied to diseased TMs.
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  • 170
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    Medical & biological engineering & computing 31 (1993), S. 340-342 
    ISSN: 1741-0444
    Keywords: Doppler radar ; Liveliness ; Motion quantifier ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The Doppler radar device which is described here is shown to be a reliable and accurate device to quantify the liveliness of an experimental rat. During recording the animal did not seem to be disturbed in any way by the device. It could stay in its normal cage, move freely, walk around and eat and drink ad libitum. Measurement did not require extra light, sound or other stimuli. Interpretation of the data was easy. The computer which samples the Doppler radar output signal generates activity curves which were easily interpreted for different ranges of vitality, varying between high liveliness and apnoea or cardiac arrest. The apparatus is low priced, and simple to build and use.
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  • 171
    ISSN: 0003-276X
    Keywords: Hepatic lipase ; Blood vessel heterogeneity ; Gonadotropin ; Ovary ; Rat ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We used biochemical and structural approaches to analyze the influence of gonadotropic hormones on the association of hepatic lipase with specific subsets of ovarian blood vessels. Western blotting was used to detect this enzyme in effluent collected from heparin-perfused ovaries of nonhormone-treated immature rats and those primed with pregnant mare's serum gonadotropin (PMSG) alone or in combination with human chorionic gonadotropin (hCG). The effects of these hormones on hepatic lipase distribution among oyarian blood vessels was assessed before and after hCG and/or PMSG treatment by immunofluorescence and immunogold cytochemistry. For the latter, immunoreagents and fixative were delivered directly to chilled, unfixed ovaries by in situ vascular perfusion. Data from biochemical and structural analyses indicated that hepatic lipase was absent from nonhormone-treated ovaries. As shown by Western blotting of ovarian effluent, the enzyme appeared following treatment with PMSG and PMSG-hCG; it increased in amount in a time-dependent manner, with a transient decline in the early hours after hCG injection. Enzyme levels paralleled growth and vascularization of follicles and corpora lutea; the fall tended to coincide with early events in luteal angiogenesis. Immunogold microscopy showed that hepatic lipase was abundant in thin-walled blood vessels of theca interna of follicles, corpora lutea, and interstitial cells but sparse in those of the stroma. Moreover, during neovascularization of differentiating corpora lutea, vascular sprouts arising from hepatic lipase-laden thecal vessels appeared to lose, then regain, the enzyme as development progressed. Our findings thus suggest (1) that hormones influence the establishment of endothelial cell heterogeneity within the microvasculature of a single organ and (2) that development of novel endothelial cell properties in specific subsets of blood vessels underlies compartmentalization of function within a tissue. © 1993 Wiley-Liss, Inc.
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  • 172
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    The @Anatomical Record 236 (1993), S. 427-432 
    ISSN: 0003-276X
    Keywords: Secretory cell ; Acinus ; Submandibular gland ; Rat ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A new, third type of secretory cell was found in the acini of the submandibular gland in rat. In paraffin sections stained with hematoxylin-eosin or reacted with periodic acid-Schiff, acini containing the third type of secretory cells were found as a mass of darkly stained secretory endpieces at the periphery of the lobule. In semi-thin sections stained with toluidine blue, these cells showed numerous dense secretory granules in their cytoplasm. Some acini consisted entirely of these cells, whereas other acini consisted of an admixture of such cells and typical seromucous cells. Acini containing the third type of secretory cell tended to form clusters. Electron microscopically, the cells had well-developed rough endoplasmic reticulum and Golgi apparatus. The secretory granules showed a wide range of variation in substructure, even within the same cell. Well-developed intercellular interdigitation and intercellular canaliculi also were observed between adjacent third type of secretory cells. Although little is known about the biological significance of these cells and the properties of their secretory granules, the present study shows that the rat submandibular gland possesses three types of secretory cells in their secretory endpieces. © 1993 Wiley-Liss, Inc.
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  • 173
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    The @Anatomical Record 236 (1993), S. 602-610 
    ISSN: 0003-276X
    Keywords: Rat ; Rectus abdominis muscle ; Nonspanning fibers ; Myomyonal junctions ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Using digital image analysis and several anatomical methods, morphometric analysis of nonspanning fibers which had tapering profiles at their intrafascicular termination sites and represented overlapping arrangements within the fiber fascicles was performed in the rat rectus abdominis. Special emphasis was focused on dimensional relationships occurring between overlapping portions and tapering segments and sarcomere lengths in non- and overlapping portions. Nonspanning fibers were found to overlap each other for more than 40% of their length. In length, their overlapping portions generally corresponded to their tapering segments, which were also greater than 40% of the fiber length. In addition, despite the presence of overlapping linkages, nonspanning fibers maintained a fairly uniform length irrespective of their overlapping and non-overlapping portions. Overlapping linkages in fibers without tapering profiles have a larger cross-sectional area in the overlapping portion than in the non-overlapping one, resulting in a phenomenon which will cause different sarcomere lengths between the two portions during fiber stretching. The present results suggest that tapering profiles in the overlapping portion ensure uniform sarcomere lengths within nonspanning fibers, thereby providing mechanical stability in each fiber. © 1993 Wiley-Liss, Inc.
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  • 174
    ISSN: 0003-276X
    Keywords: Aortic endothelium ; Permeability ; Peroxidase perfusion ; Rat ; Three-dimensional reconstruction ; Transendothelial channel ; Transport pathway ; Ultrathin serial section ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Three-dimensional organization of structures labeled by horseradish peroxidase as a tracer molecule in rat aortic endothelium was examined to elucidate the transport pathways for macromolecules. Aortic endothelium was divisible morphologically into four distinct parts, i.e., the parajunctional region (JR), peripheral region (PR), organelle region (OR), and nuclear region (NR). Almost all vesicles, intercellular clefts, and phagosomes were labeled by horseradish peroxidase. Peroxidase-positive vesicles tended to gather in the PR, occasional JR, and the upper part of the NR. Ultrathin serial micrographs revealed the transcellular channels composed of vesicles in the PR and JR, and the paracellular channels composed of the intercellular cleft without constrictions of tight and gap junctions. Transcellular channels were subdivided into three morphologically different types, where not only vesicles but invagination of abluminal membrane and intercellular cleft occasionally participated in their formation. Three-dimensional reconstructions from three series of consecutive electron micrographs revealed that almost all peroxidase-positive vesicles were connected directly or indirectly with the cell surface. These results indicate that the transcellular and paracellular channels are the transport pathways for macromolecules in the aortic endothelium and may suggest that the “shuttle” hypothesis is unsuitable to explain transport system for macromolecules because it postulates the existence of many free vesicles in the cytoplasm. © 1993 Wiley-Liss, Inc.
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  • 175
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    The @Anatomical Record 237 (1993), S. 358-364 
    ISSN: 0003-276X
    Keywords: Endothelium ; Permeability ; Rat ; Three-dimensional reconstruction ; Channel ; Vesicular transport ; Vesicle ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Three-dimensional organization of vesicles was examined to elucidate the transendothelial transport properties for macromolecules in rat aortic endothelium using ultrathin serial sections and horseradish peroxidase (HRP) as a tracer molecule. A total number of reconstructing vesicles was 1,298 in nine series electron micrographs, if each vesicular entity was counted as one regardless of composite number of vesicles. The vesicles could be classified into the following six types: HRP-positive luminal, abluminal and intercellular invaginations; HRP-positive channels; HRP-positive and -negative vesicles. The vesicular invaginations and the channels occupied 97.8% and 0.9% of the total vesicles, whereas HRP-positive and -negative free vesicles were found in 0.8% and 0.5%, respectively. The average numerical density of the luminal invagination was 41.1/μm2 and approximately equal to that of the abluminal invagination (42.0/μm2), whereas the frequency of the latter was 1.4 times higher than that of the former since the abluminal surface of the endothelium was more irregular to increase a surface area. Each endothelial region varied in the vesicular density and the peripheral region generally showed the higher density, although the transendothelial channels composed of vesicles were not always found in every peripheral region. These results suggest that the shuttle hypothesis is unsuitable to explain “vesicular transport” in the arterial endothelium as well as in the capillary endothelium and that the channels in the peripheral region mainly control transendothelial transport for macromolecules via vesicles. © 1993 Wiley-Liss, Inc.
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  • 176
    ISSN: 0003-276X
    Keywords: Rat ; Male ; Castration ; Pituitary gland ; Gap junctions ; Folliculo-stellate cells ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Cell-to-cell communication by gap junctions was investigated in the male rat anterior pituitary gland following several experimental regimens involving castration. The regimens included the following animals: (1) Group 1, castrated at 10-day intervals from day 10 to 50 and sacrificed at 60 days of age; (2) Group 2, castrated every 10 days from days 10 to 50 and sacrificed 50 days after castration; (3) Group 3, castrated at 5 days of age and sacrificed every 10 days from day 10 to 60; or (4) Group 4, remained intact and sacrificed every 10 days from days 10 to 60. In all of the castrated animals, numerous so-called castration cells were scattered throughout the pars distalis of the pituitary gland, with occasional “signet ring cells” being observed. In Groups 1 and 2, the pattern of gap junction development and their number was no different from the intact control (Group 4). In contrast, the number of gap junctions in the animals castrated on day 5 remained very small even into adulthood. These data demonstrate that gonadal steroids are important in the intial development of gap junctions within the pituitary gland but are not necessary to sustain their presence once an animal becomes an adult. © 1993 Wiley-Liss, Inc.
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  • 177
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    The @Anatomical Record 235 (1993), S. 611-621 
    ISSN: 0003-276X
    Keywords: Peroxidase ; Parotid gland ; Salivary gland ; Rat ; Growth and development ; Biochemistry ; Cytochemistry ; Ultrastructure ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The course of development of salivary peroxidase, an enzyme that has an important role in oral defense mechanisms, has been well documented in rat submandibular glands. However, the only report on salivary peroxidase activity in the other major salivary glands of the rat has been a cytochemical study of the adult parotid gland. In the present investigation, the accumulation of salivary peroxidase activity in developing parotid glands of rats was followed both biochemically and cytochemically. Specific activity (units per mg protein) attributable to salivary peroxidase began at 1 day after birth, then rose rapidly but unevenly, with peaks at 21 and 70 days, and no difference between the sexes at any age. Activity per gland increased progressively to 42 days in both sexes and was significantly higher in males at 70 days. The cytochemical observations on peroxidase activity localized to the rough endoplasmic reticulum and secretory granules of the developing acini were well correlated with the biochemical findings. Peroxidase-negative cells occurred in immature acini at 1 and 7 days, but only in the intercalated ducts thereafter. This observation suggests that the acini are a source of some of the ductal cells, at least during early postnatal development. The developmental pattern of specific activity differed from those of other rat parotid secretory enzymes, indicating that control of their synthesis during development is noncoordinate. The patterns of specific activity of the parotid and submandibular glands were complementary, suggesting that their combined secretions may supply biologically significant peroxidase activity to the oral cavities of rats throughout postnatal development. © 1993 Wiley-Liss, Inc.
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  • 178
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    The @Anatomical Record 236 (1993), S. 213-225 
    ISSN: 0003-276X
    Keywords: Lung development ; Neuroepithelial bodies ; Calcitonin gene-related peptide ; Organ culture ; Rat ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Knowing that small-granule endocrine cells develop in organ cultured fetal lungs, we investigated whether the cells produce regulatory peptides in vitro, and if sufficient amounts appear to permit using the cultures as an experimental system for physiological study of secretory mechanisms. The paired lungs from 14-day and 15-day fetal rats were organ cultured for 1-8 days and examined daily for development of immunoreactivity against marker proteins and regulatory peptides associated with small-granule endocrine cells and nerves. They proved reactive against protein gene product 9.5 (PGP) and calcitonin-gene related peptide (CGRP) but not against calcitonin or neurofilament protein 200 K, although positive controls were obtained for these substances in lungs from postnatal animals. Initially PGP-like immunoreactivity is associated with cell bodies and processes of neuroblasts which run medial to the bronchial axis on day 14 and are increasingly prevalent on day 15. In 15-day explants PGP becomes detectable after a day in vitro in rare “clear cell” precursors of small-granule cells located in the epithelium lining proximate parts of the lungs, although in 14-day explants comparable reactivity is not seen until the third day (14 + 3 days). In culture PGP-positive neuroblasts increase in number, and nerve processes gradually extend down the airway to encircle the sleeve of smooth muscle that develops as the bronchial tree expands. Concurrently, the initially small clusters of small-granule cells increase in size, and new ones appear in the airway lining. By 15 + 5 days they extend to the boundary between a taller, more proximal epithelium and a glycogen-rich cuboidal layer that lines one or two most-distal generations of branches. Thereafter, the trachea and central, cartilage-bound segments of the primary bronchi mainly contain solitary endocrine cells and the more peripheral lung a mixture of single cells and clusters, much as in near-term lungs in vivo. At this stage PGP-positive nerves extend as far as the entrances of the terminal sacs, and most are distributed to the airway muscle plexus. Exceptionally, they may innervate a small-granule cell cluster, converting it into a neuroepithelial body. CGRP-like immunoreactivity initially appears in small-granule cells of 15 + 2-day cultures but does not develop in ganglion cells or nerves. It localizes to endocrine cells at all conducting airway levels, increasing in staining intensity and accounting for most if not all of the PGP-positive population between 15 + 4 - 15 + 8 days. Similar localizations with anti-PGP and anti-CGRP were obtained in lungs of 16-day explants grown for 7 days. CGRP is present in sensory nerves of intact rat lungs. Its absence from nerves in vitro confirms that the cultures are deafferented and the PGP-positive nerves are mainly parasympathetic efferents. Small-granule cells and ganglion cells become concentrated in lung organ cultures because elongation of airway branches is severely curtailed, and this affords an advantage for functional studies on these populations. In addition, any experimentally induced fluctuation in release of CGRP to the medium can be ascribed to effects on the endocrine cells and not the sensory nerves. © 1993 Wiley-Liss, Inc.
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  • 179
    ISSN: 0003-276X
    Keywords: Insulin ; Islet ; Isolation ; Secretion ; Morphology ; Rat ; Immunoassay ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Laboratories engaged in secretory studies of rat pancreatic islets often encounter high baseline insulin secretion with poor secretory response to secretagogues, such as glucose. The specific morphologic abnormalities that accompany this unregulated release have not been described. We isolated islets comparing two approaches. Both used stationary digestion with collagenase. In method I, we distended the biliary duct extracorporeally with collagenase and minced the pancreas after a 28 min digestion (37°C). In method II, we distended the pancreas intracorporeally and digested for 40 min without mincing. Both methods utilized a similar collagenase concentration (2 μg/ml in Hank's balanced salt solution (HBSS)). Both methods yielded over 300 islets/rat. Islets from both methods appeared intact, when viewed under the dissecting microscope. We found that adequate secretion from incubated islets was evoked with method I, i.e., low basal insulin levels at low glucose (3.3 mM), tripling at 11.0 mM glucose, and nearly quadrupling in response to higher glucose (16.7 mM). In contrast, method II was characterized by high basal levels without response to higher glucose. Ultramicroscopic examination of islet B cells in method I revealed normal cytological features, while B cells in method II showed marked degranulation, profiles of swollen endoplasmic reticulum, and swollen mitochondria. Morphometric analysis of B cells confirmed quantitatively a decrease in secretory granule density and mitochondrial enlargement in method II compared to method I. Anatomic changes, largely confined to the B cells of islets may account for functional alterations of responses. Defects cannot be predicted from gross appearance of islets. © 1993 Wiley-Liss, Inc.
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  • 180
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    The @Anatomical Record 237 (1993), S. 8-20 
    ISSN: 0003-276X
    Keywords: Implantation ; Rat ; Uterine remodeling ; Collagen ; Laminin ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: This study investigated the immunohistochemical distribution of collagen type I and laminin during remodeling of the uterine extracellular matrix in response to embryo implantation in the rat. Collagen type I was found to be virtually absent around the embryo on the evening of day 5 of pregnancy. On days 6 to 8 of pregnancy the areas of primary and secondary decidualized tissue contained very little collagen in contrast to the outer nondecidualized stroma and myometrial tissues in which the staining patterns did not appear to alter. Day 8 of pregnancy was also notable for the appearance of collagen type I at the site of the developing placenta. Localization of laminin corresponded to areas of basement membrane and was associated with the redistribution of blood vasculature during implantation. By day 7 laminin staining was diminished in the basal areas of the lumenal epithelium around the implanting embryo. Laminin was also located in a punctate fashion at the margins of the primary decidual cells on day 6 of pregnancy, but by days 7 and 8 this staining pattern was no longer evident. This study has provided further evidence for a decline in a major fibrillar collagen during natural decidualization and also revealed a localized and transient expression of laminin in association with the differentiation of cells during primary decidual formation. © 1993 Wiley-Liss, Inc.
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  • 181
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    The @Anatomical Record 237 (1993), S. 71-88 
    ISSN: 0003-276X
    Keywords: Rat ; Aging ; Light morphometric ; Degeneration ; Ultrastructural ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The suprachiasmatic nucleus (SCN) is a principal controller of mammalian circadian rhythms. However, in spite of documented disturbance of biological rhythms in old animals, few significant age-related changes have been observed in this nucleus. This study examined age-related differences in SCN volume, neuronal number, density, and ultra-structural features in the entire rat SCN and in its two divisions, the denser ventromedial (compacta) and less dense dorsolateral (dissipata). Light and electron microscopic morphometric techniques were utilized in weanlings (21-28 days), young adults (3-6 mo), and aged (30-36 mo) animals.The total SCN volume, as well as volumes of-the compacta regions, were significantly greater in young adult and aged rats than in weanlings. Thus, as the rat ages the SCN increases in total size. However, the dissipata region appears to decrease in volume while the compacta increases. Even though the total number of SCN neurons was quite constant in the three age groups, the number of neurons in the dissipata region was decreased significantly in the young adult and aged groups as compared to the weanling.Neurons in the compacta region were usually spindled-shaped with two dendritic processes, while oval to spheroidal cells with 3-4 processes predominated in the dissipata. Nuclei of SCN cells were often invaginated. In weanlings, more SCN neuronal nuclei had invaginated nuclei in the dissipata region (66%) compared to the compacta (37%). In the two older age groups of rats, a higher percentage of invaginated neuronal nuclei were found in both regions. However, more were still found in the dissipata (90%) compared to the compacta (72%), even though the number of these cells in the compacta doubled. Thus, there was a large increase in the number of invaginated nuclei, as well as the number of invaginations, in the young adult rats compared to the weanling group, and this increase persisted in aged rats.SCN neurons usually had nuclei surrounded by a thin perimeter of cytoplasm containing sparse mitochondria and granular endoplasmic reticulum, multiple Golgi regions, and a moderate number of free ribosomes. In weanlings, mitochondria contained dense cristae and the granular endoplasmic reticulum was relatively prominent. Degenerative ultrastructural changes which included mitochondrial enlargement/vacuolation, Golgi vacuolation, lysosome, and lipofuscin development occurred in less than 10% of young adult SCN cells, and were more frequently found in the dissipata. In aged, rats 30% of the neurons showed degenerative changes in the dissipata compared with 18% in the compacta. Degenerative changes appeared highly correlated with the degree of membrane folding. Ultrastructural degenerative cell changes and light microscopic morphometric observations are discussed in relation to loss of circadian rhythms with advancing age. © 1993 Wiley-Liss, Inc.
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  • 182
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    The @Anatomical Record 237 (1993), S. 453-457 
    ISSN: 0003-276X
    Keywords: Heat shock proteins ; Hsp 25 ; Immunohistochemistry ; Muscle ; Rat ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The distribution of the 25 kDa heat shock protein (hsp 25) in a number of tissue types from unstressed rats was investigated. Immunohistochemical analysis showed that hsp 25 was not found in the thymus, brain (cerebral cortex and cerebellum), testis, adrenal, liver, spleen, or kidney. A number of cells in the anterior pituitary showed strong staining. These cells were tentatively identified as being either gonadotropes or thyrotropes. Strong staining was also observed in the blood vessels within these tissues. Hsp 25 was found to be localised predominantly to intestinal smooth muscle of the duodenum and colon and to vascular smooth muscle. Smooth muscle from other sites, such as the trachea, was also intensely stained. Lower and more variable amounts of staining were observed in cardiac and skeletal muscle. These observations suggest that hsp 25 is associated with cytoskeletal elements in muscle, and that the high staining intensity in smooth muscle might be due to the lack of internal architecture present in this muscle type. © 1993 Wiley-Liss, Inc.
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  • 183
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    The @Anatomical Record 235 (1993), S. 51-60 
    ISSN: 0003-276X
    Keywords: Abnormal epithelial growth ; Efferent ductules ; Microcanals ; Occlusion ; Carbendazim ; Rat ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Occlusions of the rat efferent ductules were induced by an oral gavage of carbendazim and the capacity for regeneration or recanalization of the ductules was histologically evaluated between 2 and 70 days post-treatment. At 2 days post-treatment, the efferent ductules were occluded by sloughed materials and showed various degrees of inflammation. Severely damaged epithelium showed few regenerative features at later intervals. On the other hand, epithelia with medium inflammation often exhibited irregular epithelial growth along the luminal contents or the formation of multiple abnormal ductules. These abnormal ductules were formed by migrated and original epithelia at the periphery of the occluded lumen at 16 days post-treatment, indicating attempted recanalization. At later time periods, 32 and 70 days post-treatment, the occluded original lumen was filled in by fibrotic connective tissue and surrounded by a series of abnormal ductules. These abnormal ductules were characterized by cuboidal epithelia, a small luminal diameter, fewer cilitated cells than normal, less developed organelles in the epithelial cells, and basal laminae of irregular thickness. However, there was no evidence that occluded ductules formed patent re-connections via abnormal ductules. The results suggest that occluded efferent ductules have the ability to initiate epithelial regrowth and to form new ductules, but the newly formed ductules are abnormal and are not adequate to recover from azoospermia at least at 70 days post-treatment. © 1993 Wiley-Liss, Inc.
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  • 184
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    The @Anatomical Record 235 (1993), S. 61-73 
    ISSN: 0003-276X
    Keywords: Vasectomy ; Vasovasostomy ; Epididymis ; Granulomatous inflammation ; Rat ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The response of the male reproductive tract to vasectomy includes inflammation of the interstitial tissue of the epididymis. The pathogenesis of epididymal interstitial reactions and characteristics of the responding cells were studied by electron microscopy in Lewis rats at intervals following bilateral vasectomy, vasectomy followed 1 month later by vasovasostomy, or sham operations. In areas of interstitial reaction, numerous macrophages, monocytes, lymphocytes, neutrophils, and plasma cells occupied the connective tissue. Macrophages, containing many lysosomes and vesicles, aggregated and assumed the appearance of epithelioid cells. Processes of adjacent macrophages interdigitated with one another and closely approached the surfaces of lymphocytes. Many plasma cells with distended rough endoplasmic reticulum appeared in the interstitium. The majority of animals in the vasectomy and vasovasostomy groups exhibited epididymal interstitial changes by 2-3 months; the cauda epididymidis was the region most often affected. The ultrastructural features were indicative of chronic granulomatous inflammation and were consistent with an immune response that includes antigen presentation by macrophages to lymphocytes, lymphocyte differentiation, and local antibody production by plasma cells. The nearly complete absence of sperm or recoghizable parts thereof in the interstitial tissue in the areas of the reactions suggests that these lesions formed in response to soluble antigens leaking from the duct. Vasovasostomy was not effective in reversing or retarding epididymal inflammation at the intervals studied. © 1993 Wiley-Liss, Inc.
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  • 185
    ISSN: 0003-276X
    Keywords: Rat ; Pituitary gland ; Cell proliferation ; PCNA ; BrdU ; Immunohistochemistry ; Estrous cycle ; Sexual difference ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Proliferative activity of the anterior pituitary gland in 10 week-old male and female rats under normal conditions was investigated by counting mitotic figures and using single and double immunostaining of 5-bromo-2′-deoxyuridine (BrdU), proliferating cell nuclear antigen (PCNA), and six pituitary hormones. To determine which proliferative changes depend on the estrous cycle and circadian changes, respectively, six groups of female and two groups of male rats were studied at various times of day. Additionally, BrdU-incorporated cells were further classified by the six types of hormones they contained, or as immunonegative cells. Cell proliferative activity in the females fluctuated drastically with the highest activity in estrus and the lowest in diestrus. In the males, proliferative activity was at a relatively low level, and was similar to that in females in proestrus or early estrus, with the greater activity at night. Identified by their pituitary hormones, the distribution of the proliferating cells was almost the same in each sex, with prolactin (PRL) cells accounting for the highest proportion, followed by growth hormone (GH) cells, and adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH) cells. These percentages agreed well with previously reported levels of cell types among all pituitary cells of the rat. It is therefore suggested that the life span and cycle of rat pituitary cells does not differ among cell types. In another test, male and female rats were given BrdU continuously via an osmotic pump for 8 days to compare cell proliferative activity between sexes, exclusive of the influence of estrous cycle and circadian changes. In this way, we were able to demonstrate that the cumulative incorporation of BrdU in females was consistently twice as high as in males over a constant period of time, and to conclude that cell renewal occurs at a doubled rate in the pituitary of female rat. © Wiley-Lis, Inc.
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  • 186
    ISSN: 0003-276X
    Keywords: Spermatogenesis ; Testosterone ; Germ cell degeneration ; Testis ; Rat ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Rapid and complete withdrawal of intratesticular testosterone was achieved via the destruction of all Leydig cells with the specific Leydig cell cytotoxin ethane dimethanesulphonate (EDS). Restoration of testosterone levels was accomplished by administration of a single dose (25 mg) of testosterone esters (T) known to reverse the antispermatogenic effects of androgen withdrawal. Quantitation of the degenerating germ cells in cross sections of seminiferous tubules (ST) at stages IV-V, VII, IX, and X-XI of the spermatogenic cycle was used as a sensitive biological index of the effects of testosterone withdrawal and restoration upon the function of the Sertoli cells. Compared to control testicular tissues, the mean numbers of pyknotic germ cells per ST cross section at stages VII, IX and X-XI increased significantly (P 〈 0.01-0.001) between 4 to 8 days post-EDS treatment, but only in stage VII tubules was this trend reversed significantly (P 〈 0.005) within 2 days by T supplementation. In EDS-treated rats, stages VII, VIII, IX, and X-XI also exhibited significant (P 〈 0.05-0.001) increases (compared to controls) in the volumetric proportions by which intraepithelial vacuoles appeared within the seminiferous tubules. Again, in EDS+T supplemented rats, the appearance of vacuoles was significantly (P 〈 0.001) suppressed in stage VII and VIII. In contrast to tubules at stages VII-XI, those at stages IV-V were completely unaffected by testosterone withdrawal or replacement. The results show that at selected time intervals after EDS treatment, testosterone supplementation is capable of preventing/reversing these morphological changes within 2 days in stage VII tubules. It is suggested that the induction and subsequent prevention of seminiferous epithelial damage will serve as an important in vivo and in vitro approach for studies on the androgen-mediated changes in Sertoli cell biology during phases of impairment and recovery of their function. Manipulation of adult Sertoli cell function as provided by our model should permit identification of androgen-regulated gene products together with an understanding of their role(s) in normal and abnormal spermatogenesis. © 1993 Wiley-Liss, Inc.
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  • 187
    ISSN: 0003-276X
    Keywords: Sertoli cell ; Cycle of the seminiferous epithelium ; Morphometry ; Organelles ; Rat ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Seminiferous tubules in mammals are composed of cell associations that show a cyclic pattern of renewal and development. The cyclic nature of germ cell development suggests that the cells supporting the spermatogenic process, the Sertoli cells, might also differ structurally during the spermatogenic cycle in terms of the quantity of their constituents. In the present study, cyclic differences in volumes, and surface areas were determined using a sampling technique at the electron microscope level that proportionally samples the Sertoli cell within the seminiferous tubule. Among the many parameters studied, only the surface area of the cell, the volume of lipid, and the volume and surface area of the rough endoplasm reticulum were shown by statistical analysis to vary cyclically. Regarding rough endoplasm reticulum, the volume and surface area of this organelle peaked at mid-cycle and its low was recorded near the end of the cycle, exhibiting an approximate 15-fold difference between extremes. The rough endoplasm reticulum parameters generally correlated with known patterns of protein secretion within the tubule and with the secretion of specific proteins as well as the factors important in controlling protein secretion. Many Sertoli cell structural parameters suggested to be influenced cyclically in the rat in other studies could not be confirmed by the present study. Methodological differences in the present study and past studies are discussed as potential sources of error for these discrepancies. © 1993 Wiley-Liss Inc.
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  • 188
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    Journal of Computational Chemistry 14 (1993) 
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
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  • 189
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    Journal of Computational Chemistry 14 (1993), S. 237-245 
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: The affinity of a ligand for a receptor is usually expressed in terms of the dissociation constant (Ki) of the drug-receptor complex, conveniently measured by the inhibition of radioligand binding. However, a ligand can be an antagonist, a partial agonist, or a full agonist, a property largely independent of its receptor affinity. This property can be quantitated as intrinsic activity (1A), which can range from 0 for a full antagonist to 1 for a full agonist. Although quantitative structure-activity relationship (QSAR) methods have been applied to the prediction of receptor affinity with considerable success, the prediction of IA, even qualitatively, has rarely been attempted. Because most traditional QSAR methods are limited to congeneric series, and there are often major structural differences between agonists and antagonists, this lack of success in predicting IA is understandable. To overcome this limitation, we used the method of comparative molecular field analysis (CoMFA), which, unlike traditional Hansch analysis, permits the inclusion of structurally dissimilar compounds in a single QSAR model. A structurally diverse set of 5-hydroxytryptamine1A (5-HT1A) receptor ligands, with literature IA data (determined by the inhibition of 5-HT sensitive forskolin-stimulated adenylate cyclase), was used to develop a 3-D QSAR model correlating intrinsic activity with molecular structure properties of 5HT1A receptor ligands. This CoMFA model had a crossvalidated r2 of 0.481, five components and final conventional r2 of 0.943. The receptor model suggests that agonist and antagonist ligands can share parts of a common binding site on the receptor, with a primary agonist binding region that is also occupied by antagonists and a secondary binding site accommodating the excess bulk present in the sidechains of many antagonists and partial agonists. The CoMFA steric field graph clearly shows that agonists tend to be “flatter” (more coplanar) than antagonists, consistent with the difference between the 5-HT1A agonist and antagonist pharmacophores proposed by Hibert and coworkers. The CoMFA electrostatic field graph suggests that, in the region surrounding the essential protonated aliphatic amino group, the positive molecular electrostatic potential may be weaker in antagonists as compared to agonists. Together, the steric and electrostatic maps suggest that in the secondary binding site region increased hydrophobic binding may enhance antagonist activity. These results demonstrate that CoMFA is capable of generating a statistically crossvalidated 3-D QSAR model that can successfully distinguish between agonist and antagonist 5-HT1A ligands. To the best of our knowledge, this is the first time this or any other QSAR method has been successfully applied to the correlation of structure with IA rather than potency or affinity. The analysis has suggested various structural features associated with agonist and antagonist behaviors of 5-HT1A ligands and thus should assist in the future design of drugs that act via 5-HT1A receptors. © 1993 John Wiley & Sons, Inc.
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  • 190
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    Journal of Computational Chemistry 14 (1993), S. 30-36 
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: We consider the tree search problem for the recurrence relation that appears in the evaluation of molecular integrals over Cartesian Gaussian basis functions. A systematic way of performing tree search is shown. By applying the result of tree searching to the LRL2 method of Lindh, Ryu, and Liu (LRL) (J. Chem. Phys., 95, 5889 1991), which is an auxiliary function-based method, we obtain significant reductions of the floating point operations (FLOPS) counts in the K4 region. The resulting FLOPS counts in the K4 region are comparable up to [dd|dd] angular momentum cases to the LRL1 method of LRL, currently the method requiring least FLOPS for [dd|dd] and higher angular momentum basis functions. For [ff|ff], [gg|gg], [hh|hh], and [ii|ii] cases, the required FLOPS are 24, 40, 51, and 59%, respectively, less than the LRL1 method in the K4 region. These are the best FLOPS counts available in the literature for high angular momentum cases. Also, there will be no overhead in either the K2 or K0 region in implementing the present scheme. This should lead to more efficient codes of integral evaluations for higher angular momentum cases than any other existing codes. © 1993 John Wiley & Sons, Inc.
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  • 191
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    Journal of Computational Chemistry 14 (1993), S. 19-29 
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: A method is proposed to perform computer simulations of protein dynamics in the long-time regime. The method is based upon a Monte Carlo technique. The only molecular degrees of freedom considered are bond rotations. All other degrees of freedom including the amide plane torsions are kept rigid. These constraints approximately account for all interactions related to chemical bonding. An individual Monte Carlo step adopts the Go and Scheraga algorithm where local conformational changes in a small window of the protein backbone are performed. By using correlated rotations, the conformation of residues outside the window remains invariant. To test the reliability of the method, the nonbonded interactions are turned off in the present application. Exact statistical averages are compared with values obtained from data of computer simulation involving 2 × 106 scans of the window along the protein backbone. Time is related to the number of scans of the window along the protein backbone. End-to-end distance autocorrelation functions decay to 1/e of its initial value in about 103-104 scans of the window algorithm. Time decay follows a stretched exponential Kohlrausch decay law. © 1993 John Wiley & Sons, Inc.
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  • 192
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    Journal of Computational Chemistry 14 (1993), S. 45-53 
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: The antitumor drug cis-diamminedichloroplatinum(II) (cisplatin) binds preferentially to GpG and ApG sequences of DNA, forming N7,N7 intrastrand chelates. Molecular modeling of the intrastrand adducts have been handicapped, so far, by the lack of force-field data describing the Pt-guanine and Pt-adenine binding. We used ab initio calculations with relativistic pseudopotentials to evaluate three important parameters for the platinum-adenine model complex [Pt(NH3)3(Ade)]2+: (1) the force constant for the Pt—N7 bond bending out of the adenine plane; (2) the energy profile for the torsion about Pt—N7; (3) a set of fractional atomic charges that reproduce the ab initio potential for a number of space points placed around the adduct. A population analysis and comparative study on the tetrammine complex [Pt(NH3)4]2+ have shown that for platinum adenine is a better σ-donor than NH3, but its capacity as a π-acceptor is weak. © 1993 John Wiley & Sons, Inc.
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  • 193
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    Journal of Computational Chemistry 14 (1993), S. 422-437 
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: A procedure is reported for the prediction of dense crystal structures of C-, H-, N-, O-, and F-containing organic compounds in the primitive triclinic, monoclinic, and orthorhombic space groups with Z ≤ 4. The crystal environments of molecules in 242 crystal structures have been analyzed to determine the common coordination sphere pattens. This led to the development of the MOLPAK (MOLecular PAcKing) program, which uses a rigid-body molecular structure probe to build packing arrangements (possible crystal structures) in the various space groups. A MOLPAK search, which involves the investigation of all unique orientations of a central molecule and the construction of the appropriate coordination patterns about the central molecule, provides a 3-D map of minimum unit cell volume as a function of the orientation of the central molecule. MOLPAK uses a repulsion-only potential and a preset threshold to place molecules in contact with each other. The 5-10 smallest volume packing arrangements from a search are subjected to a lattice energy minimization refinement with the WMIN program to yield possible crystal structures. The results are described from the analyses of several known compounds starting with the crystal molecular structures as the MOLPAK search probes in the P1, P21, P21/c, and P212121 space groups. In addition, several examples are given in which the search probes were created by AM1 geometry optimization of preliminary molecular models. More extensive data are given in supplementary tables. © 1993 John Wiley & Sons, Inc.
    Additional Material: 7 Ill.
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  • 194
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    Journal of Computational Chemistry 14 (1993), S. 312-329 
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: A fully functional parallel version of the molecular dynamics (MD) module of AMBER3a has been implemented. Procedures parallelized include the calculation of the long-range nonbonded Coulomb and Lennard-Jones interactions, generation of the pairlist, intramolecular bond, angle, dihedral, 1-4 nonbonded interaction terms, coordinate restraints, and the SHAKE bond constraint algorithm. As far as we can determine, this is the first published description where a distributed-memory MIMD parallel implementation of the SHAKE algorithm has been designed to treat not only hydrogen-containing bonds but also all heavy-atom bonds, and where “shaken” crosslinks are supported as well. We discuss the subtasking and partitioning of an MD time-step, load balancing the nonbonded evaluations, describe in algorithmic detail how parallelization of SHAKE was accomplished, and present speedup, efficiency, and benchmarking results achieved when this hypercube adaptation of the MD module AMBER was applied to several variant molecular systems. Results are presented for speedup and efficiency obtained on the nCUBE machine, using up to 128 processors, as well as benchmarks for performance comparisons with the CRAY YMP and FPS522 vector machines. © 1993 John Wiley & Sons, Inc.
    Additional Material: 10 Ill.
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  • 195
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    Journal of Computational Chemistry 14 (1993), S. 349-352 
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: We report the development of a new approximate method of calculating molecular surface areas. Our technique is based upon the method of Sharake and Rupley but incorporates several major advances. First, we represent the state of surface points as bits in a bit string so we can utilize Boolean operations to simultaneously turn off multiple test points in one Boolean AND operation. Second, we use a series of Boolean mask look-up tables to reduce the time complexity of the calculation of molecular surface area down to the same magnitude as doing a potential energy evaluation. When we use a 256 surface point sphere for all of the atoms in BPTI, a 454 nonhydrogen atom protein, and a 1.4-Å solvent probe, we in general underestimate the total solvent-accessible surface area (SASA) by approximately 1.25% with a correlation coefficient of 0.9990 over a wide range of conformations. The average CPU time required to calculate the SASA of a BPTI conformer is 0.58 s on an SGI 4D/220 workstation. We also describe a method by which we can calculate an approximate finite difference SASA gradient for BPTI in 0.79 of CPU time. © 1993 John Wiley & Sons, Inc.
    Additional Material: 5 Ill.
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  • 196
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    Journal of Computational Chemistry 14 (1993), S. 378-378 
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Type of Medium: Electronic Resource
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  • 197
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    Journal of Computational Chemistry 14 (1993), S. 728-735 
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: A method is proposed for calculating the forces in path integral theory and tested on semiclassic systems. It takes the range of the classic and quantum interactions into account and uses a second table within the neighbors table for the nearest neighbors. This method is found to be much more efficient than either the standard direct method or the traditional neighbors table, the efficiency increasing with the size of the system. The method can also be applied to clusters whose interaction centers are much farther apart than the distances between two consecutive members of the cluster. © 1993 John Wiley & Sons, Inc.
    Additional Material: 1 Ill.
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  • 198
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    Journal of Computational Chemistry 14 (1993) 
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Type of Medium: Electronic Resource
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  • 199
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    Journal of Computational Chemistry 14 (1993), S. 445-451 
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: Parallelization of the SCF method for closed-shell molecules on the highly parallel transputer-based system PARAM is described. The parallelization has been implemented on three different hardware and software environments: (1) a network of bare 64 transputers; (2) configuration 1 plus a back-end file system (BFS); and (3) configuration 2 with one INTEL i860 processor. The evaluation of electron repulsion integrals (ERIs) and setting up of the Fock matrix is carried out in parallel on 64 nodes using minimal communication strategies. A good load balance is achieved for ERI evaluation with the help of bounds, local symmetry features, and the shell concept, as well as a data randomization technique, resulting into almost linear speedup (for ERI evaluation). In configurations 2 and 3, BFS is used for parallel storage and retrieval of ERIs. Further, in 3 matrix operations are implemented as remote procedure calls on the i860 processor. Routine techniques of level shifting and extrapolation are used for accelerating SCF convergence. The resulting package, INDMOL, has been tested for some randomly selected molecules having up to 255 contractions. Using configuration 3, a factor of 2 to 5 in computation time is obtained over 1, for the systems for which the ERIs cannot be stored in the distributed core memory. In summary, a heterogeneous system, as in configuration 3, can indeed be optimally exploited for programming peculiar diverse requirements of the SCF procedure. © 1993 John Wiley & Sons, Inc.
    Additional Material: 4 Ill.
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  • 200
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    Journal of Computational Chemistry 14 (1993), S. 471-477 
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: One of the features of the polypeptide backbone is that it represents a flexible chain that contains almost rigid CO—NH peptide bonds. One may try to substitute one or more such bonds by another relatively rigid unit to maintain the overall conformational properties of the backbone and at the same time modify some other properties of the molecule (“pseudopeptide”), such as the ability to form hydrogen bonds. By a detailed conformational analysis, it is shown that the carbon—carbon double bond is quite isosteric with the peptide bond and for this reason suitable for such a substitution. This is accomplished by applying molecular mechanics in calculation of the φ, ψ maps for pseudopeptide analogs of the N-acetyl-Ala-NHMe molecule. © 1993 John Wiley & Sons, Inc.
    Additional Material: 10 Ill.
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