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  • 1985-1989  (770)
  • 1987  (770)
  • Engineering General  (448)
  • Rat  (195)
  • pharmacokinetics  (127)
  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 91 (1987), S. 330-333 
    ISSN: 1432-2072
    Keywords: Yawning ; D1 and D2 DA receptors ; DA agonists ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The subtype of dopamine (DA) receptors mediating the yawning response to DA agonists was determined in rats. Yawning was elicited both by the mixed D1–D2 agonist apomorphine and by the specific D2 agonist LY 171555, but not by the selective D1 agonist SKF 38393. Both apomorphine- and LY 171555-induced yawning were antagonized not only by the selective D2 antagonist sulpiride but, unexpectedly, also by the selective D1 antagonist SCH 23390. The results suggest that DA receptors mediating the yawning response are of the D2 type, and that these receptors are connected with D1 receptors in such a way that the blockade of the latter results in the functional inactivation of the former.
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  • 2
    ISSN: 1432-2072
    Keywords: SK & F 38393 ; Behavioural assessment ; Stereotypy ; Behavioural check list ; Grooming ; Dopamine ; Apomorphine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The behavioural effects of the D-1 dopamine receptor agonist SK & F 38393 were assessed in the intact adult rat using a conventional stereotypy rating scale and a rapid time sampling behavioural check list procedure. This combination technique allowed description of the nature of any behavioural response and quantification of the number of counts of individual behaviours. Using this combined procedure, SK & F 38393 clearly failed to induce typical stereotyped behaviour. However, in the well-habituated animal, SK & F 38393 dose-dependently increased the number of recordings of non-stereotyped sniffing, locomotion and grooming; some occasional rearing was also noted. An unusual pattern of intense grooming behaviour was a characteristic response to this drug. Using the resolved R-and S-enantiomers of SK & F 38393, promotion of sniffing, locomotion, rearing and grooming resided stereoselectively in the R-configuration. Under appropriate experimental conditions, specifically a requirement for prolonged habituation and the use of a rapid sampling behavioural check list to supplement the rating scale, it is possible to demonstrate that SK & F 38393 is behaviourally active in the whole animal.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 92 (1987), S. 313-319 
    ISSN: 1432-2072
    Keywords: Pentylenetetrazol ; Morphine ; Fentanyl ; U 69 593 ; Mr 2034 ; Bremazocine ; Phencyclidine ; Drug discrimination ; Anxiety ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats were trained to detect the stimulus properties of pentylenetetrazol (PTZ), 16 mg/kg, and prototypic drugs for mu, kappa and sigma opioid receptors were tested for their ability to block or substitute for PTZ. Only the sigma agonist, phencyclidine, showed any capacity for blocking the PTZ stimulus. Drugs with selective kappa or sigma actions did not substitute for PTZ. However, morphine, fentanyl and Mr 2034 did substitute for the PTZ stimulus. This substitution was found to be centrally mediated in that quaternary morphine did not produce a PTZ-like stimulus. In contrast to the substitution of these drugs for PTZ, in rats trained to detect the stimulus properties of fentanyl, no substitution of PTZ for the fentanyl stimulus occurred. In tests of the capacity of various drugs to block the PTZ-like stimulus of mu agonists, the stimulus produced by morphine or fentanyl was blocked by naloxone, diazepam and haloperidol, but not by scopolamine. These results demonstrate that drugs with mu agonist properties show a one-way substitution for the discriminative stimulus produced by PTZ. The observation that haloperidol blocked the PTZ-like stimulus of mu agonists suggests the possible involvement of dopaminergic mechanisms in the mediation of the effect.
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  • 4
    ISSN: 1432-2072
    Keywords: Amphetamine-conditioned excitation ; Neuroleptic drugs ; Clonidine ; Lithium ; Animal model ; Mania ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats with a history of daily (21 days) amphetamine (2.5 mg/kg) treatment showed enhanced activity when under placebo in their amphetamine-associated environment. We found that this conditioned effect was reduced by haloperidol (0.06; 0.125; 0.25 mg/kg), pimozide (0.25; 0.5 mg/kg) and sulpiride (8; 16; 32 mg/kg) but only at doses similar to or, in the case of pimozide, higher than those required to antagonize the unconditioned stimulant effects of amphetamine (2.5 mg/kg). Conversely, we observed that clonidine (7; 15; 30; 60 μg/kg) or lithium regimen (between days 15 and 21) leading to lithium plasma levels of 1.3±0.1 mEq/1, abolished amphetamine-conditioned hyperactivity but did not affect the unconditioned stimulation of amphetamine or locomotor activity in control rats. Moreover, we found that hyperactivity induced by the daily anticipation of food delivery shared identical pharmacological sensitivity with the behavioural excitation produced by a conditioning history with amphetamine. In light of the antimanic properties of lithium and clonidine and the ability of this latter drug to reduce noradrenergic transmission, our findings raise the posibility that incentive activity may model noradrenergic-dependent aspects of mania.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 91 (1987), S. 119-121 
    ISSN: 1432-2072
    Keywords: Successive discrimination ; Chlordiazepoxide ; Naloxone ; Benzodiazepines ; Opiates ; Nonreward ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Naloxone reduces the effects of chlordiazepoxide on punishment and on acquisition of differential reinforcement of low rates of response. The present experiments tested whether naloxone also reduces the effects of chlordiazepoxide on a second type of nonreward schedule — successive discrimination. Rats were tested on a variable interval baseline of responding for food with signalled intrusion periods when food was no longer available. Naloxone (3 mg/kg IP) failed to change the effects of chlordiazepoxide (5 mg/kg IP) on either acquisition or performance of this successive discrimination. DRL and successive discrimination differ both in their timing of events and their use of explicit visual stimuli. If these or similar parametric differences account for the present results they considerably weaken conventional accounts of the control of behaviour by reward omission.
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 92 (1987), S. 478-483 
    ISSN: 1432-2072
    Keywords: Rat ; Marmoset ; Serotonin agonists ; Serotonin antagonists
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The actions of the serotonin precursor 5-hydroxytryptophan (5-HTP), the agonist 5-methoxy-N,N-dimetyltryptamine (MeODMT) and quipazine (QPZ) and the antagonists cyproheptadine, methysergide and metergoline, were studied in the rat and in the common marmoset (Callithrix jacchus). The precursor and agonists elicited head shakes, forepaw padding, splayed hindlimbs, tremor and Straub tail in the rat. However, head shakes were not observed after MeODMT and Straub tail was not observed after QPZ. Carbidopa plus 5-HTP potentiated only head shakes, while tranylcypromine (TCP) plus 5-HTP potentiated all the behaviors above. In the marmoset, the action of these drugs elicited drowsiness, teeth chattering, ataxia, vomiting and decreased motor activity, although vomiting was not elicited by MeODMT and ataxia and drowsiness by QPZ. Although TCP plus 5-HTP potentiated all these behaviors, carbidopa plus 5-HTP was not effective. Rats treated with the antagonists (1.0, 5.0 and 10 mg/kg doses) did not show any of these behaviors, but marmosets treated with the same drugs developed “drowsiness”, vomiting, and decreased motor activity; nonetheless, cyproheptadine (5.0 and 10 mg/kg doses) did not elicit “drowsiness”, while increasing motor activity and the number of head shakes. Pretreatment of marmosets with these antagonists blocked only teeth chattering elicited by MeODMT (4.0 mg/kg) and QPZ (10 mg/kg). Pretreatment with haloperidol, p-chlorophenylalanine and α-methyl-P-tyrosine had no effect. The data obtained show that rats and marmosets present differential behavioral responses to the 5-HT drugs used. Marmosets have a richer behavioral repertoire and show greater sensitivity to 5-HT agonists and antagonists. The data suggest that this animal might become a useful biological model for the study of central 5-HT systems.
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 92 (1987), S. 473-477 
    ISSN: 1432-2072
    Keywords: Opiates ; Morphine ; Naloxone ; Place preference ; Saccharin ; Genetic strain ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Two strains of rats — LC2-Hi and LC2-Lo — selected for high and low self-stimulation rates, respectively, were tested for responses to opiates and to naloxone using conditioned place preference paradigm. In the two experiments which used opiates as UCS, conditioning was carried out in the non-preferred compartment while in the experiment which used naloxone, conditioning was performed in the preferred compartment. The preference changes were determined on the basis of times spent in the compartments before and after conditioning with drugs. LC2-Hi rats showed positive changes in the preference to the initially non-preferred side when morphine or heroin (5 mg/kg and 1 mg/kg, respectively) were used; no such effect was observed with LC2-Lo rats. Both lines exhibited aversive reactions to naloxone by diminishing the time spent in the environment paired with this drug, but again the response of LC2-Hi animals was significantly larger than the response of LC2-Lo rats. Chronic intake of a sweet solution (3 mM saccharin for 4 weeks) tended to amplify the aversive reaction to naloxone in both lines. It may be inferred from the present findings that there exists a common genetic factor, as revealed by the conditioned place preference paradigm, underlying positive reinforcing properties of opiates and aversive effects of naloxone.
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  • 8
    ISSN: 1432-2072
    Keywords: Chlordiazepoxide ; Midazolam ; GABA ; R0 15-1788 ; CGS 8216 ; FG 7142 ; Serotonin ; 8-OH-DPAT ; Methysergide ; Amygdala ; Conflict ; Successive discrimination ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Interactions between the benzodiazepines (BZs) chlordiazepoxide (CDP) and midazolam (MDZ), the BZ antagonist R0 15-1788, the inverse BZ receptor agonists CGS 8216 and FG 7142, γ-aminobutyrate (GABA), serotonin (5-HT), the 5-HT2 antagonist methysergide and the putative 5-HT agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) were investigated using peripheral and intra-amygdaloid treatments. A multiple schedule consisting of rewarded, nonrewarded (Time out: TO) and conflict periods was used to compare in parallel effects on successive discrimination between rewarded and nonrewarded periods and punished responding. The three components were presented in both a fixed order (Experiment 1) and a random order (Experiments 2 and 3). Intra-amygdaloid treatments with GABA and the BZs selectively increased rates of punished responding. CDP given systemically, on the other hand, increased both TO and conflict rates, suggesting an additional impairment of discrimination, which was more marked in the random than the fixed order condition. R0 15-1788, CGS 8216 and FG 7142 given by both routes counteracted the anti-conflict effects of CDP given centrally or systemically. However increases in TO rates induced by IP CDP were antagonized only by IP treatments with these compounds. The two inverse agonists, but not R0 15-1788, also counteracted increases in punished responding which were found after intra-amygdaloid GABA infusions. In Experiments 2 and 3 where baseline rates of pressing in Conflict periods were sufficiently high to detect decreases, CGS 8216 and FG 7142 reduced responding below control level, suggesting a specific anxiogenic activity. Evidence for effects of R0 15-1788 by itself was inconclusive. 5-HT injected into the amygdala also reduced punished responding below control level, whereas methysergide increased it with both central and peripheral treatment. Effects of 8-OH-DPAT varied according to route of administration. With IP treatment Conflict rates were increased, but after amygdaloid infusion both TO and Conflict rates were marginally reduced below control level, with a more consistent depression of punished responding. These results provide evidence that effects of BZs on punished responding are mediated by a GABAergic system which includes the lateral/basolateral amygdala, but which does not participate in BZ-induced disruption of discrimination. They also indicate that the antagonistic effects of CGS 8216 and FG 7142 involve a decrease in GABA transmission, and that these compounds may also be anxiogenic. Finally, the results suggest that 5-HT utilizes the same system for regulating resistance to punishment, but plays no significant part in reward-nonreward successive discrimination, which is impaired after systemic BZs.
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  • 9
    ISSN: 1432-2072
    Keywords: Ethanol ; Tolerance ; Tail-flick ; Classical conditioning ; Rat ; Antinociception
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In rats, ethanol increases the latency of the tail-flick reflex to radiant heat. Three experiments examined the contribution of classical conditioning to the acquisition of tolerance to this antinociception. Experiment 1 showed that the antinociception produced by ethanol was dose dependent. The results of Experiment 2 demonstrated that rats exposed to a series of ethanol injections paired with a distinctive environment developed tolerance to this antinociception. In Experiment 3, tolerance was more pronounced in animals that had been exposed to ethanol and tested in the distinctive environment than in animals that had received ethanol in a nondistinctive environment. In contrast to previous reports in the literature, these results show that animals need not practice the tail-flick reflex while intoxicated in order to develop tolerance. Additionally, the data suggest that classical conditioning may contribute to tolerance to the antinociceptive effects of ethanol.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 91 (1987), S. 345-351 
    ISSN: 1432-2072
    Keywords: Amphetamine ; Latent inhibition ; Conditioned suppression ; Animal model of schizophrenia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Latent inhibition (LI) is a behavioral paradigm in which animals learn to ignore a repeatedly presented stimulus not followed by meaningful consequences. We previously reported that LI was disrupted following the administration of 1.5 mg/kg dl-amphetamine. The present experiments investigated the effects of 6 mg/kg dl-amphetamine administration on LI in a conditioned emotional response (CER) procedure consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where LI was indexed by animals' suppression of licking during tone presentation. The three stages were conducted 24 h apart. In Experiment 1, the drug was administered in a 2×2 design, i.e. drug-no drug in pre-exposure and drug-no drug in conditioning. LI was obtained in all conditions. In Experiment 2, animals were given either 5 days of 6 mg/kg amphetamine pretreatment and amphetamine in pre-exposure and conditioning or 7 days of saline. LI was not obtained under amphetamine, but this outcome reflected a state-dependency effect. In Experiment 3, animals received either 5 days of amphetamine pretreatment and amphetamine in pre-exposure, conditioning and test or 8 days of saline. LI was obtained in both the placebo and amphetamine conditions. Experiments 4a and 4b compared the effects of two drug doses, 1.5 (4a) and 6 mg/kg (4b), administered in pre-exposure and conditioning. LI was abolished with the 1.5 mg/kg dose but not with the 6 mg/kg dose.
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  • 11
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 91 (1987), S. 363-368 
    ISSN: 1432-2072
    Keywords: Memory ; Neuropeptides ; Vasopressin ; Oxytocin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Adult male rats spend a great amount of time investigating novel juveniles. In contrast, rats re-exposed to the same juvenile 30 min after the initial exposure display little investigatory behavior. If the re-exposure occurs 2 h later, the juvenile is thoroughly investigated. These results have been interpreted to mean that rats form a transient memory for a particular juvenile. In the present study, memory was enhanced when the initial exposure to the juvenile was followed by another exposure to the same juvenile (retroactive facilitation) and impaired when exposure to the original juvenile was followed by exposure to another juvenile (retroactive interference). Arginine vasopressin had retroactive facilitating effects on social memory and these effects were blocked by the vasopressor antagonist dPTyr(Me)AVP. Moreover, the antagonist had retroactive interfering effects, since it impaired the recognition of a familiar juvenile. Oxytocin shared the same inhibitory pattern of action. These results suggest that neurohypophyseal peptides may have a prepotent role in modulating the mnemonic processing of chemosensory information associated with social interactions.
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  • 12
    ISSN: 1432-2072
    Keywords: Chronic neonatal antidepressant treatment ; Desipramine ; Zimeldine ; Active (REM) sleep deprivation ; Open field behavior ; Alcohol intake ; Monoamines ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To study the relationship between neonatal antidepressant administration, active (REM) sleep and adult alcohol-related behavior, rat pups were treated daily with 5 mg/kg despramine (DMI) or 25 mg/kg zimeldine SC from the 6th to the 19th postnatal days. Movement sensitive mattress (“SCSB”) measurements showed that zimeldine treatment suppressed active sleep throughout the whole treatment period, but DMI was more effective during the first 8 days than during the last treatment days. At the age of 70 days, the zimeldine-treated rats expressed a selective increase of some components of activity in the open field test, and the DMI rats had a higher defecation score compared to the controls. Furthermore, the zimeldine-rats responded with a decrease in ambulation in the open field to an alcohol dose which generally stimulates locomotion in rats. At the age of 3 months the DMI and zimeldine rats showed increased voluntary intake of 10% (v/v) alcohol. Measurement of brain monoamines revealed that the neonatal treatment with DMI or zimeldine interfered with the normal development and function of the monoamine neuronal systems: the concentrations of noradrenaline, dopamine and 5-hydroxytryptamine (5-HT), and their metabolites were altered in several brain regions. The results thus suggest that neonatal treatment with DMI or zimeldine suppresses active sleep and has an influence on later alcohol-related behavior, possibly due to a long-lasting defect in brain monoaminergic transmission.
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  • 13
    ISSN: 1432-2072
    Keywords: d-Amphetamine ; Attention ; Discrimination ; Dopamine-Noradrenaline interaction ; Dorsal noradrenergic bundle ; alpha-Flupenthixol ; Nucleus accumbens ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A series of experiments examined the effects of lesions of the dorsal noradrenergic bundle (DNAB), induced by 6-hydroxydopamine (6-OHDA), on the behavioural response to systemic and intra-accumbens amphetamine, using a rat analogue of Leonard's 5-choice serial reaction time task for humans. Although the 6-OHDA DNAB lesion produced a profound depletion of cortical noradrenaline (NA) (to around 5% of control levels) it did not impair any aspect of performance on this task. Both systemic and intra-accumbens amphetamine increased behavioural measures of impulsivity of responding, but neither impaired discriminative accuracy in the sham-operated control rats. However, the DNAB lesioned rats did show a discriminative impairment following both low doses of systemic amphetamine, and intra-accumbens amphetamine. The latter effect was antagonised by systemic administration of the specific dopaminergic (DA) antagonist alpha-flupenthixol. The DNAB lesion did not alter the effect of amphetamine on any other behavioural measure, including speed and impulsivity of responding. These results suggest that although DA and NA participate in qualitatively different behavioural processes, the effects of DNAB lesions on attentional processes depend on the level of DA activity within the nucleus accumbens.
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  • 14
    ISSN: 1432-2072
    Keywords: Striatum ; Limbic ; Catalepsy ; GABA ; Muscimol ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To establish the role of the GABA-ergic mechanism within the striatal-pallidal complex in hindlimb disturbances, forelimb disturbances and catalepsy and the relationship between these phenomena, the effects of the locally injected GABA agonist muscimol (0.5 μl per side) were investigated in rats using several specific tests of catalepsy. The time required for retracting free-hanging hindlimbs was dose-dependently prolonged by 2–10 ng muscimol. The time required for releasing a rod that was clasped between the forelegs of otherwise free-hanging rats was dose-dependently prolonged by 5–10 ng muscimol. Likewise, the time required for retracting the free-hanging forelimbs was dose-dependently prolonged over the same dose range. Finally, the time during which standing rats kept their forelimbs on a block of 9 cm height (the dependent variable used in “classic” tests of catalepsy) was only prolonged at the highest dose (10 ng) of muscimol. The effects of the latter dose, which lasted at least 30 min, were inhibited by the GABA antagonist bicuculline (50 ng) for a minimum period of 5 min. The present data show that the GABA-ergic mechanisms within the striatal-pallidal complex are involved in hindlimb disturbances, forelimb disturbances and catalepsy, and that catalepsy requires a stronger dysfunctioning of these GABA-ergic mechanisms than do disturbances in hindlimbs and forelimbs.
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  • 15
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 92 (1987), S. 215-218 
    ISSN: 1432-2072
    Keywords: Ethanol ; Naloxone ; Locomotor activity ; Open field ; Active avoidance ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The action of naloxone (0.5 and 2 mg/kg IP) on the behavioural effects of a low (2 g/kg PO) and a high dose (4 g/kg PO) of ethanol was studied in rats. Ethanol at the low dose increased spontaneous motility, enhancing open-field external ambulations and reducing shuttle-box latency. All these effects were antagonized by naloxone. Ethanol at the high dose produced hypomotility, decreasing open-field external ambulations and impairing shuttle-box performance. In this case, naloxone also reduced the ethanol effect, but its action was less consistent. Therefore, although mechanisms other than a specific opioid receptor blockade by naloxone must be considered, an involvement of opioid peptides in the effects of ethanol cannot be discounted.
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  • 16
    ISSN: 1432-2072
    Keywords: Morphine dependence ; Withdrawal syndrome ; Locus coeruleus ; Norepinephrine, clonidine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Naloxone HCl (10 μg/0.5 ml) was injected in the locus coeruleus (LC) of morphine-dependent rats and the behavioural manifestations of morphine withdrawal and the cortical levels of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) were measured 30 min later. Naloxone precipitated a withdrawal syndrome and raised cortical MHPG-SO4 in animals made dependent by ascending doses of morphine for 11 days. An injection of clonidine intraperitoneally (200 μg/kg) or in the LC (5 μg/0.5 μl) blocked most aspects of the withdrawal syndrome except jumping and had no effect on the naloxone-induced rise in cortical MHPG-SO4. The findings confirm the hypothesis that the LC is one of the sites where naloxone and clonidine, respectively, precipitate and reduce the narcotic withdrawal syndrome but argue against a role of noradrenergic neurons originating in the LC and innervating the cortex in the ability of clonidine to suppress some aspects of withdrawal syndrome precipitated by naloxone in morphine-dependent animals.
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  • 17
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 93 (1987), S. 477-482 
    ISSN: 1432-2072
    Keywords: Cis-flupentixol ; Reinforced responding ; Motor effects ; Reinforcement efficacy ; Dopamine receptors (D1 and D2) ; Matching law equation ; Variable-interval schedule ; Water reinforcement ; Lever press ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We evaluated the effects of cis-flupentixol on reinforced responding. The experimental subjects were rats and the reinforced response was a lever press. The procedure was a five-component multiple schedule that provided five different reinforcement rates. Cis-flupentixol produced dose-dependent decreases in reinforced responding. An equation, the matching law, was fitted to the results. One parameter of this equation represents the estimated response rate asymptote. Cis-flupentixol produced dose-dependent decreases in the asymptotes. A second parameter of the equation represents the rate of reinforcement that maintains a one-half asymptotic response rate. Cis-flupentixol did not appear to affect this measure. There is evidence that the response rate asymptote measures motor components of response rate and that the reinforcement parameter measures the efficacy of the reinforcement maintaining the response. According to these results, cis-flupentixol systematically affected the motor-component of reinforced responding — it slowed down lever pressing — without affecting the subject's sensitivity to the reinforcer maintaining the response. In contrast, other neuroleptics have decreased the subjects' sensitivity to reinforcement, according to the matching law measures.
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  • 18
    ISSN: 1432-2072
    Keywords: Noradrenaline ; Dorsal noradrenergic bundle ; 6-Hydroxydopamine ; Operant behaviour ; Herrnstein's equation ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The possible role of the dorsal noradrenergic bundle (DNAB) in the maintenance of operant behaviour by positive reinforcement was examined using a quantitative behavioural paradigm based on Herrnstein's (1970) equation which defines a hyperbolic relationship between steady-state response rate and reinforcement frequency in variable-interval schedules. Twelve rats received bilateral injections of 6-hydroxydopamine (4 μg/2 μl) into the DNAB; ten rats received sham injections. The rats were trained to steady state in a series of six variable-interval schedules of sucrose reinforcement affording reinforcement frequencies of 8–350 reinforcers per hour. Herrnstein's equation was fitted to the data obtained from each rat and to the averaged data obtained from the two groups. The values of both R max (the parameter of the equation expressing the theoretical maximum response rate) and K H (the parameter expressing the reinforcement frequency needed to maintain the half-maximal response rate) were significantly higher in the DNAB-lesioned group than in the sham-lesioned group. At the end of the behavioural experiment the rats were sacrificed for determination of catecholamine levels in the brain by high-performance liquid chromatography. The levels of noradrenaline in the neocortex and hippocampus of the DNAB-lesioned rats were approximately 10% of those of the sham-lesioned rats. The results indicate that destruction of the DNAB reduced the “value” of the reinforcer without impairing the animals' capacity to respond.
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  • 19
    ISSN: 1432-2072
    Keywords: Place preference ; Heroin ; β-endorphin ; Naloxone ; Reward ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The role of β-endorphin as a possible mediator in the reinforcing properties of opiates was investigated using a conditioned place preference paradigm. Heroin, a synthetic opiate known to have reinforcing properties, produced a strong preference for an environment previously paired with heroin injection at all doses tested (0.25, 0.5, 1.0, 2.0 mg/kg SC). No such place preference was observed following saline injections. Rats also showed dose-dependent place preference for the environment paired with β-endorphin when injected intracerebroventricularly (significant dose was 2.5 μg). At higher doses (5.0 and 10.0 μg) rats showed no preference for the paired environment, but were catatonic. Pretreatment with naloxone (0.04, 0.2, 1.0 mg/kg SC) attenuated the rewarding effect of β-endorphin (2.5 μg) at all doses tested. The lowest dose of naloxone which had no aversive effect when tested alone could also significantly block the positive effect of β-endorphin. The reinforcing dose of β-endorphin (2.5 μg) also produced an increase in locomotor activity, when tested in photocell cages. This suggests that the hyperactivity induced by β-endorphin may contribute to the preference for an environment previously paired with the same drug. The reinforcing effect of β-endorphin is most probably mediated by the mu and/or delta opioid subtype receptor, since β-endorphin has a high affinity for these receptors. These results demonstrate positive reinforcing properties of β-endorphin in the central nervous system.
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  • 20
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 91 (1987), S. 239-243 
    ISSN: 1432-2072
    Keywords: Pimozide ; d-Amphetamine ; Operant behaviour ; Variable-interval schedules ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The interaction between pimozide (a selective D2-dopamine receptor antagonist) and d-amphetamine on the operant performance of rats maintained under variable-interval schedules of positive reinforcement was examined. In Experiment 1, eight rats responded under variable-interval 30-s and variable-interval 300-s. Pimozide (0.0625, 0.125, 0.25, 0.5 mg/kg) suppressed performance maintained under both schedules in a dose-dependent manner, the degrees of suppression being equivalent in the two schedules. In Experiment 2, 12 rats responded under the same schedules. d-Amphetamine (0.1–3.2 mg/kg) suppressed performance under both schedules, the degree of suppression being somewhat greater in the case of variable-interval 30-s. Pre-treatment with pimozide (0.0625, 0.125 mg/kg) significantly attenuated the suppressant effect of d-amphetamine under both schedules. It is suggested that D2-dopamine receptors may be involved in mediating the suppressant effect of d-amphetamine on operant behaviour.
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  • 21
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    Psychopharmacology 91 (1987), S. 316-319 
    ISSN: 1432-2072
    Keywords: Methamphetamine ; Sensitization ; Ontogeny ; Autoreceptor ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The behavioral effect of repeated methamphetamine (MAP) treatment was observed in young rat to establish the ontogenetic period crucial to methamphetamine sensitization. Animals were treated with MAP (2 mg/kg, SC) once daily for 5 days (Group 1: postnatal days 2–6, G-2: 7–11, G-3: 12–16, G-4: 17–21, G-5: 22–26, G-6: 27–31). Control animals were similarly treated with an equal volume of saline. On the 35th postnatal day, all rats were challenged with MAP (2 mg/kg, IP). Behavioral sensitization to MAP was not found in G-1, G-2, G-3 or G-4, although responsiveness to MAP was observed in rats after the 2nd postnatal day. The animals in G-5 and G-6 showed hypersensitivity to MAP in locomotor activity and stereotyped behavior. These findings indicate that the period crucial to behavioral sensitization to MAP corresponds to the period of presynaptic dopamine autoreceptor formation in the rat brain.
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  • 22
    ISSN: 1432-2072
    Keywords: DSP4 ; Noradrenaline ; d-Amphetamine ; Operant behaviour ; Variable-interval schedules ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of d-amphetamine (0.1–3.2 mg/kg) on performance in variable-interval 1-min and variable-interval 12-min schedules of positive reinforcement was examined in ten rats treated with the selective noradrenaline neurotoxin DSP4 and 12 control rats. In the control group d-amphetamine had a dose-dependent suppressant effect on response rates maintained under variable-interval 1-min; under variable-interval 12-min, response rates were increased by low doses and suppressed by higher doses of the drug. In the case of both schedules, lower doses of d-amphetamine were more suppressant and higher doses less suppressant in the DSP4-treated group than in the control group. The levels of noradrenaline in the parietal cortex, hippocampus and cerebellum (determined by high-performance liquid chromatography) were reduced to approximately 15% of control levels in the DSP4-treated rats. The results indicate that treatment with DSP4 attenuated both the facilitatory and the suppressant effects of d-amphetamine on variable-interval performance. A formal model couched in terms of Herrnstein's (1970) equation is put forward to account for these results. It is suggested that the noradrenergic pathways emanating from the locus caeruleus are involved in both the facilitatory and suppressant effects of d-amphetamine on operant behaviour.
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  • 23
    ISSN: 1432-2072
    Keywords: Antidepressants ; Ergometrine ; Neuroleptics ; Nucleus accumbens ; Locomotor activity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study assesses the behavioural significance of the (-)sulpiride binding sites in the rat nucleus accumbens that bind antidepressants with high affinity and neuroleptics with low affinity. The effects were measured by intra-accumbens injections of typical and atypical antidepressants or neuroleptics, either given alone or in combination with ergometrine (1 μg/0.5 μl per side) on rat locomotor activity in a familiar environment. In addition, the after-effects of the combined ergometrine-drug treatment upon locomotor activity were analyzed. The antidepressants shared a common profile of effects. Thus, none of the antidepressants significantly altered locomotor activity in naive rats. Moreover, each antidepressant produced after-effects which were similar to those elicited in the acute ergometrine experiments. However, some antidepressants (amitriptyline and zimelidine) potentiated the ergometrine response, while other antidepressants (desipramine, mianserin and clorgyline) attenuated this response. (-)Sulpiride (0.5 μg) decreased the ergometrine response when given together with ergometrine or 48 h earlier. Haloperidol had to be given in a dose that was 20 times higher than that of (-)sulpiride in order to be effective. Clozapine (1–10 μg) failed to alter the ergometrine response when given together with ergometrine. Only (-)sulpiride produced a dose-dependent attenuation of locomotor activity in naive rats. The present data are discussed in terms of the hypothesis that drugs with antidepressive effects mediate their behavioural effects via mesolimbic (-)sulpiride binding sites.
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  • 24
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    Psychopharmacology 92 (1987), S. 376-381 
    ISSN: 1432-2072
    Keywords: Conditioned place aversion ; Nicotine ; Rat ; Time-course ; Dose-response ; Chlorisondamine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats received subcutaneous injections of either nicotine (NIC; 0.05–0.8 mg/kg) or vehicle [VEH (phosphate buffer); 1 ml/kg] immediately after conditioning sessions in a place-conditioning paradigm (delay conditioning). NIC was paired for three delay-conditioning sessions with one environment of a three-compartment place-conditioning apparatus; VEH was paired with another environment. The subjects were then tested for place preference or aversion by determining the proportion of time spent in each compartment during a 15-min test session. Delay conditioning with NIC only produced a dose-related place aversion (greater time was spent in the VEH-paired chamber on test day). Place aversion was evident when NIC, 0.8 mg/kg, was administered either immediately or 5 min after conditioning sessions but not when given 15 min after conditioning. Chlorisondamine (5 μg, lateral ventricle), but not saline, administered 2 weeks prior to delay conditioning with 0.8 mg/kg NIC completely blocked the NIC-induced place aversion. These data suggest that delay conditioning with NIC produces place aversion by a central mechanism. Since standard conditioning (NIC injection immediately before the place-conditioning sessions) with NIC only produced dose-related place preferences (Fudala et al. 1985; Fudala and Iwamoto 1986), the time of administration of the unconditioned stimulus is a strong determinant of the place-conditioning effects of NIC.
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  • 25
    ISSN: 1432-2072
    Keywords: Diazepam ; Water intake ; Holeboard behaviour ; Decision making ; Operant behaviour ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Benzodiazepines, used in the clinic as anxiolytics, have in animal models been found specifically to attenuate behavioural suppression caused by response contigent aversive stimuli, non-reward or novelty. The effects have been interpreted in more general terms as “behavioural disinhibition” or “response perseveration” or in more specific terms as reduced “reward delay” or as an attenuation of a “behavioural inhibition system”. In a recent publication we have described an experimental test in which decision making in the rat can be studied. The model is derived from ethology, in particular from optimal foraging theory. In order to solve the task, the animal must choose correctly between two options. For each option the probability of its resulting in a reward (water) has to be estimated on the basis of available information and to be related to the cost of performing it. We found that diazepam, in a dose that did not significantly affect the ability to perform the options per se, caused a strong impairment when these options, on the basis of available information, had to be combined into functional sequences in a decision making procedure. The results obtained cannot be explained on the basis of disinhibition or response perseveration. The hypothesis is advanced that benzodiazepines alter decision making in a more nonspecific may, by, for example, affecting the evaluation of the learned significance of stimuli in the environment.
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  • 26
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    Psychopharmacology 91 (1987), S. 139-146 
    ISSN: 1432-2072
    Keywords: Autoreceptors ; Bromocriptine ; CQ 32-084 ; Dopamine ; Exploratory behaviour ; Mesulergine ; Multivariate statistics ; Pergolide ; 3-PPP ; Rat ; Sulpiride
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of six putative dopamine receptor agonists on exploratory behaviour in rats were assessed: pergolide, (+)- and (-)-3-PPP, bromocriptine, mesulergine and CQ 32-084. Behaviour was automatically recorded in a holeboard apparatus and the data were analysed by the novel multivariate statistical method of partial least squares. All six substances suppressed exploratory behaviour at low doses. Pergolide and (+)-3-PPP-induced stereotyped behaviour at higher doses. The suppression of exploration induced by pergolide was completely antagonised by sulpiride, partly antagonised by metoclopramide and weakly affected by haloperidol pretreatment. The effects of a low dose of (+)-3-PPP, bromocriptine or CQ 32-084, but not (-)-3-PPP or mesulergine, were antagonised by sulpiride. These findings support the hypotheses that pergolide, (+)-3-PPP, bromocriptine and CQ 32-084 inhibit exploration via stimulation of dopamine receptors. The present data do not substantiate the hypothesis that the suppression of exploration induced by (-)-3-PPP is mediated by stimulation of dopamine autoreceptors. A detailed analysis of the dose response curves for pergolide and (+)-3-PPP indicates that the latter compound may have effects in addition to those of a dopamine receptor agonist.
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  • 27
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    Psychopharmacology 91 (1987), S. 209-212 
    ISSN: 1432-2072
    Keywords: Intracerebral drug application ; Memory ; N. raphé magnus ; Clorgyline ; Pargyline ; Deprenyl ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Conditioned taste aversion (CTA) elicited by systemic or intracerebral application of the monoamine oxidase inhibitors clorgyline (C), pargyline (P) or deprenyl (D) was studied in 402 rats. Water-deprived animals were allowed 15 min access to 0.1% sodium saccharin (CS) followed 10 min later by IP or by intracerebral injection of the drug. In the latter case, the animals were anesthetized 5 min after saccharin drinking with pentobarbital and the drug was stereotaxically injected (1 μl/min, 1–2 μl) into the target structure. CTA was assessed in a two-choice retention test performed 2 days later. A geometric progression of three to six dosages applied to groups of rats (n=10) was employed to establish the effective doses of the drugs which were 4, 20 and 32 mg/kg with IP and 2.5, 10 and 80 μg per rat with intracerebral (n. raphé magnus) injections of C, P, and D, respectively. The ratios of intracerebral to systemic dosages eliciting comparable CTA were 1:300 for C, 1:800 for P and 1:100 for D. Injections of 2.5 μg C and 10 μg P into the mesencephalic reticular formation, medial hypothalamus and cerebral cortex were ineffective, as were injections of 10 μg P into the nucleus of the solitary tract and cerebellum. The results indicate that CTA is elicited more efficiently by inhibition of monoamine oxidase A (selectively inhibited by C) than of monoamine oxidase B (selectively inhibited by D).
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  • 28
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    Psychopharmacology 91 (1987), S. 248-253 
    ISSN: 1432-2072
    Keywords: Haloperidol ; Latent inhibition ; Conditioned ; suppression ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Latent inhibition (LI) is a behavioral paradigm in which prior exposure to a stimulus not followed by reinforcement retards subsequent conditioning to that stimulus when it is paired with reinforcement. Two experiments investigated the effects of 0.1 mg/kg haloperidol administration on LI as a function of number of CS pre-exposures. The investigation was carried out using a conditioned emotional response (CER) procedure consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where LI was indexed by animals' suppression of licking during tone presentation. The three stages were conducted 24 h apart. In Experiment 1, 40 CS pre-exposures were given. LI was obtained in both the placebo and haloperidol conditions, but the effect was much more pronounced under the drug. Experiment 2 used ten CS pre-exposures. LI was not obtained in the placebo animals but was clearly evident in animals injected with haloperidol. The implications of these findings for the effects of neuroleptics on learning are discussed.
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  • 29
    ISSN: 1432-2072
    Keywords: Dopamine receptors ; Striatum ; Denervation ; Supersensitivity ; Subsensitivity ; L-Dopa ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Denervation-induced supersensitivity of the striatal dopamine receptors can be quantified by the turning behaviour induced by apomorphine. With this experimental model we found that high-dose L-dopa/carbidopa administration reduced this supersensitivity. This effect was seen on the 1st day and did not alter over 5 or 10 days of treatment, but dissappeared when medication was discontinued. The degree of reduction was the same, independent of the dose and period of administration. This effect could provide a useful model for studying the phenomenon of the irreversibility of the supersensitivity of the striatal dopamine receptors.
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  • 30
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    Psychopharmacology 93 (1987), S. 19-24 
    ISSN: 1432-2072
    Keywords: Imidazole ; Imidazole derivatives ; Lisuride ; Sexual behaviour ; Aggressiveness ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Adult male rats were treated intraperitoneally (IP) with imidazole (IMID), distilled water or saline prior to administration of lisuride either IP or intracerebroventricularly (ICV) at doses too low by themselves to elicit the behavioural signs of mounting and aggressiveness, typically induced by higher doses of this drug. Pretreatment with distilled water or saline, or the procedure of injection alone, stimulated mounting in some of the animals. At a certain range of doses IMID induced a marked increase in both mounting and aggressive posturing in the same animals, while at higher doses mounting ceased, violent aggressive behaviour appeared and some of the rats died. Seven IMID derivatives were used on the lisuride-test: N-methylimidazole, 2-methylimidazole, 4-methylimidazole, N-acetylimidazole, 4-imidazoleacetic acid, clonidine and cimetidine. Only 4-imidazoleacetic acid was completely ineffective with respect to controls. All the other drugs enhanced aggressive behaviour to varying degrees but proved to be less potent than IMID in inducing mounting, and clonidine reduced mounting at all the doses tested.
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  • 31
    ISSN: 1432-2072
    Keywords: Pituitary-adrenal function ; Behavioral despair ; Clomipramine ; Anti-depressant ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The interaction between the effects of chronic electrical tail shock and clomipramine (CMI) on exploratory activity, behavioral despair and pituitary-adrenal function was studied in adult male rats. Both CMI and shock administered alone significantly reduced exploratory activity in a novel environment (holeboard). Neither interaction nor additive effects were observed when the two treatments were combined. In contrast, chronic shock increased the immobility in the forced swimming test (behavioral despair) and this effect was completely prevented by concomitant CMI administration. Pituitary-adrenal function was not significantly influenced by any of the treatments. The results indicate that: (a) chronic CMI treatment prevented some but not all behavioral changes caused by chronic shock, and (b) no interaction with basal and stress levels of pituitary-adrenal hormones was observed.
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  • 32
    ISSN: 1432-2072
    Keywords: LY165163 ; Stereotypy ; pCPA ; 5-MeODMT ; Apomorphine ; Serotonin ; Dopamine ; 5-HT1A agonists ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The putative serotonin (5-HT)1A agonist 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluormethylphenyl) piperazine (LY165163, PAPP) induces hyperphagia and hypothermia in rats, but unlike other 5-HT agonists, does not induce 5-HT stereotypy even at high doses (10 mg/kg sc). LY165163 (1 mg/kg) increased striatal DOPA accumulation in animals treated with the aromatic amino acid decarboxylase inhibitor 3-hydroxy-benzylhydrazine (NSD 1015) (100 mg/kg ip). This increase was also found when the drug was given to animals pretreated with parachlorophenylalanine (pCPA) (150 mg/kg ip daily for 3 days). LY165163 (2 and 4 mg/kg sc) inhibited stereotyped behaviour induced by the dopamine (DA) agonist apomorphine (2 mg/kg sc). LY165163 (2, 4, 10 mg/kg sc) also inhibited stereotyped components of the 5-HT syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 5 mg/kg ip) which previous studies (e.g. Andrews et al. 1982) suggested to require DA (head weaving, reciprocal forepaw treading). Thus, while other 5-HT1A agonists such as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) cause stereotypy, this does not occur with LY165163, probably because the drug blocks DA receptors.
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  • 33
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    Psychopharmacology 93 (1987), S. 113-117 
    ISSN: 1432-2072
    Keywords: Ro 5-4864 ; Clonidine ; B-HT 920 ; Guanfacine ; Benzodiazepines ; CL 218, 872 ; Pentobarbitone ; Yohimbine ; Idazoxan ; Convulsions ; Rat ; Mice
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The protective effect of various alpha2 adrenoceptor agonists such as clonidine, guanfacine, B-HT 920 and ICI 106270 was investigated against Ro 5-4864-induced convulsions in mice and rats. Clonidine and ICI 106270 exhibited a profound anticonvulsant effect while equivalent doses of guanfacine and B-HT 920 were less effective. The anticonvulsant effect of clonidine and ICI 106270 was reversed by pretreatment with yohimbine or idazoxan, indicating the involvement of alpha2 adrenoceptors in their protective effect. Diazepam, clonazepam, CL 218, 872 and pentobarbitone exhibited a different profile of protective action, as these agents protected the animals from apparent mortality as compared to clonidine and ICI 106270 which prolonged the latencies of jerk and convulsion. Modulatory effects of alpha2 adrenoceptors in central GABA function and multiple sites for Ro 5-4864-induced seizures are explained.
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  • 34
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    Psychopharmacology 93 (1987), S. 146-151 
    ISSN: 1432-2072
    Keywords: d-Amphetamine ; Adaptive behaviour ; Operant behaviour ; Decision making ; Water intake ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A complex laboratory task was used to test the effects of low doses of d-amphetamine on decision making in the white rat. In particular, the animals' ability to organize their behaviour into functional sequences was studied. The rats were required to choose between two options in order to obtain rewards (water). To solve the problem efficiently, the animal must correctly use information currently available about the reward probabilities and the response costs of the two activities. The results showed that already at a dose of 0.2 mg/kg, by comparison with control, the decision rule was significantly affected and the efficiency of the behaviour decreased. At 1 mg/kg, the rats were generally unable to organize their behaviour into functional sequences resulting in rewards even though they were able to perform the separate behavioural responses required to solve the task, as shown in separate control experiments. Low doses of d-amphetamine have previously been described to be “psychomotor stimulant” and, for example, to increase locomotion and exploration. Our conclusion is that these low doses do not increase behavioural output in an adaptive way. In simple tasks where motor output is directly related to a measure of performance, these doses might be interpreted as causing increased efficiency. However, when tested in our complex decision making task, these doses result in suboptimal behaviour.
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  • 35
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    Psychopharmacology 93 (1987), S. 182-187 
    ISSN: 1432-2072
    Keywords: Nomifensine ; B-HT 920 ; Dopamine receptors ; Conditioning ; Dopamine-mediated behaviours ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Conditioning of behavioural effects produced by two drugs acting differently upon dopaminergic neurotransmission was studied. Nomifensine and the putative dopamine autoreceptor agonist B-HT 920 produce contrasting effects on motility, namely increases in locomotor activity and stereotypies as compared to hypokinesia and ptosis. The administration of each of these drugs (US) was repeatedly associated with well-defined environmental stimuli (CS): a wire cage associated with an auditory and on olfactory stimulus. The rats were conditioned for 7 days with 20 mg/kg nomifensine IP each day. After conditioning, the rats were treated with the solvent alone in presence of the CS. Not only did sniffing and licking occur, but also gnawing, even though the latter response was not evident after acute administration of the drug or during the conditioning period. Nomifensine (20 mg/kg IP) also acutely decreased the ratio of 3,4-dihydroxyphenylacetic acid/dopamine concentrations (DOPAC/DOPAMINE); this ratio was not altered in the conditioned rats, 60 min after solvent administration in presence of the CS. Rats were conditioned with 0.02 mg/kg IP B-HT 920 daily for 8 days. During the conditioning phase, akinesia and ptosis showed a slight enhancement and a faster onset. After conditioning, when the rats were treated with the solvent alone, the majority of them showed akinesia and/or ptosis during the observation period, in contrast to pseudoconditioned controls. When these rats were conditioned or pseudoconditioned, respectively, with B-HT 920 for further 5 days using 0.02 mg/kg again, treatment with the same dose in presence of the CS produced a significant enhancement and acceleration of these signs in conditioned as compared with pseudoconditioned control rats. The results show that stereotypies producd by nomifensine and akinesia and ptosis produced by B-HT 920 can be conditioned and that, in addition, a sign of stereotypies which was not manifest during the conditioning period appeared as conditioned response.
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  • 36
    ISSN: 1432-2072
    Keywords: Anorexia ; Body weight ; Food intake ; Oestradiol benzoate ; Ovariectomy ; Cyproheptadine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Repeated bodily immobilization significantly reduced the food intake of ovariectomized rats. Additionally, immobilization and oestradiol benzoate were found to produce additive effects in depressing feeding. To determine whether serotonergic mechanisms are involved in the stress-and oestrogen-induced anorexia, the 5-HT antagonist cyproheptadine was given to ovariectomized rats that were immobilized and treated with oestradiol benzoate. Cyproheptadine had no effect on the anorexia produced by oestradiol. The food intake of immobilized rats treated with cyproheptadine was similar to control values, suggesting 5-HT involvement in the stress-induced anorexia. However, cyproheptadine had no ameliorating effects on the changes in body weight following immobilization treatment. The implications of these findings are discussed in relation to a possible neuroendocrine basis for anorexia.
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  • 37
    ISSN: 1432-2072
    Keywords: Behavioural tolerance ; Benzodiazepine ; Chlordiazepoxide ; Instrumental learning ; Rat ; Sedation ; Self-stimulation ; Tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Sedative and facilitatory effects on variable-interval hypothalamic self-stimulation were monitored during chronic treatment with chlordiazepoxide (CDP; 7.5 mg/kg IP), given at 48-h intervals in two groups of rats. Group 1 was injected immediately before each of 40 1-h self-stimulation sessions (“drugged responding”); Group 2 was injected after self-stimulation for the first 20 sessions (“undrugged responding”), and before self-stimulation for a further 20 sessions (“drugged responding”). Significant sedation occurred in both groups in initial sessions of drugged responding, even though Group 2 had already received 20 injections of CDP (after undrugged sessions). Sedative effects showed very rapid tolerance, and disappeared after 1–3 sessions, but only in rats which had been responding while drugged (and which thus had had opportunities to develop coping strategies against the sedative effects). After further sessions of drugged responding, sedation was replaced by apparently stimulant effects. Stimulant effects showed no tolerance at all in either group even after 40 injections, thus differing from anti-conflict (and other) effects of BZDs, which generally show gradual tolerance. These results show that coping strategies acquired by instrumental learning can account for rapid and selective tolerance to sedative effects. Coping strategies do not account for the differing rates of tolerance to stimulant and to other effects of BZDs; these differences may indicate pharmacologically distinct brain systems downstream from the BZD receptor.
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  • 38
    ISSN: 1432-2072
    Keywords: Yawning ; Apomorphine ; 6-Hydroxydopamine ; Autoreceptors ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Apomorphine-induced yawning was studied in male rats with bilateral 6-hydroxydopamine lesions of the substantia nigra. Apomorphine 10, 20 and 50 μg/kg SC induced dose-dependent yawning in unoperated controls and animals with sham lesions. In the lesioned animals (in which the mean striatal dopamine depletion was 67%), the maximum yawning response rate was greatly attenuated with no evidence that the dose response curve was shifted in either direction. Furthermore, blockade of yawning in the lesioned animals was not simply due to suppression by other stereotyped behaviours, since there was no evidence of increased sniffing or chewing in these animals. These data provide further support for the hypothesis that apomorphine-induced yawning is mediated by dopamine autoreceptors and requires intact nigrostriatal projections.
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  • 39
    ISSN: 1432-2072
    Keywords: Animal model ; Catalepsy ; Neuroleptics ; Paw test ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An often used animal model based on the effects of neuroleptics on spontaneous behaviour is the catalepsy test. However, this test seems to be particularly insensitive to the atypical neuroleptics thioridazine and, especially, clozapine. We have therefore developed an alternative test, the paw test, which measures the ability of drugs to prevent the spontaneous withdrawal of fore- and hindlimbs in rats, and have compared this with the classical catalepsy test. The results show that: 1) the classical neuroleptic drugs haloperidol and chlorpromazine, the atypical neuroleptic drugs clozapine and thioridazine, the potential atypical neuroleptic drugs molindone and SCH 23390, and the potential classical neuroleptic drug metoclopramide are potent in increasing the hindlimb retraction time; 2) the paw test discriminates between classical neuroleptics which are equipotent in prolonging both the forelimb (FRT) and hindlimb retraction time (HRT) and atypical neuroleptics which are much more potent in prolonging HRT than in prolonging FRT; 3) the non-neuroleptic drugs desipramine, diazepam and morphine do not influence the variables measured in the paw test, although morphine does produce catalepsy; 4) Molindone as well as SCH 23390 behave like atypical neuroleptic drugs in the paw test. In comparison with the classical wood block catalepsy test, the paw test is shown to be superior for predicting the profile of the neuroleptics tested. Although more neuroleptics and non-neuroleptics have to be tested to determine whether false positives and false negatives do occur, we feel that the paw test might be an interesting animal model, because the increase in hindlimb retraction time was associated with the antipsychotic potential, whereas the increase in forelimb retraction time was associated with the potential to induce so-called extrapyramidal side effects.
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  • 40
    ISSN: 1432-2072
    Keywords: 5-HT1A receptors ; Anxiolytics ; Interactions ; Feeding ; Rat ; 5-HT autoreceptors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of the novel anxiolytics gepirone, buspirone and ipsapirone on free feeding and on feeding induced by the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), were examined. Gepirone dose-dependently increased feeding 2 and 4 h after injection, the magnitude of the response being larger than previously observed with any other 5-HT1A receptor ligand. Previous studies have suggested that buspirone and ipsapirone can block some of the behavioural effects of 8-OH-DPAT. However, gepirone, buspirone and ipsapirone did not inhibit feeding induced by 8-OH-DPAT. These results indicate that gepirone is a very efficacious appetite stimulant in rats and suggest that gepirone, buspirone and ipsapirone act as 5-HT autoreceptor agonists in the feeding model.
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  • 41
    ISSN: 1432-2072
    Keywords: Animal model of depression ; DMI ; Stress ; Saccharin ; Sucrose ; Saline ; Preference ; Anhedonia ; Corticosterone ; Glucose ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats exposed chronically (5–9 weeks) to a variety of mild unpredictable stressors showed a reduced consumption of and preference for saccharin or sucrose solutions. Preference deficits took at least 2 weeks to develop and were maintained for more than 2 weeks after termination of the stress regime. Sucrose preference was unaffected by 1 week of treatment with the tricyclic antidepressant DMI but returned to normal after 2–4 weeks of DMI treatment. DMI did not alter sucrose preference in unstressed animals. No significant changes were seen in saline preference either during stress or following drug treatment. DMI reduced blood corticosterone and glucose levels, but stress did not significantly alter either measure. The results are discussed in terms of an animal model of endogenous depression.
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  • 42
    ISSN: 1432-2072
    Keywords: Methiothepin ; 2-Deoxy-d-glucose ; Glucose utilization ; Brain metabolism ; Behavior ; Serotonin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Local cerebral glucose utilization (LCGU) was measured, using the quantitative autoradiographic [14C]2-deoxy-d-glucose method, in 92 discrete brain regions of awake rats, at 1, 2, 3, or 4 h after administration of the serotonergic antagonist methiothepin 0.1 mg/kg IP. The drug produced a cataleptic behavior that peaked in intensity at 3 h after its administration. LCGU declined significantly in 35% of the 92 regions at one or more time points after methiothepin administration. No area of increased metabolism was found. The time-course of the decline in LCGU closely paralleled the intensity of catalepsy; the peak effect was at 3 h, when LCGU was significantly reduced in 32% of the regions examined (mean decline for all regions was 15%). Metabolic depression after methiothepin was most notable in the forebrain, where LCGU declined in many regions of the cerebral cortex, basal ganglia, and thalamus. Most of the regions affected by methiothepin possess a substantial number of serotonin receptors, although LCGU was also reduced in a few regions not primarily involved in serotonergic neurotransmission.
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  • 43
    ISSN: 1432-2307
    Keywords: Human ; Rat ; Breast ; Mammary
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Normal human breast organoids, derived by collagenase digestion of reduction mammaplasty tissue specimens, have been cultured in vitro for up to 28 days after injection into organ cultures of virgin rat mammary fat pads. The culture medium was serum-free Waymouth's MB 752/ 1 with hormonal additives. The rat mammary tissue responded well to growth-promoting and lactogenic stimuli in the culture medium, in agreement with previous investigations. Using immunohistochemistry casein was identified in rat epithelia exposed to lactogenic medium. Human organoids in culture remained viable but did not show hormone-responsiveness. Electron microscopy confirmed the presence of both luminal epithelial cells and myoepithelial cells. The serum-free culture of normal human breast organoids in a three-dimensional matrix provides a system in which to study factors controlling growth and differentiation.
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  • 44
    ISSN: 1432-1912
    Keywords: Substance P ; Neurokinin A ; Intrathecal injection ; Sciatic nerve transection ; Scratching, biting and licking response ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of unilateral sciatic nerve transection on behavioural responses produced by intrathecal administration of substance P (SP), neurokinin A, eledoisin and physalaemin was investigated in the rat. The injection of SP (3 nmol/rat) into the subarachnoid space was followed by reciprocal scratching, biting and licking of the fore- and hind-limbs. There was no observable difference in the behavioural response to SP between rats with nerve transection and sham operated rats at 5 days after operation. Whereas at 10, 20, and 30 days after nerve transection the response to SP was significantly increased as compared with sham operated rats. This phenomenon was also observed with neurokinin A (1.5, 3.0 and 6.0 nmol/rat), eledoisin (0.05 and 0.10 nmol/rat) and physalaemin (0.05 and 0.10 nmol/ rat) at 10 days after operation. Ipsilateral depletion of SP from the lumbar (L4-L6) spinal cord was observed at 5, 10, 20, and 30 days after the unilateral transection of the sciatic nerve. These results suggest that sciatic nerve transection may produce an increased response to tachykinins through an enhanced sensitivity of tachykinin receptors in the lumbar cord.
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  • 45
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    Journal of molecular evolution 24 (1987), S. 260-271 
    ISSN: 1432-1432
    Keywords: Mouse ; Rat ; Two-dimensional electrophoresis ; Quantitative variability of proteins ; Qualitative variability of proteins ; Protein classes ; Membrane proteins ; Organ-specific proteins ; Regulatory genes ; Speciation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Proteins of membranes and cytosols were extracted from the livers and brains of mice (inbred strain DBA/6J) and rats (inbred strain DA/Han) and separated by two-dimensional electrophoresis (2-DE). The 2-DE patterns were compared with regard to qualitative (spot position) and quantitative (spot intensity) characteristics of the proteins of these two species. The following results were obtained: (1) Brain had more (higher percentage) conservative proteins (proteins found in both mice and rats) than liver; (2) plasma membranes had more conservative proteins than the cytosols; (3) organ-unspecific proteins contained more conservative proteins than relatively organ-specific proteins; (4) the pattern of distribution of genetic variability among different classes of proteins represented by findings 1–3 was the same for the qualitative and quantative characteristics of the proteins; and (5) some observations indicated that quantitative variability occurred more frequently among proteins than did qualitative variability. Our conclusion is that regulatory sequences in the DNA (regulatory genes) are subjected to functional constraints that differ in strength among different classes of proteins by the same ratios as the constraints acting on the structural genes. The overall effect of the selective pressure is, however, less stringent for regulatory genes than for structural genes. The results obtained here by comparing two different species are very similar to previous results we obtained by studying different subspecies (inbred strains of the mouse). From this finding arises a new concept: the study of molecular evolution on the basis of different classes of proteins. Our results were compared with data from the literature that were obtained in part from studies on cultured cells. The comparison suggested that cultured cells have lost their tissue-specific proteins, and so generate predominantly extremely conservative proteins.
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  • 46
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    Pediatric nephrology 1 (1987), S. 498-501 
    ISSN: 1432-198X
    Keywords: Hydronephrosis ; Vasoconstriction ; Renin-angiotensin system ; Prostaglandins ; Indomethacin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We studied the effects of inhibition of either prostaglandins or the role of prostanoids and the renin-angiotensin system on renal function in rats with congenital unilateral hydronephrosis. Wistar rats with congenital unilateral hydronephrosis were infused with normal saline (control), captopril dissolved in normal saline or indomethacin dissolved in a solution of sodium chloride and sodium carbonate. In the control group both glomerular filtration rate (GFR) and effective renal plasma flow were reduced in the right hydronephrotic kidney (RHK) compared with the normal left kidney. Indomethacin did not improve renal function in the RHK. Captopril significantly improved GFR in the RHK. These results support the conclusion that the renin-angiotensin system is an important mediator of reduced GFR in congenital unilateral hydronephrosis in rats.
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  • 47
    ISSN: 1432-1912
    Keywords: (±)-Baclofen ; Micturition reflexes ; Rat ; Pelvic ganglia ; GABA B receptors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. The effect of (±)-baclofen on micturition reflexes was investigated in urethane-anaesthetized rats. A ‘low’ dose of (±)-baclofen (0.5 mg/kg i.v.) barely affected the early phase of the transurethral cystometrogram (CMG) which involves activation of a spinal vesico-vesical excitatory reflex. 2. At a higher dose (2.5 mg/kg i.v.) (±)-baclofen suppressed both the spinal and supraspinal components of the bladder response to transurethral saline filling. 3. When the bladder was filled by the transvesical route a series of regular voiding cycles was obtained which are due to activation of a supraspinal vesico-vesical excitatory reflex. In this model, voiding efficiency of the rat bladder was markedly reduced even after a low dose of (±)-baclofen (0.5 mg/kg) and almost suppressed at 2.5 mg/kg. 4. (±)-Baclofen reduction of voiding efficiency was mainly ascribable to an inhibitory effect on the expulsive phase of the voiding cycle which, in rats, depends critically upon the activation of a reflex which induces a twitch-like contraction of urethral/periurethral skeletal muscles. 5. (±)-Baclofen produced a small inhibition of the pinching-induced somatovesical excitatory reflex. (±)-Baclofen (2.5 mg/kg i.v.) produced also a marked but transient inhibition of bladder contractions induced by preganglionic nerve stimulation. However the time course of this effect was markedly shorter as compared to the long lasting suppression of voiding cycle observed with this same dose of the drug. 6. (−)-Baclofen, which is more potent than (±)-baclofen as a GABA B receptor agonist, affected bladder response to transurethral or transvesical filling in a manner similar to that observed with the racemate, but at lower doses (0.1–0.5 mg/kg i.v.). 7. These findings indicate that: a) (±)-baclofen affects markedly various types of reflexes concerned with micturition; b) a central site seems the main determinant of its action; c) at a low dose level inhibition of the reflex activation of urethral/periurethral skeletal muscles rather than the detrusor is a main target for (±)-baclofen action and d) GABA B receptors may modulate excitatory neurotransmission in rat pelvic ganglia.
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  • 48
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    Naunyn-Schmiedeberg's archives of pharmacology 335 (1987), S. 255-260 
    ISSN: 1432-1912
    Keywords: Tyramine ; Neuropeptide Y ; Calcium-independence ; Desipramine ; Norepinephrine ; Vas deferens ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of tyramine on the isolated vas deferens of rats was investigated. Tyramine induced a dose-dependent contraction which was blocked by phentolamine and disappeared in adrenergic denervated tissues. In the presence of an antiserum to neuropeptide Y (NPY), the contraction induced by concentrations of tyramine greater than 10 μM was markedly increased. In addition to inducing the release of 3H-norepinephrine (NE), tyramine evoked a concentration-dependent efflux of NPY-like immunoreactivity (NPYLI) from synaptosomal preparations. This action was not modified either by the removal of calcium ion from the medium or by the pretreatment with tetrodotoxin (0.5 μM). Desipramine suppressed the NPY-LI release induced by tyramine apparently by the inhibition of the uptake of tyramine is suggested by the significant positive correlation between the reduction of 4C-tyramine uptake and the inhibition of NPY-LI release induced by desipramine (r = 0.946). Therefore, we suggest that tyramine does induce the release of NPY from rat vas deferens, in addition to effecting NE secretion.
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  • 49
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    Naunyn-Schmiedeberg's archives of pharmacology 336 (1987), S. 670-676 
    ISSN: 1432-1912
    Keywords: Vascular smooth muscle ; Calcium entry blockers ; Rat ; Depolarisation ; Serotonin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of the calcium entry blockers verapamil (V), diltiazem (D), nifedipine (NF) and nicardipine (NC) have been studied on calcium concentration-effect curves elicited in depolarized (K+, 40 mmol/l) and in serotonin-exposed (6 μmol/l) rat middle cerebral arteries (RMCA) in order to compare the relative potencies of the blockers against these two calcium channel activating mechanisms. In control conditions, Ca2+ sensitivity expressed as pD2 and maximal active wall tension (AWT) were not significantly different in depolarized and in 5-HT-exposed vessels: pD2: 3.39 ±0.08 vs 3.50 ± 0.06 and AWT: 0.93 ± 0.15 mN · mm−1 vs 0.90 ± 0.16 mN · mm−1 respectively. V, D, NF and NC displaced Ca2+ control curves to the right and depressed the maximum contractile response in the two experimental conditions, which suggests a noncompetitive type of antagonism. All the blockers were more potent inhibitors of Ca2+-induced contractions in depolarized than in serotonin-exposed middle cerebral arteries. The IC50 values (concentration of blockers producing a 50% inhibition of maximal control contractile response) were (nmol/l) : V = 20, D = 120, NF = 0.4, NC = 1 and V = 400, D = 10000, NF = 20, NC = 7 in depolarized and serotonin-exposed arteries respectively. From these IC50 values, the relative order of potency of the CEB's was not the same in the two experimental conditions suggesting that while serotonin and K+ both promote the entry of Ca2+ into vascular smooth muscle cells of RMCA, they either activate a different gating mechanism associated with a single common channel or perhaps distinct channels. Comparison of the results obtained in this study for depolarized rat middle cerebral arteries with those previously obtained in depolarized rat mesenteric resistance arteries (RMRA) revealed that while Ca2+-induced contractile responses were inhibited in a similar non-competitive manner by the four CEB's, the respective IC50 values showed that potencies and rank of relative potency of the blockers were different in the two types of vessels. D and NC were equally potent in both preparations (IC50 ratio = 2.5 and 3 respectively) but RMCA were more sensitive to V and NF than RMRA (IC50 ratio = 6.5 and 11 respectively). These results are discussed and it is proposed that regional differencies in the conformation and/or the activation of the voltage-gated Ca2+ channels may exist in different vascular beds.
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  • 50
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    Archives of toxicology 59 (1987), S. 341-345 
    ISSN: 1432-0738
    Keywords: Rat ; Lead ; Brain ; Myelin basic protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Postnatal exposure of rats to lead has been shown previously to cause CNS hypo-myelination. Since rats intoxicated with lead often show retarded growth, the superimposed malnutrition, which as such can cause hypomyelination, may contribute to myelin deficit. In the present study control rats and lead exposed rats which did not have any retardation of growth were examined by radioimmunological assay of myelin basic protein (MBP) of homogenates of cerebrum and cerebellum at 30, 60 and 120 days of age. Lead was administered on postnatal days 1–15 by daily intraperitoneal injections of 10 mg lead nitrate/kg body weight. This lead dose results in light microscopically discernible hemorrhagic encephalopathy in the cerebellum of 15-day old rats, but does not induce growth retardation (Sundström et al. 1983). The controls were injected with vehicle only. The amount of lead in the blood and brain homogenates of lead-exposed and control rats 15–200 days old was estimated by atomic absorption spectrophotometry. Significant differences between the lead-exposed and control rats were not found in the cerebral or cerebellar content of MBP. Considering the results of previous investigations, the findings do not exclude a hypo-myelinating effect of lead, but they suggest that exposure to lead without concomitant malnutrition does not cause hypo-myelination in the cerebrum and cerebellum of the developing rat.
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  • 51
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    Archives of toxicology 60 (1987), S. 77-80 
    ISSN: 1432-0738
    Keywords: n-Hexane ; Pharmacokinetics ; Man ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of inhaled n-hexane in rat and man were compared. In the rat metabolism was saturable. Up to 300 ppm, the metabolic rate was directly proportional to the concentration in the atmosphere, reaching 47 μmol/(h· kg). Only 17% of n-hexane was exhaled unchanged. Above 300 ppm, the amount of n-hexane in the body rose with increasing atmospheric concentrations from 1.6 up to a limiting value of 9.6, which corresponded to the thermodynamic distribution coefficient of n-hexane between the organism and the atmosphere. Up to 3000 ppm, the rate of metabolism increased to 245 μmol/ (h· kg); only a slow further increase was found up to 7000 ppm (285μmol/(h· kg)). In man the steady-state concentrations of n-hexane were about 1 ppm. The metabolic clearance was 1321/h, and n-hexane accumulated to a factor of 2.3 in the organism. The thermodynamic distribution coefficient was calculated to be 12. Twenty per cent of n-hexane in the body was exhaled unchanged. At low concentrations the rate of metabolism of n-hexane is limited in both species by transport to the enzyme system. Under these conditions the rate of metabolism of n-hexane should not be influenced by xenobiotics which induce the n-hexane metabolizing enzyme system.
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  • 52
    ISSN: 1432-0738
    Keywords: Drug-metabolizing enzymes ; Liver ; Rat ; Hepatocarcinogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The expression, inducibility, and regulation of four different cytochrome (cyt.) P-450 isoenzymes (PB1, PB2, MC1, and MC2) NADPH-cytochrome P-450 reductase, the glutathione transferases (GSTs) B and C and microsomal epoxide hydrolase (mEHb) have been studied during nitrosamine-induced hepatocarcinogenesis using immunohistochemical techniques. The investigations revealed basic differences in the expression of the individual drug metabolizing enzymes in the course of neoplastic development. While the two GSTs and mEHb were increased in all preneoplastic and benign neoplastic lesions, the levels of the distinct cyt. P-450 isoenzymes were characteristically different from each other. Following initial changes in the expression of these enzymes in early preneoplastic lesions (i. e., increase of cyt. P-450 PB1 versus slight decrease of the other cyt. P-450 isoenzymes), a continuous reduction of all cyt. P-450 isoenzymes was observed during the further course of hepatocarcinogenesis. In progressed neoplastic nodules, all cyt. P-450-isoenzymes and NADPH cyt. P-450 reductase were decreased to varying extents. Treatment of animals with inducers of the monooxygenase system, such as phenobarbital, 3-methylcholanthrene and polychlorinated biphenyls, led to a rather heterogenous pattern of enzyme alterations in preneoplastic and neoplastic lesions. Following administration of phenobarbital, some islets responded to the same degree as the surrounding tissue, others were less or not at all inducible and a few of the lesions showed a prominent increase in cyt. P-450 PB2 and NADPH-cyt. P-450 reductase levels. The interesting finding that these two enzymes always showed concurrent changes may be indicative of a common regulation. Similar to phenobarbital, an induction of cyt. P-450 isoenzymes within carcinogen-induced lesions was also observed following administration of 3-methyl-cholanthrene or polychlorinated biphenyls. The results demonstrate that drug-metabolizing enzymes are abnormally regulated in carcinogen-induced lesions. The multiplicity of enzyme deviations within individual lesions and especially the enzyme inducibility strongly suggest that the focal enzyme alterations result from genotoxic effects of the carcinogen on regulatory systems of a higher order rather than from mutational events in individual structural genes.
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  • 53
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    Acta neuropathologica 75 (1987), S. 41-45 
    ISSN: 1432-0533
    Keywords: Cerebellar hypoplasia ; Critical period ; Hyperbilirubinemia ; Purkinje cell ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The critical period of Purkinje cell degeneration and cerebellar hypoplasia due to bilirubin was examined in rats with transient hyperbilirubinemia induced by a serial subcutaneous injection of novobiocin from 1 to 3, 5 to 7, 10 to 13, or 16 to 20 days after birth. Animals showing total plasma bilirubin levels of 5 to 7 mg/100 ml 6 h after the final injection were used for this study. In nearly midsagittal sections of the culmen, the percentage of the affected Purkinje cells was 0.9%, 17.1%, 0% and 0% at days 3, 7, 13 and 20, respectively. Thus, the Purkinje cells were most vulnerable to bilirubin between days 5 and 7. Cerebella from the rats which showed transient hyperbilirubinemia at day 3, 7, 13 or 20 were weighed at day 30. The cerebellar weight was significantly low only in rats showing hyperbilirubinemia at day 7. Thus, the critical period of the cerebellar hypoplasia due to bilirubin coincided with the period when the Purkinje cells were most sensitive to bilirubin. These results suggest that the Purkinje cell damage leads to the cerebellar hypoplasia in hyperbilirubinemia.
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  • 54
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    Acta neuropathologica 75 (1987), S. 116-122 
    ISSN: 1432-0533
    Keywords: Rat ; Lead ; Brain edema ; Electron microscopy ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Newborn rats were exposed to daily intraperitoneal injections of 10 mg lead nitrate per kg body weight for the first 15 postnatal days. The growth and mortality of the lead-exposed animals did not differ from their control litter-mates, injected with vehicle only. In our previous studies, focal hemorrhages and spongy areas as well as breakdown of blood-brain barrier to plasma proteins were shown by light microscopy in the cerebellar parenchyma of 15-day-old rats exposed to this dose. In spite of these signs of edema, measurements of brain tissue specific gravity did not show increased water content. In the present investigation we examined the ultrastructure of the brain lesions in these rats with low-dose lead encephalopathy, focusing on signs of edema, and evaluated astroglial reaction by immunocytochemical staining for glial fibrillary acidic protein (GFAP). The electron microscopic findings were compatible with extracellular edema in the cerebellum of 15-day-old lead exposed rats. The number of GFAP-positive cell bodies in the gray substance of the cerebellar cortex was increased in the 15-day-old lead-exposed rats as compared with the controls of the same age, a finding which is presumably related to the leakage of plasma proteins. Both these findings were lacking at 20 days of age, suggesting reversibility of the lead-induced changes.
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  • 55
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    Anatomy and embryology 177 (1987), S. 183-188 
    ISSN: 1432-0568
    Keywords: Glia ; Cerebellum ; Rat ; Development ; Morphometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Bergmann glial (Golgi epithelial) cells in the cerebella of rats of various ages were stained by the rapid Golgi technique, and their radial stem processes were measured for length and diameter. Additionally, the average number of such processes per cell was counted, and the development of bushy lateral protrusions was quantified. The length of radial processes—depending on the thickness of the molecular layer—was found to increase up to the end of the 2nd year of life. This elongation was accompanied by a reduction of the mean process diameter which was, however, not sufficient to prevent an increase in the cytoplasmic volume of the elongating cells. A marked outgrowth of lateral protrusions was observed up to at least the 5th month of life. These data are compared with earlier findings on the development of rat brain stem fetal radial glia, and of rabbit retinal Müller cells. Common mechanisms of glial cell development are discussed.
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  • 56
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    Anatomy and embryology 175 (1987), S. 477-487 
    ISSN: 1432-0568
    Keywords: Cochlea ; Development ; SEM ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Maturation of the rat cochlea, from postnatal days 2 to 60, was studied using scanning electron microscopyt (SEM), with emphasis on stereocilia and tectorial membrane (TM). Two days after birth, the organ of Corti was very immature. An adult appearance of its surface was observed by day 16 in the basal turn, and by the end of the 3rd postnatal week in the apex. Stereocilia started their development first on inner hair cells. By contrast, the apical pole of outer hair cells ended its maturation before that of inner hair cells. Top-links were detected very early in inner hair cell stereociliary development (postnatal day 2). Marginal pillars temporarily attached the TM to the organ of Corti; they disappeared first in the apical region. This transient attachment seems to play a role in the coupling of outer hair cells to the TM, as prints of their longest stereocilia appeared at the undersurface of the TM by the same time. Moreover, these prints were more clear and regular at the base than at the apex of the cochlea. Results are discussed in relation to ultrastructural and functional data on rat cochlea maturation.
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  • 57
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    Anatomy and embryology 176 (1987), S. 303-311 
    ISSN: 1432-0568
    Keywords: Nonspecific cholinesterase ; Neural crest ; Mandibular process ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Cholinergic traits in rat mandibular processes were examined histochemically, under the electron microscope, scope, at early developmental stages (Stages 20 to 23, by Christie's nomenclature). The histochemical reaction for detection of enzymes was performed by the thiocholine method. Nonspecific cholinesterase (EC 3.1.1.8) activity was found in ectomesenchymal cells, vascular endothelial cells, and in some epidermal cells at stages 20 and 21. The enzymatic activity was localized in the perinuclear and endoplasmic reticular cisternae. At stage 22, the number of cells with enzymatic activity decreased gradually, except in the case of the capillary endothelial cells. At stage 23, when the trigeminal nerve fiber was obvious in the mandibular processes, nonspecific cholinesterase activity was restricted to some of the endothelial cells and trigeminal ganglionic cells. In contrast, acetylcholinesterase activity was found on the membrane of trigeminal nerve fiber. Thus, the transient, nonspecific, cholinesterase activity, found in rat mandibular processes, may serve some functions in transmission, lipid metabolism or destruction of toxic cholinesters during the period that precedes organogenesis.
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  • 58
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    Anatomy and embryology 176 (1987), S. 367-372 
    ISSN: 1432-0568
    Keywords: Cajal-Smirnow ansiform fibers ; Mossy fibers ; Axonal guidance ; Cerebellar cortex ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The present light and electron microscopic study deals with the morphology and organization of Cajal-Smirnow ansiform fibers (AFs) in the molecular layer of the cerebellar cortex. The cerebella of normal adult rats were processed with Cajal's reduced silver method and conventional electron microscopy. With the silver method AFs appear as isolated elements or, more frequently, as small bundles of myelinated fibers, which emerge from the medullary rays, ascend through the granular, Purkinje cell and molecular layers and curve back to reenter the granular layer or cerebellar white matter. They traced an arciform trajectory of variable width and height in the molecular layer. Relatively large bundles of AFs were rarely found. The occurrence of AFs was confirmed in semithin sections as myelinated fibers of variable diameter ranging from 1 to 6 μm. Oligodendrocytes were often observed near AFs. At the ultrastructural level, the most common type of AF is large, with a relatively thin myelin sheath and a moderately dense axoplasm. Nodal or terminal synaptic differentiations were not observed. We suggest that AFs are misoriented cerebellar mossy fibers and their occurrence may be the consequence of a small-scale error in the axonal guidance of growing mossy fibers.
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  • 59
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    Anatomy and embryology 177 (1987), S. 37-49 
    ISSN: 1432-0568
    Keywords: Pudendal nerve ; Onuf's nucleus ; Spinal cord ; Rat ; HRP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Central distribution of efferent and afferent components of the pudendal nerve was examined in the rat by the horseradish peroxidase (HRP) method after HRP application to the central cut end of the pudendal nerve. The pudendal motoneurons were located in the dorsolateral, dorsomedial and lateral groups at L5 and L6. Each of the dorsolateral and dorsomedial groups constituted a slender longitudinal cell column. Pudendal motoneurons in the lateral group were scattered at L5, rostrodorsally to the dorsolateral group. The neurons in the dorsolateral and lateral groups were labelled with HRP applied to the nerve branch innervating the ischiocavernosus and sphincter urethrae muscles. The neurons in the dorsomedial group were labelled with HRP applied to the branch supplying the sphincter ani externus and bulbospongiosus muscles. Some dendrites of pudendal motoneurons in the dorsomedial group extended to the contralateral dorsomedial group. These crossing dendrites were observed not only in male rats but also in female. The average number of the pudendal motoneurons in the dorsolateral and dorsomedial groups were larger in male rats than in female. A few neurons of the intermediolateral nucleus at upper L6 were also labelled with HRP applied to the dorsalis penis (clitoridis) nerve. Axon terminals of the pudendal nerve were distributed, bilaterally with an ipsilateral predominance, to the gracile nucleus, as well as to the dorsal horn and dorsal commissural gray from L4 to S2. A few labelled axons were seen in the intermediolateral nucleus at L6 and S1. Axon terminals from the dorsalis penis nerve were distributed more medially in the dorsal horn than those from the perinealis nerve.
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    Acta neuropathologica 72 (1987), S. 335-340 
    ISSN: 1432-0533
    Keywords: Glycogen ; Synapses ; Clarke's nucleus ; Nerve injury ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Glycogen accumulation in the Clarke's nucleus neuropil of young adult rats whose sciatic nerves were crushed in the first postnatal day was investigated with the electron microscope. Glycogen was observed in synaptic boutons and in small myelinated axons. In some terminals, glycogen accumulated in membranebound structures resembling mitochondria and formed large multigranular bodies which were entirely separated from the axoplasm. The multigranular body reached the size of 1.3 μm. Glycogen was present as single beta particles of about 25–40 nm in diameter and in aggregations of large alpha clusters. The astrocytic glycogen distribution was almost similar to that of the control specimens. Glycogen was not observed in other glial cells. It is probable that glycogen accumulation in synaptic terminals of partially deafferentiated Clarke's nucleus may result from impaired glycolysis due to deficient resupply of the distal axon with glycolytic enzymes caused by a defect in axoplasmic transport from the hypoplastic sensory neuronal perikarya.
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  • 61
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    European journal of clinical pharmacology 31 (1987), S. 583-588 
    ISSN: 1432-1041
    Keywords: cotinine ; pharmacokinetics ; non-smokers ; absolute bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cotinine, the main metabolite of nicotine, was administered intravenously to healthy male non-smoking volunteers in doses of 5, 10 and 20 mg, and orally in doses of 10 and 20 mg. Intravenous administration was characterized by a dose-independent half-life of 12.2 h, mean residence time of 15.9 h, total clearance of 3.64 l h−1 and a volume of distribution of 56.5 l. Renal clearance was 0.46 l h−1 and approximately 12.0% of the dose was excreted unchanged in the urine. The mean absorption time after oral dosing ranged between 1 and 3 h, the peak concentration was reached within 45 min and the mean elimination half-lives were 12.9 and 11.7 h, respectively, after the 10 and 20 mg doses. Systemic bioavailability ranged between 0.84 and 1.11 following 10 mg and between 0.97 and 1.03 following the 20 mg dose. Mean urinary recovery and renal clearance were almost identical with the values after iv administration.
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  • 62
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    European journal of clinical pharmacology 31 (1987), S. 595-600 
    ISSN: 1432-1041
    Keywords: caffeine ; exercise ; obesity ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of obesity, exercise, and the interaction of obesity and exercise were examined in 6 caffeine naive, untrained, nonsmoking, college males (3 lean (LV), 3 obese (OV)). Each subject received caffeine (oral, 5.83 mg·kg−1 lean body weight) or placebo (50 mg citrate) prior to 3 h of seated rest and prior to 90 min of treadmill walking (40% of their maximal aerobic power) followed by 90 min of seated recovery. Serum samples were collected at various times and analyzed for caffeine by HPLC. Pharmacokinetic analysis indicated that at rest, OV had a significantly higher absorption rate constant (Ka 0.0757 vs. 0.0397 min−1), lower elimination rate constant (Ke 0.0027 vs. 0.0045 min−1), and longer serum half-life (t1/2 4.37 vs. 2.59 h) in comparison to LV. In exercise, as well as at rest LV and OV had a large difference in the volume of distribution (43.2 vs. 101. 1) (rest, 54.1 vs. 103.1). Exercise consistently resulted in a decrease in the maximal serum concentration of caffeine and the area under the curve in OV while having no consistent effect on LV. The interactive effects of obesity and exercise could not be dissociated. However, these results demonstrate that both obesity and exercise have modified the pharmacokinetics of caffeine.
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  • 63
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    European journal of clinical pharmacology 31 (1987), S. 617-619 
    ISSN: 1432-1041
    Keywords: chronopharmacology ; indomethacin ; suppository ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single 100 mg indomethacin suppository were studied in 12 healthy volunteers on two occasions at least 7 days apart. Suppositories were administered in randomised order at 9.00 and 21.00 hours to see if there was evidence of a diurnal variation in kinetic parameters. The study failed to show a significant change in single dose kinetics with the time of suppository administration. This is in contrast to previous work [1] demonstrating a circadian rhythm in the kinetics of a single oral dose of indomethacin. This suggests that the chronopharmacokinetics of indomethacin is dependent on the function of the upper gastrointestinal tract.
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  • 64
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    European journal of clinical pharmacology 31 (1987), S. 625-627 
    ISSN: 1432-1041
    Keywords: verapamil ; breast milk ; norverapamil ; breast feeding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The concentrations of verapamil and norverapamil have been measured in milk and plasma samples from a 32year-old woman treated with verapamil 80 mg tds while breast-feeding her child. The average steady-state concentrations of verapamil and norverapamil in milk were, respectively, 60% and 16% of the concentrations in plasma. The breast-fed child received less than 0.01% of the dose of verapamil given to the mother. No verapamil or norverapamil (〈1 ng/ml) could be detected in the plasma from the child.
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  • 65
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    European journal of clinical pharmacology 31 (1987), S. 701-704 
    ISSN: 1432-1041
    Keywords: theophylline ; miocamycin ; drug interaction ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interaction between a new macrolide antibiotic, miocamycin, and theophylline was evaluated in a single cross-over study in 5 asthmatic children. Each patient received a single dose of theophylline (4.3 mg/kg) delivered in 15 min using a constant-rate infusion pump, immediately before and after a 10 day course of miocamycin 17.5 mg/kg b.d. The pharmacokinetics of theophylline were calculated for each phase of the study. The elimination rate constant (3.92 vs 3.74 h−1), the mean total body clearance (1.71 vs 1.8 ml·min·kg−1) and the mean apparent volume of distribution (0.57 vs 0.58 l·kg−1) did not differ. The result can be explained by the inability of the antibiotic to form inactive cytochrome P-450 metabolite complexes which can interfere with the metabolism of theophylline. Thus, miocamycin can safely be administered to asthmatic children requiring theophylline treatment, when they have an infection due to susceptible pathogens.
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  • 66
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    European journal of clinical pharmacology 31 (1987), S. 733-736 
    ISSN: 1432-1041
    Keywords: meptazinol ; pharmacokinetics ; elderly patients ; healthy volunteers ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have determined the pharmacokinetics of meptazinol after its intravenous and intramuscular administration in a crossover study in 7 elderly hospital in-patients (〉70 years), and have compared with the results from 14 healthy, young volunteers (ages 20–40 years). The systemic availability after i.m. administration was comparable to that after i.v. administration, a result consistent with the physicochemical properties of the drug. There was a slight, but statistically significant (p〈0.01) prolongation in t1/2z in the elderly (mean 2.93 h) compared with the young (mean 2.06 h). This was associated with a 25% lower clearance in the elderly rather than with any alteration in volume of distribution. However, these changes would not appear to be substantial enough to require a revised dosage recommendation for meptazinol for this age group.
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  • 67
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    European journal of clinical pharmacology 31 (1987), S. 743-743 
    ISSN: 1432-1041
    Keywords: chloroquine ; dose dependence ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 68
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    European journal of clinical pharmacology 32 (1987), S. 17-22 
    ISSN: 1432-1041
    Keywords: felodipine ; calcium antagonist ; normal man ; renal function ; albumin excretion ; beta2-microglobulin excretion ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute renal effects of a single oral dose of felodipine 0.15 mg/kg were studied in 8 healthy males. Thirty minutes after administration the mean plasma concentration was 25.7 nmol/l. There was a significant reduction in diastolic blood pressure (24%) and a concomitant rise in heart rate (38%), leaving the systolic pressure unchanged. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the constant infusion technique using the clearance of125I-iothalamate and131I-hippuran respectively. GFR was unchanged and the filtration fraction (FF) was reduced, whilst there was a decrease in renal vascular resistance (RVR). The glomerular filter characteristics were unchanged, as estimated by the unchanged excretion rate of albumin. There was a significant rise in the clearance of sodium (176%) but only a small and insignificant increase in urine volume. Clearance of potassium was decreased. An increase in the clearance of uric acid and a rise in the beta-2-microglobulin excretion rate were found, both suggesting a proximal tubular effect of felodipine. The excretion rate of calcium was increased.
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  • 69
    ISSN: 1432-1041
    Keywords: atenolol ; amiloride ; hydrochlorothiazide ; young ; elderly ; pharmacokinetics ; pharmacodynamics ; volunteers ; patients ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six normal young and six normal elderly volunteers and six elderly hypertensive patients took part in an acute and chronic dose study of a combination capsule containing atenolol (50 mg), hydrochlorothiazide (25 mg) and amiloride (2.5 mg) designed for the treatment of hypertension. No difference in any of the drug pharmacokinetic parameters could be detected between the hypertensives and the normal elderly subjects. The bio-availability and the 24-h blood concentrations of all three drugs, half-life of atenolol and amiloride and the peak concentration of hydrochlorothiazide was significantly greater in the elderly. The 24-h blood concentrations of atenolol and hydrochlorothiazide did not alter with chronic dosing, but amiloride concentrations were significantly higher at this time in all groups. A significant fall in the blood pressure was observed in the hypertensive group. Heart rate fell more in the normal and hypertensive elderly subjects than in the young. The combination has shown to be an effective and well tolerated antihypertensive in the elderly patient with a 24-h duration of action.
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  • 70
    ISSN: 1432-1041
    Keywords: captopril ; uraemia ; captopril disulfide ; dialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have measured the plasma concentrations of captopril and total disulfide conjugates of captopril after a 50 mg oral dose in 6 uraemic patients on maintenance dialysis and in 8 hypertensive subjects with normal renal function. The mean peak plasma concentration of captopril was 2.5 times higher (0.447 µg·ml−1 vs 0.181 µg·ml−1) and the concentrations of the disulfides 4 times higher (3.62 µg·ml−1 vs 0.924 µg·ml−1) in the uraemic patients. Moreover captopril disulfide conjugates in the uraemic subjects reached peak concentrations at 8 h after the dose and subsequently felt. The apparent plasma half-time was 46±19 h. Only 15% of these conjugates were removed by dialysis. This marked accumulation of captopril conjugates was associated with a sustained fall in both systolic and diastolic blood pressures. In uraemic patients the mean maximum reduction in systolic and diastolic blood pressures were 37±7 mmHg and 24±9 mmHg respectively, occurring 6 h after the dose, compared with 8±7 and 8±1 mmHg respectively at 30 min in normal renal function patients. These results are consistent with the results of animal experiments, which show that captopril disulfides can be converted back to free captopril and can contribute to the antihypertensive effect of the drug. They provide a reationale for reducing the dose and frequency of administration of captopril in patients with significant renal impairment.
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  • 71
    ISSN: 1432-1041
    Keywords: adrenergic beta-receptors ; propranolol ; beta-blockade ; pharmacokinetics ; leukocyte beta-receptors ; leukocytes ; exercise tachycardia ; 4—OH-propranolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The chronotropic response to a single oral dose of propranolol in 23 healthy subjects has been related to the plasma propranolol concentration and the density of β-adrenoceptors on peripheral polymorphonuclear leucocytes. The percentage reduction in exercise-induced tachycardia was significantly correlated with the log plasma propranolol concentration within subjects but not between subjects. Taking the concentration of the active metabolite 4-hydroxypropranolol into account did not improve the interindividual correlation. The reduction in exercise-induced tachycardia was significantly correlated with the maximum binding density of (125I)-hydroxybenzylpindolol on polymorphonuclear leucocyte membrane fragments measured before medication. A response index (% reduction in exercise-induced tachycardia/plasma propranolol concentration) was correlated with the maximum binding density of (125I)-hydroxybenzylpindolol (predrug) at 2 h (rs=0.72), 4 h (rs=0.84) and 6 h (rs=0.73) after dosing. The data suggest that interindividual variation in the response to propranolol after a single oral dose is determined by interindividual differences both in plasma propranolol and adrenoceptor density.
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  • 72
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    European journal of clinical pharmacology 31 (1987), S. 695-699 
    ISSN: 1432-1041
    Keywords: doxorubicin ; sarcoma ; pharmacokinetics ; polychemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of doxorubicin has been studied in 26 sarcoma patients receiving polychemotherapy. Mean elimination half-life was 34.7±16.6 h and the total plasma clearance was 29.5±9.31·h−1·m−2. No relationship was found between the pharmacokinetic parameters and the response to treatment, or its toxicity. Special attention was paid to the early-phase kinetics of the drug (3–20 min after injection). A correlation between the early clearance and the ages of the patients was observed. The early clearance was clearly correlated with the total plasma clearance measured over 48 h after injection, indicating the importance of the distribution phase in the overall kinetics of the drug.
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  • 73
    ISSN: 1432-1041
    Keywords: dextran ; hydroxyethylstarch ; haemodilution ; ischaemic stroke ; plasma viscosity ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 21 patients with ischaemic strokes we have monitored plasma viscosity, total plasma concentration, numeric average molecular weight (Mn), and weight average molecular weight (Mw) of Dextran 40 (dextran) and hydroxyethylstarch 200/0.5 (HES) during 10 days of treatment (days 1–4, 2×500 ml; days 5–10, 1×500 ml). Plasma concentrations of dextran increased during the first 4 days (8.3 mg·ml−1 on the first day to 18.0 mg·ml−1 on the fifth day), reached an apparent steady state of 17.2 mg·ml−1 during the next 6 days, and declined subsequently with a half-time (t1/2) of 4.03 days. After ten days treatment Mn and Mw were shifted towards higher values. Plasma viscosity increased from 1.26 mPas to 1.69 mPas on Day 10 (p〈0.01) and was linearly correlated with the total plasma concentration of dextran (p〈0.001; r=0.88). Total plasma concentrations of HES averaged 11.7 mg·ml−1 on Day 1 and 12.4 mg·ml−1 on Day 5. The molecular weight distribution did not change during the infusions but decreased in comparison with the administered solution. Plasma viscosity fell from 1.40 mPas to 1.30 mPas at Day 10 (p〈0.05) and was not related to the concentration of HES. The haemodiluting effect, as indicated by a decrease of the haematocrit, was 22% and 16.8% for dextran and HES respectively. These data suggest several advantages of HES compared with dextran in haemodilution therapy of ischaemic stroke.
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  • 74
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    European journal of clinical pharmacology 31 (1987), S. 729-731 
    ISSN: 1432-1041
    Keywords: chloroquine ; pharmacokinetics ; dose-dependence ; exponential equations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have shown that apparent nonlinearities in the pharmacokinetics of chloroquine and wide variability in reported kinetic values are possibly artefacts of experimental design. We have used simulated data based on linear equations to demonstrate that chloroquine kinetics may appear to be dose-dependent if samples are collected over a short period or if they are assayed with a method of low sensitivity.
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  • 75
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    European journal of clinical pharmacology 32 (1987), S. 165-172 
    ISSN: 1432-1041
    Keywords: warfarin ; cimetidine ; ranitidine ; stereochemistry ; drug-drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Stereochemical aspects of the potential interaction between the oral anticoagulant warfarin and the H2-antagonists, cimetidine and ranitidine, were investigated. A single 25 mg oral dose of racemic warfarin was administered on Day 4 of a randomised 9-day multiple dosing regimen of either cimetidine (800 mg o.d.) ranitidine (300 mg o.d.) or placebo. The degree of anticoagulation produced by warfarin was quantificated by the determination of both the prothrombin and Factor VII clotting times. Ranitidine had no effect on the pharmacodynamics of warfarin or the pharmacokinetics of the individual warfarin enantiomers. Cimetidine whilst producing no statistically significant change in the pharmacodynamics of warfarin or in the pharmacokinetics of the pharmacologically more potent (S) enantiomer, did produce a statistically significant decrease in the clearance of the (R) enantiomer, possibly due to metabolic inhibition of this species.
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  • 76
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    European journal of clinical pharmacology 31 (1987), S. 575-578 
    ISSN: 1432-1041
    Keywords: felodipine ; metoprolol ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary This double-blind, cross-over study in healthy male subjects evaluated the pharmacokinetics of felodipine and metoprolol given both separately and in combination. During three, five-day study periods, felodipine 10 mg b.d., metoprolol 100 mg b.d. and a combination of the two, were given in random order. There was at least a 7-day washout period between each pharmacokinetic study day. Plasma levels of unchanged felodipine and metoprolol were measured for 24 h after the last dose, on the 5th day of each treatment period. Eight subjects, aged 19–22 years, completed the study. Both felodipine and metoprolol, given alone and in combination, were well tolerated. None of the felodipine pharmacokinetic variables (tmax, Cmax, Cmin, AUC (0–12) and t1/2) changed significantly when felodipine and metoprolol were given in combination. Cmax and AUC (0–12) for metoprolol increased significantly when metoprolol and felodipine were combined, although tmax, Cmin and t1/2 for metoprolol remained unchanged. The changes in metoprolol pharmacokinetics induced by felodipine are small and unlikely to be clinically important.
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  • 77
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    European journal of clinical pharmacology 32 (1987), S. 309-311 
    ISSN: 1432-1041
    Keywords: digoxin ; verapamil ; cirrhosis ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of a single low dose of verapamil (80 mg) on the serum levels of digoxin (single dose of 0.5 mg) was studied in 6 patients with hepatic cirrhosis and in 6 healthy volunteer controls. In the cirrhotic patients verapamil increased the peak serum level and the total AUC of digoxin by 98% and 32%, respectively. There was an associated 23% decrease in the renal digoxin clearance. In normal subjects only marginal alterations in digoxin kinetics were observed following verapamil administration. The results indicate that cirrhosis magnifies the influence of verapamil on digoxin kinetics.
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  • 78
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    European journal of clinical pharmacology 32 (1987), S. 303-307 
    ISSN: 1432-1041
    Keywords: azapropazone ; arthritis ; pharmacokinetics ; synovial fluid level ; synovial tissue level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The concentration-time curves of azapropazone in synovial fluid and tissues have been studied in arthritic patients after an i.v. bolus (600 mg) and under steady-state conditions. Synovial fluid and tissue samples were taken intraoperatively 0.45–60 h after administration. The azapropazone concentrations in synovial fluid, synovial tissue and plasma were correlated. The levels in synovial fluid were usually lower than corresponding plasma levels. Under steady-state conditions azapropazone did not accumulate in synovial tissues.
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  • 79
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    European journal of clinical pharmacology 32 (1987), S. 317-320 
    ISSN: 1432-1041
    Keywords: ranitidine ; amitriptyline ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of an interaction of ranitidine with amitriptyline was assessed by means of amitriptyline and nortriptyline plasma concentration measurements, blood pressure and pulse rate, digit symbol substitution, and visual analogue scales. Ranitidine had no effect on amitriptyline or nortriptyline concentrations. Responses recorded by the digit symbol substitution and visual analogue scale tests correlated with changes in concentrations of amitriptyline and nortriptyline in plasma. No effects on blood pressure or pulse rate were observed. We concluded that there was no effect of ranitidine on amitriptyline kinetics or response in the conditions of our study.
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  • 80
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    European journal of clinical pharmacology 32 (1987), S. 351-355 
    ISSN: 1432-1041
    Keywords: nifedipine ; cimetidine ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma pharmacokinetics of nifedipine and the formation of its metabolites have been studied in volunteers under conditions which would affect the activity of the cytochrome P-450 system. The pharmacokinetics of a 10-mg capsule of nifedipine were not significantly different between smokers and non-smokers of similar age. After pretreatment with cimetidine, which inhibits the activity of cytochrome P-450, the peak plasma concentration and area under the plasma-time concentration curve for nifedipine were increased by a mean 84%. In contrast, pre-treatment with ranitidine which has little effect on cytochrome P-450, did not significantly alter nifedipine pharmacokinetics. Smoking does not contribute significantly to the variability in nifedipine pharmacokinetics. However, the interaction between nifedipine and cimetidine, but not ranitidine, may be of clinical importance.
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  • 81
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    European journal of clinical pharmacology 32 (1987), S. 357-360 
    ISSN: 1432-1041
    Keywords: nitrendipine ; food intake ; pharmacokinetics ; variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of nitrendipine were measured, after single (20 mg) oral doses, in young healthy volunteers. On three occasions the subjects ingested the dose having fasted overnight. Data from these three occasions were used to assess variability in nitrendipine pharmacokinetics and both inter- and intra-subject variability were high. On a fourth occasion, the subjects took the tablet after a standard meal. The effects of food on nitrendipine pharmacokinetics, based on the comparison of data from the first fasting visit and the food visit, were negligible.
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  • 82
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    European journal of clinical pharmacology 32 (1987), S. 377-382 
    ISSN: 1432-1041
    Keywords: morphine ; renal failure ; pharmacokinetics ; morphine-3-glucuronide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of morphine and its glucuronidated metabolites were investigated in seven patients with advanced renal failure. The terminal elimination half life of morphine varied between 1.5 and 4.0 h (mean 2.4 h), the volume of distribution between 2.5 and 6.3 l·kg−1 (mean 4.4 l·kg−1) and the total plasma clearance between 13.3 and 31.3 l·min−1·kg−1 (mean 21.1 l·kg−1). There were no statistically significant differences between the pharmacokinetic data in the uraemic patients and in a control group of cancer patients with normal kidney function. The concentrations of the glucuronidated metabolites rapidly rose to levels above those of morphine. The elimination half-life of M3G varied between 14.5 and 118.8 h (mean 49.6 h) in the renal failure patients, which is distinctly different from the 2.4 to 6.7 h (mean 4.0 h) found in patients with normal kidney function. There was a significant correlation between the half-life of M3G and renal function estimated as serum urea. Thus, the metabolism of morphine in patients with kidney disease is not significantly impaired. The clinical importance of the high concentrations of glucuronides in uraemic patients is not known.
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  • 83
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    European journal of clinical pharmacology 32 (1987), S. 395-401 
    ISSN: 1432-1041
    Keywords: probenecid ; Michaelis-Menten kinetics ; protein binding ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy volunteers were given probenecid 0.5, 1 and 2 g p.o. and 0.5 g i.v. The protein binding of probenecid at different concentrations in human plasma was estimated by equilibrium dialysis. The free fraction was found to increase nonlinearly with increasing total probenecid concentration, up to a maximum free fraction of 26%. The plasma concentration-time data after the oral doses were described by a one-compartment open model with first-order absorption and Michaelis-Menten elimination. The mean absorption rate constant 0.0072 min−1 was dose-independent, and the maximal rate of elimination (mean 1429 µg/min) did not differ between doses whether calculated from the total or free concentrations. The Michaelis-Menten constant decreased significantly from 67.1 to 55.5 µg/ml as the dose increased from 1 g to 2 g, while the unbound Michaelis-Menten constant remained unchanged. The elimination of probenecid after the 0.5 g dose was in the linear region of the Michaelis-Menten elimination when calculated from the total and the free concentrations. The volume of distribution increased only slightly from 9.5 to 11.4 l as the dose increased from 0.5 to 2 g, but the unbound volume of distribution decreased significantly from 164 to 99 l. Absorption was complete and was independent of the dose administered.
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  • 84
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    European journal of clinical pharmacology 32 (1987), S. 35-41 
    ISSN: 1432-1041
    Keywords: metronidazole ; antipyrine ; cimetidine ; phenobarbitone ; drug interaction ; drug metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of cimetidine, antipyrine and phenobarbitone on the pharmacokinetics of intravenous metronidazole and oral antipyrine has been examined in 7 healthy volunteers. The administration of cimetidine for 24 h before and throughout the sampling period failed to alter the total clearance of metronidazole or the rate of formation of the hydroxy metabolite, whereas the total and partial clearances of antipyrine were decreased 0.74 and 0.6–0.7-fold, respectively, Seven days of phenobarbitone or antipyrine administration increased the total clearance of metronidazole 1.51- and 1.86-fold, respectively, and the total antipyrine clearance was 1.22 or 1.46-fold increased, respectively. The rate of metronidazole hydroxylation was significantly enhanced by both enzyme inducers. The partial clearance of antipyrine to the normetabolite was significantly increased by both inducers, wheras the rate of 4-hydroxylation was significantly increased only by prior antipyrine administration. The results indicate that the hydroxylation of metronidazole is not inhibited by cimetidine, but that it is inducible by phenobarbitone or antipyrine. It is suggested that metronidazole and antipyrine are metabolized by different enzymatic pathways.
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  • 85
    ISSN: 1432-1041
    Keywords: urapidil ; hypertension ; alpha-adrenoceptor blocker ; antihypertensive agent ; pharmacodynamics ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and haemodynamic effects of infused urapidil and an infusion-capsule combination were followed to study the correlation between the serum urapidil level and the blood pressure. Prior to urapidil administration, basal blood pressure and heart rate were measured for 16 h in 12 male hypertensive patients. Six patients received infusions lasting for 4 h of urapidil 10, 2.5 and 5 mg/h. Six patients were infused with urapidil 10 mg/h for 4 h and 2 h after the end of the infusion each took a 60-mg capsule. After a 5 day washout period the procedures were crossed over. A maximum serum urapidil level of 625±232 ng/ml was achieved at the end of the 10 mg/h infusion, when the fall in blood pressure was 37/21 mmHg. During the 2.5 and 5 mg/h infusions the serum urapidil level was 330 and 420 ng/ml, respectively, and the corresponding decreases in blood pressure were 28/16 mmHg and 31/8 mmHg. Although the urapidil concentration 1 hour after beginning the infusion was only 184±89 ng/ml a near maximal blood pressure decrease had already occurred 33±9/20±8 mmHg, whereas, 1 h after the end of the infusion the reduction in blood pressure was only 10±12/3±8 mm, with a urapidil concentration of 358±120 ng/ml. During the plateau phases of both the infusion and infusion-capsule treatments the falls in blood pressure followed the serum urapidil levels. Only in the initial rising and final falling phases of the treatments were the pharmacodynamics and pharmacokinetics of urapidil not correlated.
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  • 86
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    European journal of clinical pharmacology 32 (1987), S. 93-95 
    ISSN: 1432-1041
    Keywords: tiaprofenic acid ; arthritis ; pharmacokinetics ; elderly
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the single dose and steady-state pharmacokinetic of tiaprofenic acid in ten elderly arthritic patients living in the community (5 men and 5 women) taking 200 mg tid for 8 days. The mean area under the plasma concentration-time curves to 8 h (AUC (0–8)) did not alter significantly from day 1 to day 8 (77.25 to 79.61 µg·ml−1. h). The mean terminal phase half-life (t1/2) was 2.05 h and 2.25 h on Days 1 and 8 respectively in patients in whom the calculations were possible (7 patients on Day 1 and 6 patients on Day 8). The median observed time of maximum concentration (tmax) and the mean observed maximum plasma concentration (Cmax) of 100 min and 21.3 µg·ml−1 respectively on Day 1 were not significantly different from the values obtained on Day 8 (tmax 120 min; Cmax 20.7 µg·ml−1). The kinetic data suggest that there should be no significant accumulation of tiaprofenic acid in elderly ambulant people suffering from arthritis.
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  • 87
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    European journal of clinical pharmacology 32 (1987), S. 111-113 
    ISSN: 1432-1041
    Keywords: ornidazole ; neonates ; pharmacokinetics ; intravenous infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single dose pharmacokinetics of ornidazole has been evaluated in 12 neonates or infants (aged 1 to 42 weeks) after the infusion of 20 mg/kg over 20 min. Plasma disposition was described by a two-compartment open model. The distribution phase was short (T1/2 (1)=0.31 h) and was followed by an elimination phase (t1/2 (2)=14.67 h). The mean apparent volume of distribution was 0.96 l/kg−1. These results did not differ from data previous by reported in adults. Total plasma clearance was between 0.4 and 1.4 ml·min−1·kg−1. The plasma concentration 24 h after the infusion was 7.32 mg·l−1, which was above the minimum inhibitory concentration for clinically significant anaerobic bacteria. Based on the pharmacokinetic results and residual concentrations at 24 h, a single daily infusion of ornidazole 20 mg·kg−1 appears adequate for therapy in neonates and infants.
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  • 88
    ISSN: 1432-1041
    Keywords: salicyl phenolic glucuronide ; rheumatoid arthritis ; aspirin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of salicyl phenolic glucuronide (SPG) and other salicylic acid (SA) metabolites were studied at three aspirin dosage regimens in eight patients with rheumatoid arthritis. Each patient received 1, 2 and 4 g enteric coated aspirin (ASA) daily in ascending order. At the end of each 2-week dosage period, plasma and urine were collected over a dosage interval for the estimation of various pharmacokinetic parameters. With increasing ASA dosage, mean clearance of SA to SPG was approximately constant (1.8±0.3, 1.7±0.2, and 1.5±0.2 ml/min at 1, 2 and 4 g/day, respectively) when related to plasma concentrations of total SA. The percentage of the ASA dosage recovered in urine as SPG increased from 5.2±1.1 to 7.1±1.1 to 10.5±1.7 at 1, 2 and 4 g/day, respectively. It was concluded, however, that the conversion of SA to SPG is saturable, since the mean clearance of SA to SPG decreased when calculated with respect of the plasma concentration of unbound SA (13.4±1.6, 11.0±1.4, and 6.6±1.9 ml/min at 1, 2 and 4 g/day, respectively). The kinetics of the formation and excretion of salicylurate and the excretion of gentisate were similar to those found in previous studies.
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  • 89
    ISSN: 1432-1041
    Keywords: hypothermia ; fentanyl ; pharmacokinetics ; cardiopulmonary bypass ; hypothermia-induced hypoperfusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of hypothermia on the disposition of fentanyl was evaluated in 18 children undergoing corrective cardiac surgery. They received a bolus of fentanyl followed by a continuous infusion which was stopped when cardiopulmonary bypass was established and profound hypothermia was achieved (18 °C–25 °C). Fentanyl plasma concentration remained essentially unchanged during hypothermia (6.45 ng/ml 5 min into hypothermia and 5.26 ng/ml 100–140 min later; p〉0.1). In subsequent experiments, the effect of hypothermia on the pharmacokinetics of fentanyl was studied in 4 piglets serving as their own controls. Both distribution volume (Vz) and total body clearance (CL) were significantly smaller during hypothermia. Our studies indicate that being a drug with a large distribution volume and a high hepatic extraction ratio, both CL and Vz are significantly reduced by hypothermia-induced hypoperfusion. In addition, TBC is influenced by the temperature-dependent hepatic metabolism of fentanyl.
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  • 90
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    European journal of clinical pharmacology 32 (1987), S. 503-505 
    ISSN: 1432-1041
    Keywords: isosorbide-5-nitrate ; renal failure ; haemodialysis ; peritoneal dialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of isosorbide-5-nitrate (IS-5-N) was studied in ten patients on haemodialysis (HD) after a single oral dose of 20 mg IS-5-N, and in six patients on continuous ambulatory peritoneal dialysis (CAPD) after repeated oral doses of 3×20 mg IS-5-N. There was significant removal of IS-5-N from blood during HD; Cmax decreased by about 20%, AUC(0–8 h) by 30% and t1/2 by about 20% from 4.3 to 3.4 h, and plasma clearance was increased by 81 ml/min. No important loss of IS-5-N was observed in patients on CAPD.
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  • 91
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    European journal of clinical pharmacology 32 (1987), S. 493-498 
    ISSN: 1432-1041
    Keywords: theophylline ; erythromycin ; drug interaction ; aminophylline ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the interaction of erythromycin with theophylline. We gave ten healthy volunteers theophylline as an intravenous loading dose (5 mg·kg−1) over 1 h, followed by a maintenance infusion (0.5 mg·kg−1·h−1) for 5 h. A second infusion of theophylline was given after 9 days of treatment with 1 g erythromycin base daily, and the concentrations of theophylline were determined during the infusion periods. The concentrations of erythromycin were measured for 8 h, after one week of treatment, and also after the last erythromycin dose, simultaneously with the second theophylline infusion. Concentrations within the therapeutic range were obtained with both drugs. A significant increase in both AUC and mean plasma concentrations of theophylline was seen during erythromycin treatment. The plasma clearance of theophylline was reduced in 9 of the 10 subjects. Renal clearance increased correspondingly, but the change was not statistically significant. Serum concentrations of erythromycin fell significantly, by more than 30%, with concurrent theophylline medication. We conclude that an interaction between theophylline and erythromycin, affecting both drugs, can be shown with concentrations of the drugs within the therapeutic range.
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  • 92
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    European journal of clinical pharmacology 32 (1987), S. 631-634 
    ISSN: 1432-1041
    Keywords: salbutamol ; albuterol ; pharmacokinetics ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Salbutamol was administered to sixteen healthy male volunteers intravenously and by mouth in liquid, tablet, and capsule form using a Latin-Squares design. Pharmacokinetic parameters from intravenous data were similar to previously reported values obtained with oral administration, with a mean terminal half-life of 3.8 h and a mean clearance of 439 ml·min−1·1.73 m−2. Peak plasma concentrations of 10–20 ng·ml−1 were obtained 1–3 h following oral administration. The absolute bioavailability of each of the oral preparations was 44%. While statistically significant differences in lag time and time to peak concentration were noted among the various oral preparations, the drug is rapidly absorbed in all three dosage forms and the observed differences are unlikely to be of clinical significance.
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  • 93
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    Archives of toxicology 59 (1987), S. 328-331 
    ISSN: 1432-0738
    Keywords: Aristolochic acid ; Toxicology ; Acute toxicity ; Rat ; Mouse
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The acute toxic effects of aristolochic acid (AA) were tested in rats and mice of both sexes. Oral or intravenous administration in high doses was followed by death from acute renal failure within 15 days. Histologically, the predominant features were severe necrosis affecting the renal tubules, atrophy of the lymphatic organs and large areas of superficial ulceration in the forestomach, followed by hyperplasia and hyperkeratosis of the squamous epithelium. The LD50 ranged from 56 to 203 mg/kg orally or 38 to 83 mg/kg intravenously, depending on species and sex.
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  • 94
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    Archives of toxicology 61 (1987), S. 21-26 
    ISSN: 1432-0738
    Keywords: m-Xylene inhalation ; Xenobiotic enzymes ; Lung effects and morphology ; Blood concentrations ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats were exposed to 0, 75, 150 or 300 ppm (1 ppm=1 cm3/m3=4.35 mg/m3) m-xylene for 24 h and then killed. In the lungs, the cytochrome P-450 decreased to 45, 13 and 20% of the control value with the increasing exposure intensity and the activity of 7-ethoxycoumarin O-deethylase to 70, 27 and 14%, respectively. The activity of epoxide hydrolase increased slightly after exposures both at 150 (1.6-fold) and 300 cm3/m3 (1.4-fold), while the other measured drug-metabolizing enzyme activities showed no consistent changes. The non-protein sulfhydryl group content of the lungs was not affected. The concentrations of m-xylene in blood indicated that the solvent uptake increased in the different exposure groups more than expected, based on atmospheric concentrations alone. Morphologic studies of the lungs with scanning electron microscopy showed no apparent changes after exposure to 300 cm3/m3 or after a high oral dose (2 ml/kg/day, 3 days). Inhalation exposure to m-xylene for 5 weeks (7 h/day, 4 days/week) at a concentration of 300 ppm lowered the contents of cytochrome P-450 in rat lungs to 65% and the activity of 7-ethoxycoumarin O-deethylase to 41% without any other marked effects on the other drug-metabolizing enzymes or on the levels of non-protein sulfhydryl groups. In this study, the selective destruction of cytochrome P-450 in rat lung could be shown both after acute and subacute exposures and at concentrations low enough to warrant occupational concern.
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  • 95
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    Archives of toxicology 60 (1987), S. 394-396 
    ISSN: 1432-0738
    Keywords: Barbiturate poisoning ; Pentobarbitone ; Phenobarbitone ; Gastric emptying ; Gastrointestinal transit ; Peristaltic reflex ; Rat ; Guinea-pig
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Anaesthetic doses of pentobarbitone (50 mg/kg) were found to inhibit gastric emptying and gastrointestinal transit in the rat. Gastric emptying was more profoundly suppressed than gastrointestinal transit. Phenobarbitone (150 mg/kg) had a similar effect. Since pentobarbitone and phenobarbitone also blocked the peristaltic reflex in the isolated small intestine of the guinea-pig, it would appear that the inhibitory effect of anaesthetic doses of barbiturates on gastrointestinal motility is mainly due to a direct action on the digestive tract. Together with the observation that considerable amounts of phenobarbitone were found in the stomach of an intoxicated patient 3 days after drug intake, these results might indicate that gastric lavage should also be considered in the treatment of protracted barbiturate poisoning.
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  • 96
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    Archives of toxicology 59 (1987), S. 443-447 
    ISSN: 1432-0738
    Keywords: Rat ; Cadmium ; Injection route ; Teratogenesis ; Maternal liver damage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In rats of the present (re-derived) Wistar-Porton strain that are dosed either intravenously (i.v.), or intraperitoneally (i.p.) with Cd (1.25 mg/kg body weight) on day 12 of gestation (gd 12), foetal uptake of Cd is at least 6-fold greater than that reported in an earlier study (Webb and Samarawickrama 1981). Higher doses (1.5 and 2.0 mg/kg body weight) are lethal to the maternal animal when administered i. v., but not if given ip. The foetotoxicity of i.p. injected Cd, however, increases with the dose over the range 1.25–2.0 mg Cd/kg body weight. The teratogenic response, which is also wider than that observed previously, is maximal after the injection of 1.25 mg Cd/kg body weight i.v. on gd 10 and i.p. on gd 12. Whilst the incidences of hydrocephalus, urogenital abnormalities, cleft palate and other less common defects are similar after dosing by both routes, the incidence, range and severity of skeletal malformations are greater after i. p. than after i.v. administration of Cd on gd 12. This difference in response is unlikely to be explained by a difference in either foetal, or placental uptake of the metallic ion since, at 4 h after i.p. dosing, the foetal concentration of Cd is not significantly different from that after i.v. injection, whilst the placental concentration is about 33% less. It is suggested that damage to the maternal liver, which is more severe after the i.v. injection of the optimum dose, may be an additional factor that, in conjunction with the inhibition of transport in the placenta and biosynthetic processes in the embryo/foetus, contributes to the teratogenic effects of Cd in the pregnant rat.
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  • 97
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    Archives of toxicology 60 (1987), S. 325-327 
    ISSN: 1432-0738
    Keywords: Bromofenofos ; Dephosphate bromofenofos ; Embryolethality ; Teratogenicity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bromofenofos (BF) and dephosphate bromofenofos (DBF) were administered at equimolar doses to rats on day 10 of pregnancy. The dams were killed on day 21, and the fetuses were removed, weighed and examined by routine teratological methods. BF caused a significant increase in fetal resorptions at 58.2 mg/kg. Approximately 69% of the implants were resorbed at this dose level. In rats given DBF equimolar to 58.2 mg/kg BF, the resorption rate was 81.9%. Administration of BF resulted in a dose-dependent decrease in fetal body weights which was significant at 29.1 mg/kg or more. DBF caused a significant decrease in fetal body weights, beginning at 25.1 mg/ kg equimolar to 29.1 mg/kg BF, and the decreased fetal body weights were almost the same between BF and DBF. BF at 58.2 mg/kg induced significant gross and skeletal malformations, with incidences of 35.6 and 27.6%, respectively. In rats given DBF equimolar to 58.2 mg/kg BF, gross and skeletal malformations were seen in 54.5 and 61.5% of the fetuses, respectively. There were similarities in the types of malformations observed between BF and DBF. Both compounds induced no significant internal malformations. It was concluded from these results that the embryolethal and teratogenic effects of BF is due to its metabolite, DBF, which cannot respond to cholinesterase inhibition.
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  • 98
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    Archives of toxicology 60 (1987), S. 319-324 
    ISSN: 1432-0738
    Keywords: Bromofenofos ; Organophosphorus anthelmintic ; Embryolethality ; Teratogenicity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bromofenofos, an organophosphorus anthelmintic, was administered by gavage to rats as a single dose (50 mg/kg) on one of days 6 through 14 of pregnancy. The dams were killed on day 21, and the fetuses were removed, weighed and examined by routine teratological methods. A significant increase in fetal resorptions occurred after administration on days 9 through 13, with a maximum on day 10. Approximately 72% of the implants were resorbed after administration on day 10. Fetal body weights were significantly decreased when dams were treated on day 8 or later. The greatest decrease in fetal body weights was observed on day 10, when the fetuses weighed less than the controls by about 44% on the average. The incidence of fetuses with gross, skeletal and internal malformations was significantly increased on days 8 through 10, on days 8 through 11 and on days 8 and 9, respectively. Although various types of malformations were observed, most of them occurred on day 8, when no significant increase in fetal resorptions did occur. Cleft lip, short tail, brachygnathia, anal atresia, absence of genital tubercle, fused pelvic legs and perineal testicles were seen on day 8 as gross malformations. Skeletal malformations mainly affected the vertebrae and ribs. Major internal malformations on day 8 were hydronephrosis, hydroureter, anophthalmia, cleft palate, agenesis of the bladder and renal agenesis. Anophthalmia and/or microphthalmia were observed on days 8 through 10, with the highest incidence on day 9. To further determine the no-effect levels for embryolethal and teratogenic effects, a single dose of 10, 20, 30 or 40 mg/kg was administered by gavage to rats on days 8 or 10 of pregnancy. The no-effect levels of single oral dose for embryolethal and teratogenic effects were considered to be 40 and 30 mg/kg, respectively.
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  • 99
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    Experimental brain research 66 (1987), S. 74-82 
    ISSN: 1432-1106
    Keywords: Preoptic area ; Suprachiasmatic nucleus ; Morphometry ; Rat ; Streptozotocin diabetes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Pituitary and gonadal disorders consistent with abnormal LHRH and LH secretion occur in streptozotocin-diabetic rats. A key role in the synthesis and regulation of LHRH and in the phasic LH release is played by the preoptic-suprachiasmatic region which is mainly formed by the medial preoptic area, the sexually dimorphic nucleus of the medial preoptic area, and the suprachiasmatic nucleus. Therefore we have studied this region by morphology and morphometry in normal and streptozotocindiabetic rats. In normal animals, the neurons of the above mentioned nuclei were morphologically and morphometrically dissimilar. Independent of their localization, reduced cytoplasmic and nuclear areas were observed in the neurons of diabetic animals. These lesions are consistent with hypotrophied neurons. Consequently, diabetes may impair both synthesis and regulation of LHRH and may therefore account for pituitary disorders, testicular atrophy, and lacking preovulatory LH peaks. The structural differences of the neurons of the three nuclei in normal animals underline their different physiological role. Yet, the similarity of the changes found in all three nuclei suggests a generalized hypofunction of the whole preoptic-suprachiasmatic region under diabetic condition.
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  • 100
    ISSN: 1432-1106
    Keywords: Glycine ; GABA ; Immunocytochemistry ; Cerebellum ; Golgi cells ; Colocalization ; Rat ; Baboon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An antiserum against conjugated glycine was characterized and applied to cerebellar sections of rats and baboons that had been perfusion-fixed with glutaraldehyde. After immunosorbent purification the serum reacted with brain protein-glutaraldehyde-glycine conjugates, but did not stain similar test conjugates prepared from other amino acids, including GABA and β-alanine. In the rat cerebellum the glycine antiserum selectively labelled a subpopulation of Golgi neurons. Adjacent Vibratome sections treated with an antiserum against conjugated GABA revealed an about equally large subpopulation of immunopositive Golgi cells. A proportion of the Golgi cells that were cleaved by the plane of section contained both immunoreactivities. Additional evidence for a colocalization of glycine and GABA was obtained by postembedding staining of alternate semithin sections with the GABA antiserum and glycine antiserum, respectively. The ability of the antisera to distinguish between fixed glycine and GABA was corroborated by preincubation of the antisera with glutaraldehyde-amino acid fixation complexes: glycine complexes abolished staining with the glycine antiserum but had no effect on the GABA antiserum. The opposite effects were obtained with the GABA complexes. Matching the distributions of the respective immunoreactivities, [3H]glycine uptake was restricted to glomerulus-like structures in the granule cell layer whereas [3H]GABA uptake also occurred in punctate and fibrous profiles in the molecular layer. The baboon showed a distribution of glycine-like immunoreactivity similar to that in the rat, except that a few immunopositive neurons occurred in the molecular layer. The latter neurons were interpreted as outlying Golgi neurons; however, the possibility that they represent a subpopulation of basket cells could not be excluded. The Purkinje cells were negative in both species. Glial cells were weakly stained with the glycine antiserum but were strongly immunopositive after incubation with an antiserum raised against conjugates of the structurally similar amino acid β-alanine. The present data suggest that glycine and GABA occur in about equally large subpopulations of Golgi neurons. A subpopulation of the Golgi neurons appears to contain both glycine and GABA.
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