摘要:

The reinforcing and subjective effects of orald-amphetamine (AMP) were studied in a group of non-drug-abusing adults (16 males, 13 females). A discrete-trial choice procedure was used to assess the reinforcing effects of a single dose of AMP (range 7.5–20 mg across subjects). A number of factors (gender, current and past drug use, personality, motor activity, and baseline mood state and psychophysiological and sensory indices of arousal) were examined in an attempt to explain both within- and between- subject variability in response to AMP. Of the 29 subjects, 11 chose AMP on either two or three out of a possible three occasions. Cigarette smokers reported stronger aversive responses to AMP and chose the drug significantly less often than non-smokers. Subjects with a history of non-medical stimulant use reported less subjective response to AMP than subjects without such history. Within-subject variability in AMP choice was related to variability in subjective response to the drug across choice trials, as well as to variability in baseline mood: AMP was more likely to be chosen when subjects were more aroused and in a more positive mood at the time of the choice. These results provide new information regarding factors that may be relevant in determining individual differences in vulnerability to abuse of psychomotor stimulants.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The behavioral effects of 10 days of chronic administration of the typical neuroleptic, pimozide, and the atypical neuroleptic, clozapine, were compared on a schedule of multiple random interval responding for food reinforcement and on photocell activity in rats. The low doses of both neuroleptics (0.125 mg/kg pimozide, 1.25 mg/kg clozapine) had little effect on any of the dependent variables measured. The high doses (1.0 mg/kg pimozide, 10.0 mg/kg clozapine) significantly disrupted response rates and reinforcement rates and significantly increased response duration when the drugs were first administered. Chronic administration, however, resulted in different profiles for the two drugs. While tolerance developed to the disruptive effects of clozapine, tolerance did not develop to the disruptive effects of pimozide and, on some dependent measures, an increased sensitivity developed. No tolerance developed to the disruptive effects of either drug on photocell activity. The effects of the drugs depended on the reinforcement density of the operant schedule.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Overshadowing can play an important role in conditioning with compound exteroceptive stimuli. Drug discrimination experiments have been carried out to examine overshadowing when mixtures of drugs serve as compound interoceptive stimuli. Three groups of rats were trained in a two-bar operant procedure with a tandem schedule of food reinforcement (n= 8). All rats were trained to discriminate (-)-nicotine (0.32 mg/kg s.c.) from saline, but in two groups of animals midazolam (0.1 or 0.2 mg/kg s.c.) was co-administered with the nicotine to generate a compound stimulus. Dose-response curves were determined with nicotine and midazolam in each group. In rats trained with nicotine alone, there was a steep dose-response curve for the discriminative stimulus effect of nicotine. The presence of the smaller dose of midazolam in the training stimulus clearly attenuated, and the larger dose prevented, the appearance of the discriminative effect of nicotine, whereas there was a concomitant increase in the discriminative response to midazolam. These results suggest that midazolam overshadowed the response to nicotine in a dose-related manner. In rats trained with nicotine alone, the same doses of midazolam had no effect on the discriminative response established to the nicotine stimulus, indicating the absence of pharmacological antagonism. The results illustrate how conditioning factors may provide a behavioural mechanism for interactions between abused drugs.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

This study compared behavioral and subjective effects of two anxiolytics, the benzodiazepine lorazepam and the azaspirodecanedione buspirone, in healthy male volunteers with histories of sedative drug abuse. Placebo, lorazepam (1, 2, 4, 8 mg/70 kg) and buspirone (15, 30, 60, 120 mg/70 kg) were administered p.o. in a mixed sequence in a double-blind, cross-over design. Lorazepam, but not buspirone, decreased psychomotor/cognitive performance. Both drugs produced similar increases in ratings of drug strength, however the onset and offset times for lorazepam were later than for buspirone. Lorazepam increased ratings of liking in contrast to buspirone which produced negative mood-related subjective effects (e.g. increases in ratings of disliking, bad/unpleasant effects, and tension-anxiety). Lorazepam was categorized by subjects as producing effects similar to barbiturates or benzodiazepines in contrast to buspirone which was not. When subjects were given a choice between self-administering an intermediate dose of lorazepam (4 mg/70 kg) or buspirone (60 mg/70 kg), which produced similar ratings of drug strength, eight out of nine subjects chose lorazepam. This study provides the clearest human experimental evidence to date that the abuse liability of buspirone is lower than that of a prototypic benzodiazepine, even at supratherapeutic doses.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The technique of microdialysis was employed to investigatein vivo5-hydroxytryptamine (5-HT) release in isolation-reared rats compared with socially reared rats. Two methods were employed to stimulate 5-HT release: local KCl injection into the frontal cortex of chloral hydrate anaesthetized rats, and the exposure of freely moving rats to a novel environment (the elevated x-maze). Microdialysis probes were implanted into the frontal cortex in the case of KCl stimulation and the ventral hippocampus in the case of exposure to the novel environment, and perfused with artificial CSF (1 μl/min). Dialysis samples were collected every 20 min and analysed for 5-HT and 5-hydroxyindole acetic acid (5-HIAA) by HPLC with electrochemical detection. Both KCl injection (1 μl, 100 mM) and a 20 min period on the elevated x-maze produced a significant increase in extracellular 5-HT in the socially reared rats. Neither the increase in extracellular 5-HT induced by KCl nor the increase on exposure to the elevated x-maze were observed in the isolation-reared rats. Dialysate 5-HIAA was not affected in socially reared or isolation-reared rats, in either protocol. These results suggest that isolation-reared rats have a reduced presynaptic neuronal function to release 5-HT.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The present study examined further the pharmacological specificity of the methylxanthine CNS stimulant caffeine as a discriminative stimulus in humans. Nine normal healthy volunteers (ages 19–39) were trained to discriminate between caffeine (320 mg/70 kg, p.o.) and placebo, using monetary reinforcement of correct letter code identification. After four training sessions, subjects were tested with the training conditions until they were >80% correct on four consecutive sessions. Then dose-effect curves were determined for caffeine (56–320 mg/70 kg), theophylline (56–320 mg/70 kg), methylphenidate (10–56 mg/70 kg), and buspirone (1–32 mg/70 kg). Seven of nine subjects met the discrimination criterion within four to nine sessions. During dose-effect curve determinations, caffeine and methylphenidate each produced dose-related increases in caffeine-appropriate responding. Theophylline produced caffeine-appropriate responding that was not dose related in a consistent manner across subjects, occasioning an average of 50% caffeine-appropriate responding at most doses tested. Buspirone produced predominantly placebo-appropriate responding. Caffeine-appropriate responding tended to be directly related to ARCI LSD scores, self-reported “bad” effects, “high”, and stimulant-bad effects and inversely related to ARCI PCAG scores and sedative ratings. These results agree with non-human data and suggest that the caffeine discriminative stimulus has pharmacological specificity, in that caffeine-appropriate responding generalizes to other stimulants such as theophylline or methylphenidate, but not to non-stimulant compounds such as buspirone.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The effects of ritanserin on spontaneous benzodiazepine (BZ) withdrawal-induced weight loss, anorexia and hypodipsia were studied. Groups of female rats initially received i.p. injections b.i.d. (11.00 and 17.00 h) of either saline or chlordiazepoxide (CDP). CDP doses increased by 2 mg/kg/day from 10 mg/kg to a final dose of 30 mg/kg. Treatment was maintained for 26 days. Over the next 6 days animals were either treated b.i.d. with vehicle, CDP, or ritanserin at one of three doses (0.16, 0.63 and 2.5 mg/kg). In CDP-pretreated animals subsequently treated with vehicle, significant weight loss, anorexia and hypodipsia were seen, relative to controls. In saline-pretreated animals ritanserin had no effect on body weight. However, CDP withdrawal-induced weight loss was actually exacerbated by ritanserin, in a dose-related fashion. Thus, ritanserin potentiated withdrawal-induced weight loss, by a process which did not involve functional (additive) effects of withdrawal and ritanserin treatment. Ritanserin stimulated food intake in saline-pretreated animals. Despite this effect it failed to alleviate CDP withdrawal-induced anorexia. However, in contrast to the weight loss index, no evidence was obtained for potentiation of withdrawal-induced anorexia. In saline-pretreated animals ritanserin had no effect on water intake, nor did it alleviate or potentiate CDP withdrawal-induced hypodipsia. Thus the effects of ritanserin on somatic BZ withdrawal signs depended upon the specific sign studied, different signs showing potentiation or no effect. However, for none of the signs studied was there any evidence that ritanserin alleviated the effect of CDP withdrawal. 5-HT2/1Cantagonists may therefore be of limited value in the treatment of somatic aspects of the BZ withdrawal syndrome. They may even exacerbate some BZ withdrawal signs, although a full characterization of the effects of such drugs on BZ withdrawal requires that a number of other different withdrawal signs and symptoms should be studied, since it seems likely that different BZ withdrawal signs involve different underlying mechanisms.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The excitatory amino acid (EAA) agonists,N-methyl-D-aspartate (NMDA) and kainate, elicit a copious drinking response in pigeons. NMDA-induced drinking, as compared with kainate- and water deprivation-induced drinking, is selectively antagonized by the competitive NMDA receptor antagonist CGS 19755, and appears to be mediated by NMDA receptors located in brain. There have been several studies which have reported differences between competitive and non-competitive (PCP-like) NMDA antagonists in blocking various behavioral effects of NMDA, such as discriminative stimulus effects. The present studies examined the effects of the non-competitive antagonists, phencyclidine (PCP) and dizocilpine, on drinking elicited by NMDA, kainate, and water deprivation. PCP and dizocilpine were effective antagonists of NMDA-induced drinking, resulting in surmountable shifts to the right in agonist dose-response functions. These compounds had little effect on drinking evoked by either kainate or water deprivation. These results support the notion that the dipsogenic effects of NMDA are mediated by NMDA-type receptors, and also provide important information as to the characteristics of non-competitive NMDA antagonists. EAA-induced drinking provides a useful tool for the examination of the behavioral pharmacology of EAA agonists and antagonists.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The primary purpose of the present study was to examine the interaction of buspirone with nicotine in pigeons responding under a fixed-ratio 30 schedule of food presentation. The hypothesis was that the dopamine D2 receptor antagonist activity of buspirone would attenuate the rate-decreasing effects of nicotine. When administered alone, buspirone (0.3–10 mg/kg) and (-) -nicotine (0.1–3.0 mg/kg) decreased response rates in a dose-related manner, with ED50values (∼95% C.L.) of 3.0 (1.7–5.1) mg/kg and 1.0 (0.7–1.5) mg/kg, respectively. Low doses of buspirone (0.3–1.0 mg/kg) did not significantly shift the nicotine dose-response function, while doses of buspirone (3.0–10 mg/kg) that produced rate-decreasing effects shifted the nicotine dose-response function to the left. There was no significant statistical interaction between buspirone and nicotine indicating that the shifts in the nicotine dose-response function were parallel. The buspirone analog gepirone (0.3–10 mg/kg), which like buspirone is a serotonin (5-HT1A) agonist, but unlike buspirone is relatively devoid of D2 antagonist activity, was also tested in combination with nicotine. Gepirone was less potent in decreasing response rates compared with buspirone, with an ED50value of 4.5 (3.1–6.7) mg/kg. Rate-decreasing doses of gepirone (3.0–10 mg/kg) in combination with nicotine resulted in parallel shifts to the left of the nicotine dose-response function. There was no statistically significant difference between the effects of buspirone and those of gepirone on the nicotine dose-response function. Isobolograms indicated that the pharmacological interactions between buspirone or gepirone and nicotine were not different from additivity. These results suggest that the combined effects of buspirone and nicotine on schedule-controlled behavior are independent of antagonism at D2 receptors.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Modulation of ultrasonic vocalization (20–30 kHz) emitted by adult rats under stressful conditions such as unavoidable foot- shock has been evaluated as a model of anxiety. The effects of 5-HT1Areceptor agonists with different intrinsic activities and the role of other 5-HT1receptor subtypes, and of 5-HT2and 5-HT3receptors, in mediation of ultrasonic vocalization were studied, as were the effects of increasing serotonergic activity by administration of the 5-HT releaser fenfluramine or the 5-HT precursor 1–5-HTP. The time spent vocalizing 1–6 min after four inescapable (1.0 mA) footshocks was recorded. Drugs with affinity for 5-HT1Areceptors (i.e. 8-OHDPAT, flesinoxan, ipsapirone, buspirone, gepirone, NAN-190) abolished the vocalization irrespective of their efficacy. The mixed 5-HT, receptor and β-adrenoceptor antagonists (-)-alprenolol and pindolol inhibited foot-shock-induced ultrasonic vocalization, whereas (-)-penbutolol was ineffective. The β1-adrenoceptor antagonist metoprolol and the β2-adrenoceptor antagonist ICI 118.551 were without effect. This suggests that (-)-alprenolol and pindolol act as partial 5-HT1agonists in the test model. The non-selective 5-HT1receptor agonists eltoprazine, m-CPP and 5-MeODMT and the 5-HT2receptor agonists DOI andd-LSD also abolished the vocalization, whereas the 5-HT2receptor antagonist ritanserin and the 5-HT3receptor antagonists ondansetron, ICS 205–930 and zacopride were without effect. (-)-Penbutolol reversed 8-OHDPAT-induced inhibition. Ritanserin reversed DOI-induced inhibition of ultrasonic vocalization, but not 8-OHDPAT-induced inhibition. This suggests that there is no functional interaction between 5-HT1Aand 5-HT2receptors in this model. Fenfluramine and 1–5-HTP dose-dependently inhibited footshock-induced ultrasonic vocalization. These findings indicate that the effect most likely is mediated by postsynaptic 5-HT receptors, although contribution by presynaptic 5-HT receptors cannot be excluded. In conclusion, this study indicates that 5-HT1Areceptors and 5-HT2receptors are involved in mediation of ultrasonic vocalization.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID