摘要:

Dopamine D3receptors have been implicated in the aetiology of schizophrenia and the actions of antipsychotic drugs. The initial studies reported here assessed the involvement of such receptors in thein vivoactions of the atypical antipsychotic clozapine and the putative D3‐preferring antagonist PNU‐99194A in drug discrimination assays. Rats trained to discriminate clozapine consistently generalized to PNU‐99194A in two separate studies. However, four other putative D3‐preferring antagonists (PD 152255, (+)‐S14297, nafadotride and (+)‐AJ 76) did not induce generalization to clozapine. In rats trained to discriminate PNU‐99194A, which has been suggested to induce a stimulus mediated specifically by D3antagonism, the D3‐preferring antagonist (+)‐UH 232 and clozapine both induced full generalization. However, the PNU‐99194A‐trained animals also generalized fully to the muscarinic antagonists scopolamine and trihexyphenidyl. A possible explanation for the symmetrical generalization observed between clozapine and PNU‐99194A is that these drugs have common muscarinic antagonist actions, since muscarinic antagonists have been reported to substitute for clozapine in numerous prior studies. However,in vitroreceptor binding studies with M1−M5receptors indicated that (with the possible exception of the M4receptor), no muscarinic receptor subtype had high affinity for both clozapine, PNU‐99194A and scopolamine. In addition, other binding studies indicated that whereas clozapine and PNU‐99194A had high affinity for the D3receptor, scopolamine did not. It is therefore concluded that: (1) The generalization seen between clozapine, PNU‐99194A and muscarinic antagonists may be mediated by common effects ‘downstream’ from either muscarinic or D3receptors; (2) D3antagonism does not play a critical role in the clozapine stimulus (since D3‐preferring antagonists did not consistently induce generalization to clozapine); (3) although D3antagonism plays a role in the PNU‐91994A stimulus (since the D3‐preferring antagonist (+)‐UH 232 induced full generalization, in accord with results from prior studies with other D3‐preferring antagonists), the PNU‐99194A stimulus also has commonalities with that induced by muscarinic antagonists and clozapine. Thein vivodifferences observed between PNU‐99194A and other D3‐preferring antagonists should be borne in mind when this agent is used as a tool to study D3receptor functioningin vivo. The similarities between the PNU‐99194A and clozapine stimuli suggest tentatively that compounds with a profile like PNU‐99194A may have antipsychotic actions similar to clozapine. Some preclinical data are suggestive of such effects of PNU‐99194A.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The present study assessed the interactions betweenN‐methyl‐ d ‐aspartate (NMDA) agonists or antagonists and the discriminative stimulus effects of amphetamine. Adult male Sprague–Dawley rats were trained to discriminate 0.5 mg/kg (i.p.) of amphetamine from saline under a two‐lever fixed‐ratio schedule of food reinforcement. During test sessions, i.p. injections of the glycine site agonist d ‐cycloserine, the ion‐channel blocker dizocilpine and the competitive antagonist CGP 43487 were coadministered with i.p. saline or with a full range of doses of amphetamine. d ‐Cycloserine did not substitute for amphetamine and attenuated the cueing effects of the drug. Both dizocilpine and CGP 43487 engendered intermediate levels of amphetamine‐appropriate responses and potentiated the stimulus properties of amphetamine; however, the effects of CGP 43487 were very small and not dose‐dependent. In an ancillary experiment, the training dose of amphetamine was reduced to 0.25 mg/kg; under these conditions dizocilpine, but not CGP 43487, produced full substitution for the discriminative stimulus effects of amphetamine. These results show that drugs affecting NMDA receptor‐based neurotransmission can modulate the discriminative stimulus effects of amphetamine.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Opioid antagonists, such as naltrexone (NTX), reduce ethanol consumption and opioid agonists increase or decrease ethanol consumption in rats depending upon the dose. If the opioid antagonist and agonist effects on ethanol consumption are mediated by mu‐opioid receptors, then NTX doses that reduce ethanol consumption should be similar to the doses necessary to antagonize the effects of opioid agonists on ethanol consumption. The purpose of these experiments was: (1) to determine whether morphine increases ethanol consumption in rhesus monkeys as it does in rodents; (2) to determine if the mu‐receptor mediates the effects of morphine on ethanol consumption by conducting a pKBanalysis using NTX; and (3) to determine if the mu‐receptor also mediates the NTX‐induced decreases in ethanol consumption by making comparisons between the NTX doses that affect ethanol consumption and the NTX doses that block the effects of morphine on ethanol consumption. Three male rhesus monkeys responded for 2% ethanol and water for 2 h/day on a fixed‐ratio 4 schedule of reinforcement. Morphine doses as low as 0.0032 mg/kg failed to increase ethanol fluid deliveries, whereas higher doses produced a dose‐related decrease in ethanol fluid deliveries. Although 0.01 mg/kg NTX alone had no effect on ethanol fluid deliveries, it reduced the suppressant effects of morphine with a mu‐receptor pKBof 8.21 (8.08–8.34). When given alone, 0.1 mg/kg NTX decreased ethanol fluid deliveries but failed to reverse the suppression caused by 1 mg/kg morphine. Therefore, monkeys may differ from rats in their response to morphine when ethanol consumption is the dependent variable. Furthermore, because the NTX dose that reduced the effects of morphine on responding for ethanol was smaller than the NTX doses that suppressed ethanol‐reinforced responding when given alone, NTX may exert these two effects through different mechanisms.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

We explored the effects of short, intermediate, and continuous social stress on daily ethanol and water intake in rats. The study was designed to: (1) detect increases in intake during hours when animals were not stressed; and (2) detect shifts in preference from solutions with high to low alcohol content. Male Long–Evans rats acquired ethanol self‐administration using a sucrose‐fading procedure, which was followed by continuous access to 10% and 3% ethanol solutions and water. After intake stabilized, rats were exposed to three periods of five consecutive days of social stress, with 8–10 days without stress in between. Short social stress consisted of being attacked and defeated by an aggressive opponent, followed by 30 min exposure to threats by the aggressive male while in a protective cage. Intermediate and continuous social stress consisted of a 6 h or 24 h ‘threat of attack’ exposure, respectively. All stress exposures reduced daily intake of 10% ethanol, did not cause changes in intake of 3% ethanol, and caused increases in water intake. No compensatory ethanol consumption was observed on stress days or after stress exposure was discontinued. These results are at variance with the hypothesis for increased alcohol consumption during or following social stress episodes.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Progressive‐ratio (PR) schedules have been used widely to examine the relationship between drug consumption and drug price (i.e. demand curves) in the study of the behavioral economics of drug abuse. Sequential effects produced by the increasing response requirements of progressive‐ratio schedules might influence the shape of demand curves for drug reinforcers. This study compared progressive ratio schedule and random sequences of ratio requirements, each incremented across sessions in a within‐subject design, to determine if they produced similar behavioral economic and traditional measures of reinforcer efficacy. Self‐administration of standardized cigarette puffs (70 cc each) was studied with eight smokers. Puffs were available at nine ratio requirements (e.g. 3, 100, 300, 600, 1500, 3000, 6000, 12 000, 24 000 responses/three puffs), presented in ascending (progressive‐ratio schedule) or random sequence across daily sessions. The parameter estimates obtained on measures of reinforcing efficacy (e.g. breakpoint, peak response rates, elasticity of demand) were similar for both methods of incrementing prices. We found no evidence that PR and random sequences of fixed‐ratio (FR) schedules, incremented across daily sessions, resulted in different demand curves.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Adult male Wistar rats were bilaterally implanted with indwelling cannulae in the agranular insular cortex of the prefrontal cortex. After recovery, animals were trained in a step‐down inhibitory avoidance task (3.0‐s, 0.4‐mA footshock) and received, immediately after training, a 0.5‐μl infusion of the serotonergic type 1A (5‐HT1A) receptor agonist dipropylamino‐8‐hydroxy‐1,2,3,4‐tetrahydronaphthalene hydrobromide (8‐OH‐DPAT) or of the 5‐ HT1Areceptor antagonist 1‐(2‐methoxyphenyl)‐4‐[4‐(2‐phthalimido)butyl] piperazine hydrobromide (NAN‐190), or of vehicle alone (20% DMSO). Retention testing was carried out 24 h after training. 8‐OH‐DPAT (1.25 and 6.25 μg but not 0.0125 or 0.125 μg) was amnesic. NAN‐190 was not effective at 0.125 or 1.25 μg any dose but reversed amnesia when given at 1.250 μg simultaneously with both effective doses of 8‐OH‐DPAT. These results show that an overactivation of 5‐HT1Areceptors in the agranular insular cortex impairs memory consolidation of inhibitory avoidance, in rats, immediately after training. This suggests that these receptors of the insular cortex may modulate memory consolidation.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Controversy surrounds the question of whether there are dopamine (DA) receptor abnormalities in the brains of schizophrenia patients; in particular, whether DA receptors of the D2family are elevated in density. Methodological factors and sample characteristics have been postulated to account for differences in study outcome, but there has been no systematic analysis of the contribution of these factors to study effect sizes. This meta‐analysis of the research findings sought to determine the influence of methodologic factors and sample characteristics on the magnitude of diagnostic group differences in DA D2density (Bmax) and affinity (Kd). The analysis suggests at least moderate effects, such that schizophrenia patients show an elevation in both values when compared to controls. These effects are amplified in medicated patients, but not solely attributable to antipsychotics. The group differences in DA D2receptor density and affinity increase with age among nonmedicated patients. The use of a butyrophenone ligand also yields larger effects. It is concluded that a subgroup of schizophrenia patients manifests increased DA D2receptor density and decreased receptor affinity. In the absence of medication, these changes may become more pronounced with age. Differences in study outcome are also partially due to methodologic factors, including the ligand.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Patients receiving therapy with hydrocortisone often report that this drug produces stimulant‐like effects or feelings of well‐being. However, little is known about the mood‐elevating effects of hydrocortisone after acute administration. Four healthy volunteers (two men and two women) received intravenous doses of hydrocortisone (0, 25, 50, 100 or 200 mg) on five separate sessions. Plasma levels of cortisol and adrenocorticotropic hormone (ACTH) were obtained, vital signs were monitored, and subjects completed a series of standardized subjective effects questionnaires. Despite large increases in circulating levels of cortisol, hydrocortisone did not produce any detectable stimulant‐like effect on mood or vital signs. To the contrary, hydrocortisone had a mild sedative‐like effect, decreasing ‘arousal’. These preliminary data indicate that acute increases in cortisol do not have either subjective stimulant‐like or mood‐elevating effects.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID