摘要:

Phencyclidine (PCP) can induce a model psychosis in humans that mimics the positive and negative symptoms of schizophrenia. The purpose of the present study was to determine whether PCP can induce similar behavioural effects in rats and whether these effects can be alleviated by neuroleptic drug treatment. Rats were tested in the social interaction test, and their behaviour was quantified by an automated video-tracking system and manual scorings of stereotyped behaviour and ataxia. The behavioural effects of different dose- and administration regimes of PCP were initially determined, and it was found that PCP dose-dependently induced stereotyped behaviour and social isolation in the rats. Comparison to clinical studies suggests that these behaviours correspond to certain aspects of the positive and negative symptoms, respectively, of a PCP psychosis in humans. Subsequently, the effects of 3 or 21 days of administration of the antipsychotic drugs antipsychotic or clozapine on the behaviour of either vehicle- or PCP-treated rats were determined. Haloperidol did not produce a selective antagonism of PCP, whereas chronic clozapine selectively inhibited the PCP-induced stereotyped behaviour and social isolation. These effects of haloperidol and clozapine suggest that this animal model can determine the effects of neuroleptic drugs on positive and negative symptoms, onset of action, and side-effect profile, including effects on the motor system. Together these data suggest that this may be a possible animal model of the positive and negative symptoms of schizophrenia.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

In order to classlcaly condition the behavioural effects of psychomotor stimulants within a test context, rats were treated for 10 days with (+)-amphetamine (1.5 mg/kg), (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, 30 μg/kg) or vehicle prior to a 1 h placement into a test box. Conditioned behavioural effects were then meaured in the previously drug-paired context after a vehicle injection (drug-free test day). Each rat was videotaped for the 1 h test box exposure on days 1,4,7 and 10 of the drug conditioning trials, and on the drug-free test day. Eleven of 28 behaviours that were scored for frequency, duration and mean bout duration (bout length) were significantly influenced by at least one of the two drugs. Amphetamine predominantly increased bout lengths while PHNO predominantly increased bout frequency. Only two measures that were influenced by the drugs exhibited dear increases over controls in a manner consistent with a classical conditioning teterpretation. Behavioural sensization clearly occurred to some of the effects of amphetamine and PHNO, but these were not the same effects as those increased on the non-drug day testing for classical conditioning. Most behavioural effects of amphetamine and PHNO are not classically conditioned, and behavioural sensitization to these drugs, while perhaps context-specific, is not due to classical conditioning. Automated measres of behaviours have provided misleading evidence concerning the similarity among behavioural effects of stimulants, sensitization and effects of exposure to an environment previously paired with stimulants-Analysis of transitons between behaviours does not support the view that stimulants increase switching or response competition, or that behavioural reorganization is responsible for sensitization. Rather, it is suggested that stimulants selectively facilitate current stimulus-guided behaviours.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

In the present study we have examined the effect of clozapine, an atypical antipsychotic drug, on latent inhibition (LI) using the conditioned emotional response (CER) procedure. In this procedure, ten pre-exposures to the to-be-conditioned stimulus result in weak or no LI whereas 30 pre-exposures produce robust LI. Three different experimental protocols were used to study the effects of clozapine: facilitation of LI in animals subjected to ten pre-exposures to the to-be-conditioned stimulus; antagonism of the disruptive effect of amphetamine (1 mg/kg, s.,c.) on LI in animals receiving 30 pre-exposures; antagonism of the disruptive effect of nicotine (0.6 mg/kg, s.c.) on LI in animals receiving 30 pre-exposures. High doses of clozapine (3 and 10 mg/kg, s.c.) disrupted the CER in non pre-exposed animals. Despite this, clozapine significantly facilitated the development of LI at 1 and 10 mg/kg and significantly attenuated the disruptive effects of nicotine at 0.3 and 1 mg/kg and of amphetamine at 2 and 5 mg/kg. These results demonstrate that clozapine is active in the LI model and further support the utility of this model in the study of mechanisms of action of antipsychotic drugs.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Low doses of benzodiazepines produce state-dependence (StD) of food-rewarded lever pressing in rats, and it has been hypothesized that the changes of memory states that can thus be studied constitute the mechanism whereby benzodiazepines cause their characteristic psychaopharmacological actions such as anxiolysis, apparent memory loss and dependence. Non-benzodiazepine CNS agents such as NMDA antagonists also produce StD in this procedure, suggesting that the StD hypothesis of psychophamacological drug action can be expanded to include agents other than benzodiazepines. For this expansion to be possible, however, it must be shown that the StD mechanism operates in a specific manner. The present experiments examined whether varying the extent of food deprivation affects any of a number of quantitative features of chlordiazepoxide (CDP)-induced StD of food-rewarded lever pressing in rats. The data indicate that the CDP doses required to generate StD in both drug-to-saline and dose-to-dose transfer tests, are considerably lower in relatively sated as opposed to more deprived animals; little or no difference was found in tests assaying saline-to-drug transfer. The data add behavioural to available pharmacological evidence supporting the hypothesis that changes of memory state constitute the mechanism whereby CNS agents such as benzodiazepines and NMDA antagonists cause their characteristic psychopharmacological actions. Some directions for future research are identified to explore further the pharmacological and behavioural specifity of drug-produced StD.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The present study assessed the effects of the indirect acetylcholinesterase inhibitor metrifonate on learning and memory fractions in young (3-month-old) and aged (25-month-old) rats. In the shuttle box, metrifonate at a dose of 12.5 mg/kg, P.O., 30 min before each of the daily acquisition sessions, improved the acquisition of the active avoidance response, whereas a dose of 25 mg/kg did not Metrifonate, 12.5 mg/kg, P.O., administered before each of the daily acquisition sessions, also facilitated the acquisition of the Morris water escape task in both young and aged rats: metrifonate-treated rats swam a shorter distance to reach the escape platform than did the vehicle-treated rats. The 3-month-old rats treated with metrifonate did not show the increase in swimming speed over training observed in vehicle-treated animals; no effects of metrifonate were found on the swimming speed of aged rats. In a probe trial carried out immediately after the fifth daily acquisition session, metrifonate treatment did not affect the bias of the aged rats for the quadrant in which the platform had been positioned during acquisition. It is concluded that metrifonate improves performance during the acquisition phase of two aversively motivated learning and memory tasks at the dose of 12.5 mg/kg, P.O.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Active cannabimimetic drugs are known to bind to two receptor subtypes: one, called CB1, is mainly localised in the central nervous system while the other (CB2) is expressed preferentially in the immune system. SR 141716A has been demonstrated to have a nanomolar affinity for CB1 receptor subtypes and a micromolor affinity for CB2 receptors. Moreover, it is an effective antagonist at these receptors bothin vitro(antagonism of cannabinoid activity invas deferens) andin vivo(suppression of the hypothermia elicited by WIN 55,212–2). The present experiments were thus undertaken to investigate the role of CB1 receptors in cannabinoid discrimination. Rats were trained to discriminate WIN 55,212–2 (0.3 mg/kg s.c.) from saline in a standard operant (FR10) food rewarded discrimination procedure. Acquisition of the discrimination required 16 days on average and the ED50of WIN 55,212–2 was 0.032 mg/kg s.c. CP55,940 and delta-9-tetrahydrocannabinol (Δ9-THC) generalised to the WIN 55,212–2 stimulus with the respective ED50s of 0.007 mg/kg (s.c.) and 0.64 mg/kg (P.O.). Pretreatment with SR 141716A antagonised the cue elicited by WIN 55,212–2 (ED50= 1.6 mg/kg) as well as the generalisation to CP 55,940 (ED50= 0.08 mg/kg) and to Δ9-THC (ED50= 0.15 mg/kg). SR 140098 is a CB1 antagonist as potent as SR 141716Ain vitro. This compound is unlikely to pass into the brain since it failed to displace [3H]-CP55,940 from rat brain membranesex vivo, and to reverse WIN 55,212–2-incuided hypothermia. SR 140098, in contrast to SR 141716A, did not antagonise the WIN 55,212–2 stimulus. Taken together, the present results demonstrate that the brain CB1 receptor subtype mediates the cannabinoid cue.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Bretazenil is a partial agonist at diazepam-sensitive (DS) GABAAreceptors, and it also binds with high affinity to diazepam-insensitive (DI) GABAAreceptors. A unique discriminative stimulus effect transduced by binding at DI benzodiazepine (BZ) receptors has been reported in pigeons, but has not been established in rats. Further, differences have been observed between rats and pigeons in results of drug discrimination experiments utilizing BZ receptor partial agonists. Therefore, to examine the discriminative stimulus effects of bretazenil and to explore the possibility of species differences in substitution profiles, pigeons and rats were trained to discriminate 0.3 mg/kg bretazenil from vehicle. Fretazenil (0.03–1.0 mg/kg) did not substitute for bretazenil in pigeons, despite full substitution of bretazenil for flumazenil in this species. Flumazenil (0.03–10.0 mg/kg) also did not substitute for bretazenil in rats, despite the partial agonist effects of flumazenil in rats. Likewise, midazolam (0.3–1.0 mg/kg) did not substitute for bretazenil in pigeons, despite the fact that bretazenil partially substitutes for midazolam in pigeons. However in rats, midazolam produced full, dose-dependent substitution (0.03–3.2 mg/kg). Differences may result from different fractional receptor occupancy requirements for the mediation of discriminative stimulus effects throngh DS BZ receptors, and/or from a contribution of DI BZ receptor binding in pigeons.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Rats of the Roman high- (RHA) and low-avoidance (RLA) lines are known to differ in alcohol preference, since the RHA rats freely consume more ethanol than RLA animals. In order to investigate whether this difference in alcohol intake could be due to an alteration of the gustatory quality of ethanol induced by the selection, we compared taste preference and aversion responses of RHA and RLA rats in four procedures: saccharin-water choice; gustatory negative contrast; quinine-water choice and 10% v/v alcohol-water choice. Our results confirm that RHA rats drink more alcohol than RLA rats. In the saccharin-water choice task, RHA rats tended to show higher preference than RLA rats for the most palatable concentrations, while their aversion to the highest concentration of saccharin (50 mM) was smaller than the aversion shown by RLA rats. The negative gustatory contrast test did not clearly differentiate the two lines, although only RHA rats showed significant negative contrast Lastly, while RLA rats showed only aversion to quinine as the concentration increased, RHA rats did not show any aversion and preferred quinine to water at mid-range concentrations. To explain these results three hypotheses are briefly discussed: first, selective breeding for high avoidance leaming could have enhanced brain reinforcement processes implicated in the evaluation of palatability. Secondly, selective breeding could have decreased aversiveaess to quinine-adulterated solutions, as well as to saccharin and alcohol solutions which include a quinine-like taste component. Lastly, the present results suggest that the RHA rats may be high sensation-seekers whereas RLA animals are low sensation-seekers.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Injection of the GABAAagonist muscimol into the dorsal raphe nucleus produces a marked and selective increase in voluntary ethanol intake. The purpose of the present study was threefold: first, to demonstrate that the effect of muscimol on ethanol consumption is mediated by GABAAreceptors; secondly, to test the generalizability of this effect by examining the effects of another GABAAagonist, THIP, on ethanol drinking; and finally, to examine whether GABABreceptors within the dorsal raphe also play a role in modifying voluntary ethanol consumption under the same experimental conditions. Rats were trained to drink a 12% ethanol solution in a limited access paradigm with water concurently available. Muscmol (50 ng) injected into the dorsal raphe enhanced ethanol intake by at least 100%. Peripheral administration of the GABAAantagonist bicuculline (4 mg/kg) but not the 5-HT1Aantagonist (+)-WAY100135 (1 and 3 mg/kg), antagonized the stimulatory effect of muscimol at a dose which, when administered alone, did not alter ethanol intake. This supports the suggestion that the effect of muscimol is mediated via GABAAreceptors. This conclusion was further supported by the finding that another GABAAagonist, THIP (500 ng), also selectively increased ethanol intake in this paradigm, injection of biculline (60 ng) into the dorsal raphe reduced ethanol intake, but also appeared to reduce water intake. Finally, intra-dorsal raphe injection of the GABABagonist baclofen (62.5 and 125 ng) did not produce any change in ethanol or water consumption. Together, these findings suggest that enhancement of GABAergic activity in the dorsal raphe increased voluntary ethanol intake via activation of GABAAbut not GABABreceptors.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

In rats exploring a symmetrical Y-maze, an acute injection of quinpirole or intermittent brief footshocks did not change the level of locomotion. The combined treatment of quinpirole and footshocks elicited an immediate locomotor stimulation. When the experimental session was repeated daily, there was a further increase of hyperlocomotion (i.e. sensitization). In parallel groups of rats treated with quinpirole and placed in the Y-maze daily without shock, or subjected only to daily footshock, locomotor activity did not increase. Footshock, therefore, has a synergistic effect in the development of sensitization to quinporole. When the dose-response relationships of quinpirole were compared between naive and sensitized animals, the magnitude of stimulation differed, but the threshold stimulant dose did not change. Pretreatment with sulpiride completely antagonized the hyperlocomotion in both drug-naive and quinpirole-sesitized rats. The results support a view that quinpirole facilitates the emergence of patterned motor behaviors. Non-contingent, brief footshock elicits running as the prepotent behavior in the Y-maze, and hastens the development of behavioral sensitization to quinpirole.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID