摘要:

Rats were trained in a two-lever drug discrimination procedure using saline or clomethiazole (8 mg/kg, s.c. 15 min) as the training stimuli. A criterion of 9/10 days correct lever choice was adopted to select rats for substitution tests. The clomethiazole (CMZ) cue was not especially strong, and stable performance at this level was not achieved consistently. Nevertheless, in a series of substitution tests carried out in extinction, diazepam (3 mg/kg), chlordiazepoxide (10 mg/kg), phenobarbital (60 mg/kg), dizocilpine (0.1 mg/kg) and mianserin (3.0 mg/kg) were found to substitute for the training dose of CMZ. The first two of these produced a percentage choice of the drug lever equal to that produced by the training dose of CMZ (full generalization) whereas the latter three produced only partial generalization. Ethanol, muscimol, allopregnanolone, chlorpromazine and amitriptyline did not generalize to CMZ. CMZ is known to potentiate 7-aminobutyric acid (GABAA) receptor function, a finding supported by the generalization to CMZ of the two benzodiazepines and phenobarbital. However, not all drugs acting at GABAAreceptors generalized to CMZ. Although CMZ has no affinity for the N-methyl-D-aspartate (NMDA) receptor, it antagonizes a number of pharmacological responses mediated by NMDA receptors. The generalization in the drug discrimination procedure reported here support the suggestion that altering GABAactivity can modulate NMDA-mediated responses. The lack of generalization after treatment with ethanol, chlorpromazine and amitriptyline suggests that the interoceptive cues are not mediated by a generalized sedation or druginduced motor impairment.

ISSN:0955-8810    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Animal models in behavioral pharmacology can be evaluated based on their face, predictive and construct validity. A further level of validity may be achieved if a model is reproduced precisely across species - from laboratory animal to human - using identical conditions and manipulations to elicit identical behavioral changes. Under circumstances in which a model achieves 'homologous' validity, it should be possible to demonstrate that the same pharmacological agents produce parallel changes in the same behavior (as distinct from the clinical condition that the animal behaviors are hypothesized to model), when studied in laboratory animals and in humans. Studies have demonstrated that the disruption of sensorimotor gating of the startle reflex, measured by prepulse inhibition (PPI), in rats by dopamine agonists exhibits face, predictive and construct validity for the relative loss of PPI in schizophrenia patients. To assess the homologous validity of this model, and to expand its utility in understanding the pathophysiology of sensorimotor gating deficits and in developing novel antipsychotic agents to reverse these deficits, it will be important to study PPI across species, comparing response profiles to identical pharmacological manipulations. In the present studies, we report that PPI in rats is reduced in a dosedependent manner by four dopamine agonists that can be administered with relative ease to humans. We also report that the PPI-disruptive effects of the clinically useful dopamine agonist pergolide are reversed by both typical and atypical antipsychotics. These studies establish a foundation for pursuing human pharmacological studies of PPI, and for extrapolating the substantial neurochemical and neurophysiological information from animal studies of PPI, towards understanding the neural basis for deficient sensorimotor gating in specific neuropsychiatric disorders.

ISSN:0955-8810    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Selective opioid-receptor agonists were tested in combination with cocaine to determine the effect on the motor activity of rats. Cocaine produced dose-dependent increases in locomotor activity (distance traveled). The cocaine-induced increase in locomotor activity was potentiated by the selective δ-opioid receptor agonist [D-Pen2-D-Pen5]enkephalin (DPDPE). This potentiation was blocked by the general opioid receptor antagonist naltrexone, as well as by the selective opioid receptor antagonists β-FNA (µ-opioid receptor) and naltrindole (δ-opioid receptor). DPDPE also potentiated the increase in locomotor activity produced by the selective dopamine reuptake inhibitor GBR12909, but not that produced by the direct dopamine receptor agonist apomorphine. Cocaine-induced motor activity was potentiated by the activation of central δ- opioid receptors. The synergistic effect seen with δ-opioid receptor activation may involve a (β-opioid receptor component, and is probably mediated via a dopaminergic pathway.

ISSN:0955-8810    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Behaviours associated with drug action can sometimes be elicited, in the absence of drug, by exposure to stimuli that were present during drug administration. Such a finding is usually interpreted as a conditioned drug effect. Often, however, the outcome could arise if drug administration in a particular environment retarded behavioural habituation to that environment. To test the 'habituation hypothesis' of conditioned drug effects, mice received 10 daily injections of damphetamine ('paired' group) or saline ('unpaired') in test boxes, and the converse injections in the colony room. Another group received saline in both environments. The apparatus and procedures yielded minimal habituation of behaviours (ambulation and rearing) over sessions. Only the paired group demonstrated behavioural sensitization, indicating environment-specific sensitization. The paired group also showed more ambulation and rearing than the others on the critical test of conditioning (saline injection in test box); moreover, their conditioning test scores were higher than those of the other groups on their first exposure to the test boxes, contradicting the habituation hypothesis. Further supporting the involvement of Pavlovian conditioning, levels of ambulation and rearing measured for 10min before each injection increased in the paired group, relative to the unpaired groups, over successive pairing sessions. Tests controlling for differential handling/injection experience produced results consistent with those previously obtained. Together, the findings are incompatible with the habituation hypothesis, and further support the role of Pavlovian conditioning.

ISSN:0955-8810    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Rats received, through bilaterally implanted indwelling cannulae, 0.5 µl infusions of 6-cyano-7-nitroquinoxaline2,3-dione (CNQX) (0.5 µg), D-2-amino-5-phophono pentanoic acid (AP5) (5.0 µg), muscimol (0.5 µg), scopolamine (2.0 µg), SCH23390 (2.5 µg), saline or a vehicle into the CA1 region of the hippocampus, or into the antero-lateral prefrontal (PRE), posterior parietal (PP) and entorhinal cortex (EC). The infusions were given 6min prior to one-trial step-down inhibitory avoidance training in order to measure their effect on working memory (WM), or immediately post-training in order to measure their effect on short-term (STM) and long-term memory (LTM), 1.5 and 24 h later, respectively. WM was inhibited by CNQX or muscimol given into any of the cortical areas, by SCH23390 given into CA1, PRE or PP, and by scopolamine given into PRE or EC. STM was unaffected by any of the treatments given into PRE, and was inhibited by CNQX or muscimol given into CA1, PP and EC and by scopolamine given into PP, and enhanced by SCH given into CA1. LTM was inhibited by CNQX, muscimol, scopolamine or SCH23390 given into PRE, by scopolamine given into PP, by SCH23390 given into the entorhinal cortex, and by AP5, CNQX, muscimol or scopolamine given into CA1. The results indicate a differential involvement of the various neurotransmitter systems in the three types of memory in the various brain areas, and a separation of the mechanisms and of the regions involved in each. In addition, some of the findings suggested links between WM and LTM processing in PRE, between WM and STM processing in EC and PP, and between all three types of memory in CA1.

ISSN:0955-8810    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The present study was designed to examine the effects of haloperidol (0.03, 0.1 mg/kg, intraperitoneal (i.p.)) and damphetamine (0.3, 1.0 mg/kg, i.p.) in a cone field task in which spatial working and reference memory (WM and RM, respectively) were assessed simultaneously. The apparatus is a large open field in which 16 cones are placed with four cones baited by placing a food reward in the top. After food-deprived rats had acquired this task they showed a high level of performance, that is avoided visits to non-baited cones (RM) and made few revisits to baited cones (WM). Haloperidol had a greater negative effect on RM than on WM performance, but also decreased the number of food rewards collected. On the other hand, the high dose of (damphetamine induced a clear WM performance deficit, whereas RM performance was only marginally affected. The present study suggests that spatial discrimination performance can be dissociated using the measures RM and WM in the present task. Further, the deficits induced by haloperidol and (damphetamine may not be specifically related with impaired mnemonic functions.

ISSN:0955-8810    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Previous research has shown that the rate of punished lever pressing of monkeys is typically decreased by cocaine administration. However, cocaine increases punished responding in monkeys with a history of responding maintained by the postponement of shock presentation. This raises the question of whether other behavioral effects of cocaine differ following a history of postponing shock. The present experiment examined whether a history of postponing shock alters the discriminative stimulus effects of cocaine. Three squirrel monkeys were trained to discriminate cocaine (0.56mg/kg, intramuscular) from saline. Presses on the left lever produced food following saline injections whereas presses on the right lever were reinforced following administration of cocaine. Occasional test sessions were conducted in which cocaine (0.1- 0.56mg/kg), midazolam (0.03-0.56 mg/kg) or pentobarbital (0.3-5.6 mg/kg) was injected prior to the session and responding on either lever was reinforced. Discrimination training was discontinued during a second experimental phase in which responding was maintained by shock postponement. Pulling a chain postponed mild shocks for 25 s, whereas shocks occurred every 5 s in the absence of responding. Next, the drug discrimination dose-response curves were redetermined. The dose-response curves for all drugs before and after the shock postponement history were similar. This outcome suggests that the influence of a history of shock postponement is specific to punished responding.

ISSN:0955-8810    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The dopamine D3/D2receptor agonists 7-OH-DPAT, quinpirole, quinelorane, and PD128907, the mixed dopamine agonist apomorphine, the D2agonist bromocriptine, and the D1/D5agonist SKF38393 were examined in models of hypothermia and prepulse inhibition (PPI) in Wistar rats. As dopamine agonist-induced hypothermia has been proposed as a model of D3receptor function, and dopamine agonists are known to disrupt PPI, drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI. 7-OH-DPAT, quinpirole, quinelorane, PD128907, and apomorphine, reduced body temperature and disrupted PPI with a similar rank order of potency (quinelorane>quinpirole=7-OHDPAT>PD128907=apomorphine). Bromocriptine and SKF38393 were ineffective in both models. In a separate study, the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI. In a final set of studies, the D2/D3antagonist raclopride blocked both 7-OH-DPAT-induced hypothermia and 7-OH-DPAT-induced PPI disruption. The 5-HT,A antagonist WAY 100,135, and the peripheral D2-like antagonist domperidone had no effect. These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3receptors; however, only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2or D4receptors.

ISSN:0955-8810    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

A series of experiments was carried out in which the potency of the selective α-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA)-receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (10-100 mg/kg) on locomotor activity was investigated, in mice. NBQX reduced all forms of activity studied, but its potency to do so varied according to the conditions of the experiment. The smallest dose of NBQX significantly reducing spontaneous or cocaineinduced activity was 100 mg/kg. Mice that had been repeatedly treated with 16 mg/kg cocaine once per week, for 7 weeks, showed a sensitized locomotor response to a challenge dose of cocaine (16 mg/kg). NBQX reversed the sensitized response at 30 and 100 mg/kg. The pattern of results obtained leaves open the role that AMPA-receptors may have in the expression of behavioural sensitization. In two further experiments, mice were trained to self-administer cocaine (30 µg per reinforcer) via intravenous catheters, using an operant lever pressing technique. When the amount of cocaine per reinforcer was doubled (to 60 µg) or halved (to 15 µg) the mice adapted lever pressing rates to maintain some constancy of self-dosing (but not at 7.5 µg per reinforcer) and when saline was substituted for cocaine, response rates increased considerably (extinction bursting). NBQX (10 and 30 mg/kg) reduced the self-administration of 30 µg reinforcers of cocaine, but only during the first 30 min of the test session. There was no evidence that NBQX specifically antagonized the reinforcing effect of cocaine, as responding was similarly reduced on both the reinforced and the non-reinforced lever, nor did the response to NBQX mimic behaviour seen following changes in the concentration of the reinforcer. The results of the locomotor experiments and the self-administration experiments are discussed together, in terms of current hypotheses about glutamatergic mechanisms involved in motivation for drug.

ISSN:0955-8810    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Early investigators of brain stimulation-evoked complex behaviours (attack, escape, feeding, self-grooming, sexual behaviour) reported that experience may affect the behavioural outcome of brain stimulation. This intriguing example of functional neuronal plasticity was later totally neglected. The present experiment investigated the behavioural outcome of in vivo microdialysis perfusion of the glutamate agonist kainate and/or the GABAAantagonist bicuculline into the hypothalamic attack area (HAA) of (1) animals naive to dyadic encounters; (2) animals with a recent aggressive experience (the probe being implanted 6-24 h after the last of a series of dyadic encounters); and (3) animals with an earlier aggressive experience (probe being implanted 2 weeks after the last aggressive experience). On the experimental day, rats received two 5-min infusions during a dyadic encounter lasting 35 min with an unknown opponent. Flow rate was 1.5-2 µl/min, drug concentrations were 1.8 x 10- 5and 1.5 x 10- 5for kainate and bicuculline, respectively. Behaviour was analysed before, during and after perfusions. Only the combined kainate + bicuculline treatment had significant effects on behaviour at the doses studied. A significant increase in aggressive behaviour was elicited only in animals with a recent aggressive experience, while naive animals and animals with an earlier experience responded to the treatments by grooming. These results appear to support early observations indicating that one important aspect of brain stimulation effects is previous experience.

ISSN:0955-8810    

出版商:OVID    

年代:1998

数据来源: OVID