Acute effects of morphine and chlorpromazine on the acquisition of shuttle box conditioned avoidance response

Morphine sulfate, 0.25–24.0 mg/kg, or chlorpromazine hydrochloride, 0.0625–4.0 mg/kg, were administered subcutaneously to naive rats 30 min prior to the start of massed-trials conditioned avoidance response (CAR) testing. The graded doses of both drugs were applied in each of three CAR task difficulty levels created by manipulation of the duration of conditioned and unconditioned stimuli, intertrial interval and shock intensity. Chlorpromazine, in a dose-related manner, caused a decrement in CAR acquisition in all tasks. Morphine, in comparison, produced a biphasic dose response. For a given task difficulty, low doses of morphine enhanced acquisition, whereas higher doses inhibited acquisition. With increasing task difficulty, relatively larger doses of morphine were required to inhibit or facilitate acquisition of CAR. These results emphasize the need to consider not only drug dosage levels, but also the interaction of task difficulty in the application of drugs in learning paradigms.     

Some effects of chlordiazepoxide and chlorpromazine on response force in extinction

A total of 52 male Wistar rats were continuously reinforced with food pellets for paw-pressing a silent, isometric, force-sensing manipulandum. Subsequently, extinction was introduced and the effects of chlordiazepoxide (CDP, 2.5, 5.0, 10.0 mg/kg) and chlorpromazine (CPZ, 1.0, 2.0, 4.0 mg/kg) upon response force, response rate, and resistance to extinction were observed. CPZ reduced these three extinction measures in a dose-related manner. In accord with predictions from frustration theory, CDP (5.0 mg/kg) increased resistance to extinction. However, contrary to the theory, CDP did not attenuate the extinction-related force increase. This latter result prompted an analysis of the pattern of force emission during a session of reinforced responding. Force for the first response was found to be very near extinction levels. This result, combined with the observation that the first response of a session is virtually uncued by reinforcement, suggested that high extinction force may result from a generalization decrement and not from unconditioned frustration effects.     

Mediated acquisition of a fear-motivated response and inhibitory effects of chlorpromazine

Summary A procedure for determining the effects of drug treatment on fearmotivated behavior is presented. Although basically similar to the conditioned avoidance response (CAR), this procedure separates training events so that drug effects on the conditioning process can be partially analyzed. An avoidance-escape type of response is established efficiently with minimal training. The response shows a sensitivity to inhibition by chlorpromazine comparable to that of the conventional CAR.Results of two portions of the experiment may indicate a psychological basis for reports of synergism between psychotherapy and chlorpromazine therapy. Chlorpromazine inhibited the establishment of an association between a conditioned stimulus and the internal fear state and its drive and cue functions. This inhibition constituted a hindrance to transfer or secondary generalization of the fear-motivated response to another set of circumstances. A therapeutic implication of this effect would be the prevention during chlorpromazine therapy of progressive extension of psychoneurotic symptomatology through secondary generalization. Chlorpromazine also promoted persistent extinction of the fear-conditioned response. This effect might have therapeutic value in promoting the removal of unadaptive responses and the restoration of behavior appropriate to the circumstances.This study was aided by a grant from the University of Oklahoma Research Committee.     

Effect of angiotensin II and vasopressin on acquisition and extinction of conditioned avoidance in rats

The effect of angiotensin II on the acquisition and extinction of a conditioned avoidance response was examined in rats. Angiotensin II, 1 and 2 micrograms, given intracerebroventricularly facilitated acquisition of the conditioned avoidance response but did not influence extinction. [Sar1, Ile8]-angiotensin II (1 microgram), a specific antagonist of angiotensin II receptors, unexpectedly produced an effect quite similar to that of angiotensin II. Vasopressin (1 microgram) did not influence the rate of acquisition of the conditioned avoidance response but it markedly delayed its extinction. The data are discussed in terms of learning and memory facilitating properties of angiotensin II. This action seems to be independent of an interaction of angiotensin II with its known receptors or of release of vasopressin caused by the peptide.     

Effects of angiotensin II on the acquisition of conditioned avoidance response in alcohol-dependent rats

The effect of angiotensin II (ANG II), given in a single intraventricular dose (2 micrograms ivc), on the course of acquisition of a conditioned avoidance response was studied in rats pretreated with alcohol. Ethanol administered for 6 or 18 days did not affect the acquisition, while a prolonged administration (for 2 months) markedly depressed the ability to learn. This effect was not only reversed by ANG II, but the peptide significantly elevated the acquisition rate above the control value.     

Effects of zolpidem,a new imidazopyridine hypnotic,on the acquisition of conditioned fear in mice

Benzodiazepines and other compounds which act at benzodiazepine binding sites have been shown previously to attenuate the acquisition of conditioned fear in rodents when administered before the acquisition session, an effect which may parallel the disruption of human memory produced by anxiolytics and sedatives. Such an action is usually, but not invariably, produced by doses which have direct behavioural depressant effects. The present study was carried out to extend previous work by investigating the effects of the hypnotic benzodiazepine triazolam and the nonbenzodiazepines zolpidem and CL 218,872 on the acquisition of learned fear in mice. All these drugs reduced locomotor activity shortly after injection. They also produced disruptions of the acquisition of learned fear. Triazolam exerted behavioural effects similar to those found previously with other benzodiazepines, the doses which disrupted the acquisition of conditioned fear being similar to, or lower than, the doses which depressed locomotion. In contrast, the results indicated that zolpidem was more potent at reducing locomotion than at interfering with fear conditioning, a result which may reflect the preferential sedative action of zolpidem.     

Acquisition and extinction of an alcohol-opposite conditioned response in humans

Twelve social drinkers were given a 0.7 g/kg dose of alcohol mixed with a distinctively flavoured drink in each of five sessions, and the same drink with no alcohol in a further three sessions. All sessions were conducted in the same room. The alcohol increased heart rate, but with repeated administration change was slower to begin. In the first placebo session the change in heart rate was a decrease below baseline level, particularly in the early part of the session. Repeated administration of the placebo resulted in a diminution of this alcohol-opposite conditioned response.     

Compensating and reactivating effects of quinpirole on extinction of conditioned response and amnesia in mice with alternative behavioral stereotypes

The effect of quinpirole on the passive avoidance habit retention in male C57BL/6J mice with aggressive and submissive behavioral strategies was studied during the habit extinction and amnesia. It was found that the activation of D2 dopamine postsynaptic receptors by quinpirole injections (1 mg/kg, i.p.) prolonged the passive avoidance retrieval during extinction in the submissive mice, while not affecting the basically high memory retrieval level in the aggressors. Under the amnesia conditions, quinpirole reactivated the passive avoidance retrieval irrespective of the base initial behavior status (aggressive versus submissive). It is concluded that the different basic state of the dopaminergic activity in mice predetermines the compensating-reactivating effect of quinpirole.     

Effect of LSD on acquisition, maintenance, extinction and differentiation of conditioned responses

Three experiments were conducted to compare the effects of LSD (30 nmol/kg) on the acquisition, maintenance, extinction and differentiation of the rabbit's classically conditioned nictitating membrane response. LSD significantly enhanced the acquisition of conditioned responses to tone and light conditioned stimuli as compared with vehicle injected controls (Experiments 1 and 2), but had no detectable effect on differential conditioning in Experiment 3. The conditioned responses acquired under LSD in Experiments 1 and 2 exhibited some unusual features in that: they were more rapidly extinguished under continued injections of LSD; they demonstrated a significant decrement when animals were switched from LSD to vehicle during maintenance; and they were virtually eliminated when animals were switched from LSD to vehicle during extinction. In contrast, conditioned responses acquired under saline injections in Experiments 1 and 2 were not affected when animals were switched to LSD injections during either maintenance or extinction. These results of Experiments 1 and 2 were interpreted as indicating that LSD produces an asymmetrical state-dependent learning.     

Effects of NMDA receptor antagonists and sigma ligands on the acquisition of conditioned fear in mice

Recent studies have shown that several compounds known to act as competitive or non-competitive antagonists of NMDA receptors can disrupt learning in rodents. The present study was carried out to investigate the effects of a range of NMDA antagonists, acting at several sites in the NMDA receptor complex, on the acquisition of learned fear in mice. Dose-related disruptions of learning were produced by the non-competitive antagonists phencyclidine, dizocilpine, dextromethorphan and (+) and (–)N-allylnormetazocine. The (+) enantiomer of N-allylnormetazocine was approximately twice as potent as the (–) enantiomer. The competitive NMDA receptor antagonist, CGS 19755, also blocked the acquisition of learned fear as did the non-specific glutamate antagonist riluzole. In contrast, the antiischaemic drugs ifenprodil and SL 82.0715, which probably act as NMDA antagonists through an effect on the polyamine site, had no effect on learning up to doses which substantially reduced locomotion. The sigma receptor ligand DTG was also inactive. These results confirm that both competitive and non-competitive NMDA antagonists disrupt learning but indicate that the extent to which such an effect is observed may depend on the site at which the compounds act within the receptor complex. Activity at sigma receptors is unrelated to the effect on learning.     

Effects of dopamine receptor antagonists on the acquisition of ethanol-induced conditioned place preference in mice

Rationale

Studies support differential roles of dopamine receptor subfamilies in the rewarding and reinforcing properties of drugs of abuse, including ethanol. However, the roles these receptor subfamilies play in ethanol reward are not fully delineated.

Objective

To examine the roles of dopamine receptor subfamilies in the acquisition of ethanol-induced conditioned place preference (CPP), we pretreated animals systemically with antagonist drugs selective for dopamine D1-like (SCH-23390) and D2-like (raclopride) receptors prior to ethanol conditioning trials.

Methods

Effects of raclopride (0–1.2 mg/kg) and SCH-23390 (0–0.3 mg/kg) on the acquisition of ethanol-induced CPP were examined in DBA/2J mice (experiments 1 and 2). Based on significant effects of SCH-23390, we then determined if SCH-23390 (0.3 mg/kg) produced a place preference on its own (experiment 3). To evaluate whether SCH-23390 impaired learning, we used a conditioned place aversion (CPA) paradigm and pretreated animals with SCH-23390 (0–0.3 mg/kg) before conditioning sessions with LiCl (experiment 4).

Results

Whereas raclopride (0–1.2 mg/kg) did not affect acquisition, SCH-23390 (0.1–0.3 mg/kg) impaired the development of ethanol-induced CPP. SCH-23390 (0.3 mg/kg) did not produce place preference when tested alone and SCH-23390 (0.1–0.3 mg/kg) did not perturb the acquisition of LiCl-induced CPA.

Conclusions

Our results support a role for dopamine D1-like but not D2-like receptors in ethanol’s unconditioned rewarding effect as indexed by CPP. Blockade of D1-like receptors did not affect aversive learning in this procedure.     

Effects of (-)3-PPP on acquisition and retention of a conditioned avoidance response in the rat

The administration of (-)3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) was found to partially, but significantly, suppress the acquisition (4–8 mg/kg IP) and performance (8–16 mg/kg IP) of a conditioned avoidance response (CAR) in male Sprague-Dawley rats. All statistically significant effects were observed within 2 h of injection. Furthermore, using a situation in which the CAR was dependent on a visual successive discrimination, it was shown that discriminative performance was unaffected, and that (-)3-PPP (12.5–25 mg/kg IP) but not (+)3-PPP, suppressed the CAR. When (-)3-PPP (6.25 mg/kg IP) was combined with haloperidol (0.1–0.4 mg/kg IP), additive effects on the CAR performance were observed. Considering these effects, and the doses of (-)3-PPP required to suppress the CAR performance, it is concluded that the effects obtained in the present experiments are primarily due to a blockade of postsynaptic DA receptors.     

Anxiolytic drugs and the acquisition of conditioned fear in mice

Previous studies have shown that, in rodents, chlordiazepoxide and other benzodiazepines can interfere with learning in passive avoidance or conditioned suppression procedures. The most consistent effects are observed when the drugs are administered before the acquisition trial and subjects are re-tested in the non-drugged state. It is not clear, however, whether this effect on learning is associated with the behavioural depressant actions of these drugs. In the present study mice were injected with chlordiazepoxide, diazepam, zopiclone, or CGS 9896 and locomotor activity measured in a two-compartment box. The animals were then enclosed in one of the compartments and received a series of footshocks. On a second trial, 24 h after the first, the mice were returned to the box without injection and locomotion and time spent in each compartment were measured. During trial 1 chlordiazepoxide, diazepam, and zopiclone produced dose-related decreases in locomotor activity. The same doses disrupted fear conditioning. CGS 9896 also interfered with the conditioning of fear but did not reduce exploratory activity during the first trial at any of a wide range of doses, showing that learning can be affected without direct behavioural depressant activity. In a further experiment, chlordiazepoxide and CGS 9896 disrupted fear conditioning when injected before trial 1 but not when injected immediately after this trial. Mice drugged with chlordiazepoxide or CGS 9896 before both trials 1 and 2 also showed disrupted conditioning, demonstrating that the drug effects cannot be interpreted in terms of state dependent learning.     

Analysis of the acquisition and extinction of food-reinforced behaviour in rats after the administration of chlorpromazine

The effects of chlorpromazine (2 mg/kg) on the acquisition of lever-pressing behaviour for food rewards have been examined in rats. The drug greatly impaired performance during acquisition but, during a subsequent non-drug testing session, performance was only slightly below that of controls trained and tested under saline; giving the drug to control rats before the testing session markedly impaired performance. It was concluded that chlorpromazine acted mainly on factors, such as attention or motor ability, which were important both during and after acquisition, and that it had little action on central learning processes. Dissociation of learning between drugged and non-drugged states did not occur; changes in drug state even increased responding during extinction, but not during continuous reinforcement. Simple depressant effects of chlorpromazine on attention and motor ability do not seem adequate to account for this, and a further possibility is that the changes in drug state minimised emotional responses elicited by the omission of rewards.     

Different effects of 3-chlorophenylpiperazine on locomotor activity and acquisition of conditioned avoidance response in different strains of mice

Summary Mice of C57BL/6 (C57), Balb/c (BALB), and CD-1 (CD) strains were injected with 3-chlorophenylpiperazine (CPP), 1–10 mg/kg ip, and their exploratory and basal locomotor activities and acquisition of conditioned avoidance response in a shuttle-box were tested. In C57 mice CPP did not affect either locomotor activity or shuttle-box performance. In BALB mice CPP inhibited both basal and exploratory activities (the latter only in higher doses) and facilitated the acquisition of conditioned avoidance response. In CD mice CPP did not affect exploration, but inhibited basal locomotor activity and facilitated the shuttle-box performance. It is concluded that there exist large interstrain differences in responsiveness of mice to CPP, and that the drug may facilitate acquisition of conditioned avoidance response through a strain-specific, serotonin-independent mechanism.     

The effects of chronic amphetamine administration on the acquisition and extinction of an active and passive avoidance response in mice

Long-term amphetamine treatment had no effect on the acquisition or retention of an active or passive avoidance response. In both tasks, however, mice withdrawn from chronic amphetamine administration showed a resistance to extinction relative to control animals. These findings were related to the effects of long-term amphetamine administration on attentional processes. Possible neurochemical mechanisms governing the attentional deficits induced by chronic exposure to amphetamine were discussed.     

Effects of electrical stimulation of the reticular formation and chlorpromazine on performance of trace conditioned avoidance response in the rat

The effects of electrical stimulation to the mesencephalic reticular formation and chlorpromazine on the performance of a trace conditioned avoidance response by rats were studied. Either treatment alone impaired the performance; this impairment was a function of level of stimulation or dose of the drug, respectively. The performance deficit was not present when a high intensity of stimulation of the reticular formation was combined with a moderate dose of chlorpromazine. However, the combination of a high dose of the drug with a low stimulation intensity interfered with the avoidance responding more than any other condition tested. These effects appeared to be independent of neutral or negative reinforcement effects of the stimulation, as tested in an independent situation.     

The effects of fenfluramine and fluoxetine on the acquisition of a conditioned avoidance response in rats

This study tested a behavior-suppressing punishment system and how its activity may be altered by agents known to interrupt or enhance serotonergic (5-HT) transmission. Holtzman male albino rats were tested for shuttle box avoidance acquisition and intertrial responding either 1 or 8 h following daily injections of fenfluramine (FEN) or fluoxetine (FXT). When the drug-test interval was 1 h, a time when both drugs are presumably potentiating 5-HT activity, avoidance acquisition and intertrial responding were impaired. When testing occurred 8 h after drug treatment, a time when 5-HT levels are unaltered by FXT and are maximally reduced by FEN, these drugs had no effect on avoidance acquisition, but FEN produced an increase in intertrial responses whereas FXT did not. These results support the proposal of an inhibitory 5-HT system. Furthermore, these data demonstrate that FEN is capable of exerting a biphasic action on intertrial responding and suggest that the time interval between drug administration and behavioural testing is a crucial variable when investigating FEN.     

Repeated acquisition of response sequences: effects of d-amphetamine and chlorpromazine

Pigeons obtained food by making 4 responses on 3 keys in a specified sequence, e.g., left, right, center, right. All 3 keys were the same color throughout the response sequence. Under the learning condition, the four-response sequence was changed from session to session. After learning (within-session error reduction) had stabilized, this baseline of repeated acquisition was used to assess the effects of varying doses of d-amphetamine and chlorpromazine. For comparison, the drug tests were also conducted under a performance condition in which the four-response sequence was the same from session to session. Increases in total errors and pausing were obtained at the largest dose of each drug under both the learning and performance conditions. Under the learning condition, the error rate decreased across trials within each session, but the degree of negative acceleration was less in the drug sessions than in the control sessions. In contrast, under the performance condition, the error rate was relatively constant across trials, but was higher in the drug sessions than in the control sessions.