Haloperidol and clozapine antagonise amphetamine-induced disruption of latent inhibition of conditioned taste aversion

Rationale Latent inhibition (LI) describes a process by which repeated pre-exposure of a stimulus without any consequence retards the learning of subsequent conditioned associations with that stimulus. It is well established that LI is impaired in rats and in humans by injections of the indirect dopamine agonist amphetamine (AMPH), and that this disruption can be prevented by co-administration of either the typical neuroleptic haloperidol (HAL) or the atypical neuroleptic clozapine (CLZ).Objectives Most of what is known of the pharmacology of LI is derived from studies using either the conditioned emotional response or the conditioned active avoidance paradigm. The goal of the present study was to determine whether these results would generalize to the conditioned taste aversion assay.Methods We tested whether AMPH (0.5 mg/kg) pretreatment would disrupt LI of a conditioned aversion to sucrose, and if so, which stage of the procedure is critical for mediating the disruption; in addition, we tested whether HAL (0.2 mg/kg) or CLZ (5.0 mg/kg) could restore such an expected LI disruption.Results We determined that AMPH disrupted LI when it was injected before pre-exposure and prior to conditioning, but not if the rats were injected before either stage alone. When HAL or CLZ was given 40 min before AMPH (before both pre-exposure and conditioning), it blocked LI disruption.Conclusion These results are in line with the pharmacology of LI as derived from other conditioning paradigms. We conclude that the pharmacological regulation of LI in the CTA paradigm is similar to what has been observed previously in the conditioned emotional response and the conditioned active avoidance paradigms.     

Facilitation of the expression but not the acquisition of latent inhibition by haloperidol in rats

In the latent inhibition (LI) paradigm, nonreinforced preexposure to a stimulus retards subsequent conditioning to that stimulus. The administration of haloperidol in both the preexposure and the conditioning stages was found to enhance LI in the conditioned emotional response (CER) procedure (Weiner and Feldon, 1986). The present experiments investigated the effects of 0.1 mg/kg haloperidol administration on LI in a two-way avoidance procedure, consisting of two stages: preexposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; and conditioning, in which the animals acquired a two-way avoidance response with the tone serving as the warning signal. Experiments 1 and 2 tested whether the administration of haloperidol confirmed to the preexposure stage, where learning to ignore the nonreinforced stimulus takes place, would suffice to enhance the LI effect. In Experiment 1, preexposure and conditioning were conducted 24 hr apart. LI was obtained in both the placebo and haloperidol conditions, but the effect was not more pronounced under the drug. In addition, haloperidol-treated animals exhibited impaired avoidance performance. In Experiment 2, preexposure and conditioning were given 72 hr apart. With this interval, haloperidol did not affect avoidance performance. However, also under these conditions, the magnitude of the LI effect was not larger in the haloperidol-treated groups, indicating that the administration of the drug in the preexposure stage alone did not suffice to enhance LI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low-dose clozapine pretreatment partially prevents haloperidol-induced deficits in conditioned active avoidance

The effectiveness of neuroleptics in disrupting conditioned active avoidance has led to the widespread use of this test as an index of antipsychotic efficacy, whereas the tendency for these drugs to induce catalepsy is believed to reflect their propensity to cause extrapyramidal motor side-effects. Although the typical neuroleptic haloperidol produces catalepsy as well as profound deficits in conditioned active avoidance, the atypical neuroleptic clozapine does not induce catalepsy and is less effective than haloperidol in disrupting active avoidance. Furthermore, clozapine pretreatment prevents haloperidol-induced catalepsy. We investigated whether clozapine pretreatment might also reduce the disruptive effects of haloperidol on two-way active avoidance. We assessed the avoidance acquisition of the following drug treatment groups in which all animals received two injections prior to testing: vehicle + vehicle, vehicle + haloperidol (0.1 mg/kg, i.p.), clozapine (2.5, 5.0 or 10 mg/kg, i.p.) + haloperidol (0.1 mg/kg, i.p.), or clozapine (2.5, 5.0 or 10 mg/kg, i.p.) + vehicle. Haloperidol-pretreated animals showed markedly impaired active avoidance, deficits which were improved by 2.5 and 5 mg/kg but not by 10 mg/kg clozapine pretreatment. These data suggest that the disruptive effects of haloperidol on conditioned active avoidance partially mirror its capacity to induce catalepsy and extrapyramidal motor symptoms. Furthermore, this study indicates that clozapine may be effective in reducing motor side-effects caused by typical neuroleptics.     

The latent inhibition model dissociates between clozapine, haloperidol, and ritanserin.

Latent inhibition (LI), i.e., retarded conditioning to a stimulus following its nonreinforced preexposure, is impaired in some subsets of schizophrenia patients and in amphetamine-treated rats. Typical and atypical antipsychotic drugs (APD's) potentiate LI, but to date the model has not dissociated between them. This study demonstrates such a dissociation using haloperidol (0.1 mg/kg), clozapine (5 mg/kg), and ritanserin (0.6 mg/kg) administered in preexposure and/or conditioning. Under conditions which did not yield LI in vehicle controls (40 preexposures and five conditioning trials), both haloperidol and clozapine, but not ritanserin, led to LI when administered in conditioning. Under conditions which led to LI in vehicle controls (40 preexposures and two conditioning trials), clozapine and ritanserin, but not haloperidol, abolished LI when administered in preexposure. It is suggested that LI potentiation via conditioning detects the "typical" action of APD's whereas LI disruption via preexposure detects the "atypical" action of APD's.     

Phencyclidine does not disrupt latent inhibition in rats: implications for animal models of schizophrenia.

Latent inhibition (LI) is a behavioral paradigm in which prior exposure to a stimulus not followed by reinforcement retards subsequent conditioning to that stimulus when it is paired with reinforcement. The development of LI reflects a process of learning to ignore, or tune out, irrelevant stimuli. Three experiments investigated the effects of phencyclidine (PCP) on LI. The investigation was carried out using a conditioned emotional response (CER) procedure consisting of three stages: preexposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; conditioning, in which the preexposed stimulus was paired with shock; and test, where LI was indexed by animals' suppression of licking during tone presentation. The three stages were conducted 24 h apart. In Experiment 1, 1 mg/kg PCP was administered either in the preexposure or in the conditioning stage or in both. Experiment 2 used 5 mg/kg PCP in the same procedure. In Experiment 3, 5 mg/kg PCP was administered throughout the LI procedure, including the test stage. In all three experiments, PCP did not affect LI. The implications of these findings for the development of animal models of schizophrenia are discussed.     

Abolition of the acquisition but not the expression of latent inhibition by chlordiazepoxide in rats

In the latent inhibition (LI) paradigm, prior nonreinforced exposure to a stimulus retards subsequent conditioning to that stimulus when it is paired with reinforcement. The development of LI reflects learning not to attend to, or ignore, stimuli which predict no significant consequences. The present experiment tested the effects of chlordiazepoxide (CDP) on LI using a conditioned emotional response (CER) procedure consisting of three stages given 24 hr apart: preexposure, in which the to-be-conditioned stimulus, tone, was presented without reinforcement; conditioning, in which the preexposed stimulus was paired with shock; and test, where LI was indexed by animals' suppression of licking during tone presentation. Preexposure and conditioning were given off-baseline. CDP (5 mg/kg) was administered only in preexposure, only in conditioning, in both stages or in neither. The administration of the drug during tone-shock conditioning conducted off-baseline markedly reduced animals' suppression to the tone in a subsequent licking test which was conducted without the drug. The administration of CDP during nonreinforced preexposure to the tone abolished the development of LI, i.e., drug-treated preexposed animals did not show reduced suppression as compared to drug-treated nonpreexposed animals. These results demonstrate that CDP: a) blocks the acquisition of classically conditioned fear and b) disrupts animals' ability to learn that stimuli predict no significant outcomes.     

Facilitation of latent inhibition by the atypical antipsychotic risperidone

The action of the atypical antipsychotic risperidone on latent inhibition (LI), an animal model of schizophrenia, was investigated. The parameters of the procedure were set at values insufficient to generate LI in control rats. On the first day, rats administered 0.5, 1.0, or 2.0 mg/kg ip risperidone or vehicle were preexposed (PE) to 10 tone presentations. On the second day, they were again injected with drug or vehicle and then submitted to two conditioned stimulus (CS; tone)-unconditioned stimulus (US; shock) pairings. On the third day, suppression of their drinking response under the CS was measured. Nonpreexposed (NPE) animals were submitted to the same procedure except for the tone preexposure. On the suppression test, LI was not observed in control rats as well as in animals given 0.5 mg/kg risperidone. Animals given 1.0 and 2.0 mg risperidone, however, displayed an LI effect. The facilitation of LI by risperidone gives additional support to the LI paradigm as an animal model of schizophrenia.     

Systemic administration of MK-801 produces an abnormally persistent latent inhibition which is reversed by clozapine but not haloperidol

Abstract Rationale. Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its inconsequential pre-exposure, and disrupted LI in the rat is considered to model an attentional deficit in schizophrenia. Blockade of NMDA receptor transmission, which produces behavioral effects potentially relevant to schizophrenic symptomatology in several animal models, has been reported to spare LI. Objectives. To show that systemic administration of the non-competitive NMDA antagonist MK-801 will lead to an abnormally persistent LI which will emerge under conditions that disrupt LI in controls, and that this will be reversed by the atypical neuroleptic clozapine but not by the typical neuroleptic haloperidol, as found for other NMDA antagonist-induced models. Methods. LI was measured in a thirst-motivated conditioned emotional response (CER) procedure by comparing suppression of drinking in response to a tone in rats which previously received 0 (non-pre-exposed) or 40 tone exposures (pre-exposed) followed by two (experiment 1) or five (experiments 2–5) tone – foot shock pairings. Results. MK-801 at doses of 0.1 and 0.2 mg/kg reduced conditioned suppression while no effect on suppression was seen at the 0.05 mg/kg dose. At the latter dose, intact LI was seen with parameters that produced LI in controls (40 pre-exposures and two conditioning trials). Raising the number of conditioning trials to five disrupted LI in control rats, but MK-801-treated rats continued to show LI, and this abnormally persistent LI was due to the action of MK-801 in the conditioning stage. MK-801-induced LI perseveration was unaffected by both haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) administered in conditioning, and was reversed by clozapine but not by haloperidol administered in pre-exposure. Conclusion. MK-801-induced perseveration of LI is consistent with other reports of perseverative behaviors, suggested to be particularly relevant to negative symptoms of schizophrenia, following NMDA receptor blockade. We suggest that LI perseveration may model impaired attentional set shifting associated with negative symptoms of schizophrenia. Moreover, the finding that the action of MK-801 on LI and the action of clozapine are exerted in different stages of the LI procedure suggests that the MK-801-based LI model may provide a unique screening tool for the identification of novel antipsychotic compounds, whereby the schizophrenia-mimicking LI abnormality is drug-induced, but the detection of the antipsychotic action is not dependent on the mechanism of action of the pro-psychotic drug. Electronic Publication     

The sigma ligand BMY-14802 as a potential antipsychotic: evidence from the latent inhibition model in rats

Latent inhibition (LI) is a measure of retarded conditioning to a previously-presented nonreinforced stimulus, that is impaired in schizophrenic patients and in rats treated with amphetamine. Neuroleptic drugs are known to produce two effects in this test paradigm: to antagonise amphetamine-induced disruption of LI, and to enhance LI when administered on their own. The present experiments tested the effects on LI of a potential antipsychotic, sigma ligand BMY-14802. The experiments used a conditioned emotional response (CER) procedure in rats licking for water, consisting of three stages: preexposure, in which the to-be-conditioned stimulus (a tone) was repeatedly presented without being followed by reinforcement; conditioning, in which the preexposed stimulus was paired with reinforcement (a foot shock); and test, in which LI was indexed by animals' degree of suppression of licking during tone presentation. In Experiment 1, 20 tone preexposures and two conditioning trials were given and the effects of 5, 15, and 30mg/kg BMY-14802 were assessed. Experiment 2 tested the effects of 15 and 30mg/kg on LI using ten preexposures and two conditioning trials. Experiment 3 investigated the effects of 15 and 30mg/kg on LI using 40 preexposures and extended conditioning consisting of five tone-shock pairings. Experiments 4 and 5 investigated antagonism of amphetamine-induced disruption of LI by 15 and 30mg/kg BMY-14802, respectively. BMY-14802 was found to antagonise amphetamine-induced disruption of LI and enhance LI when low numbers of preexposures and two conditioning trials were given, but not following extended conditioning. These results provide partial support for the suggestion that BMY-14802 may possess antipsychotic properties.     

Disruption of latent inhibition by acute administration of low doses of amphetamine

In the latent inhibition (LI) paradigm, nonreinforced preexposure to a stimulus retards subsequent conditioning to that stimulus. Three experiments investigated the effects of acute amphetamine administration on LI in rats. Experiments 1 and 3 used a conditioned emotional response (CER) procedure and Experiment 2 used two-way active avoidance procedure. Experiments 1 and 2 showed that, in both the CER and avoidance procedures, 1.5 mg/kg dl-amphetamine administered either in the preexposure or the conditioning stage alone did not disrupt LI. In contrast, amphetamine administered in both of the stages abolished LI. Experiment 3 showed that the abolition of LI was obtained when the preexposure and conditioning were given 24 hr apart but not when the two stages were given in one session.     

MDL 73,147EF, a 5-HT3 antagonist, facilitates latent inhibition in the rat.

Latent inhibition (LI) is a behavioral model of selective attention that has been used to study the attentional deficits seen in schizophrenia. In the present study, we examined the effect of 5-hydroxytryptamine3 (5-HT3) receptor blockade on LI using the conditioned emotional response (CER) procedure. Prior exposure to 20, 30, or 40 stimulus presentations significantly, and almost completely, inhibited the CER to that stimulus. This LI effect was much weaker when only 10 preexposures were given. 1H-indole-3-carboxylic acid, trans-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester methanesulfonate (MDL 73,147EF), a selective 5-HT3 receptor antagonist, significantly facilitated the LI effect observed after 10 preexposures at 0.1 mg/kg but not at 0.01 mg/kg. The magnitude of this effect was comparable to that observed with the classical neuroleptic haloperidol (0.1 mg/kg). Neither MDL 73,147EF nor haloperidol affected the CER in animals not preexposed to the stimulus. These results strongly corroborate suggestions that 5-HT3 receptor antagonists will be of use in the treatment of schizophrenia.     

Monosialoganglioside (GM1) attenuates the behavioural effects of long-term haloperidol administration in supersensitive rats.

In the present study we investigated the effects of co-administration of GM(1) (15.0 mg/kg, twice daily, for 30 days) and haloperidol (1.0 mg/kg, twice daily, for 30 days), as well as the effects of a 5-day treatment with this dose of GM(1) after withdrawal from haloperidol in rats. The animals were evaluated in the open-field test and apomorphine-induced stereotyped behaviour. The results show that GM(1) was able to attenuate dopaminergic supersensitivity evaluated by the locomotion frequency at 24 and 48 h after the withdrawal from haloperidol. On the other hand, rearing frequency was changed neither by haloperidol nor by GM(1.) In haloperidol-treated rats immobility time differs from 30 min observation session in comparison with the following sessions after the withdrawal from neuroleptic. Apomorphine-induced stereotyped behaviour produced a significant increase in scores of haloperidol-withdrawn rats. GM(1) did not modify the haloperidol effects and did not change the dopamine receptor affinity to apomorphine 100 h from abrupt neuroleptic withdrawal.     

Schedule-controlled behavior in the morphine-dependent and post-dependent rat

Four groups (N=8) of rats received five 15-trial sessions of one-way avoidance training. Each trial was signaled by a ten-second tone stimulus and shock followed on a random 67% of the trials. Prior to each session two groups were injected with 1.0 mg/kg of the neuroleptic pimozide and the other two groups received vehicle injections. The pimozide groups failed to acquire the avoidance response although they escaped readily when shock was presented, and the vehicle groups acquired the avoidance response. Three 15-trial nondrug test sessions followed. For one group that had been trained under pimozide and one vehicle group, shock continued to follow the tone on 67% of the test trials. The remaining two groups were tested in extinction, i.e., shocks were no longer presented. Both groups that were trained under pimozide showed gradual acquisition of the avoidance response in the first nondrug test session. The group that received vehicle during training and shock during testing continued to avoid whereas the other vehicle group showed extinction of the avoidance response across test sessions. The acquisition of responding in the extinction group trained under pimozide indicated that the association of environmental stimuli with shock had been learned during training in spite of the failure to avoid. The gradual acquisition of the response indicated that this group had failed to learn the appropriate motor response during training. These results support previous observations of associative learning in animals treated with neuroleptics but further suggest that dopamine plays a role in mechanisms of response learning.     

Differential effects of haloperidol and clozapine on attention

Haloperidol (0, 0.1, 0.3, or 1.0 mg/kg), the typical butyrophenone neuroleptic, decreased investigation of novel objects by gerbils following systemic injections. When given prior to apomorphine (1 or 3 mg/kg), haloperidol blocked apomorphine-induced disruption of selective attention in a dose-dependent manner. Thus, haloperidol acts like pimozide in this paradigm. In contrast, clozapine (0, 0.03, 0.1, 0.3, 1.0, or 3.0 mg/kg), the atypical dibenzodiazepine neuroleptic, increased frequency of investigation both soon after injection and 24 h later, suggesting interference with maintenance of attention. When given with apomorphine (1.0 mg/kg), clozapine did not block apomorphine effects on selective attention. The results are related to differential effects of these neuroleptics on other behaviors and to their individual pharmacological profiles.     

Dose-dependent effects but not sensitization of DRL 45-s performance by oral d-amphetamine with cumulative- and repeated-dosing regimens

The effects of d-amphetamine (AMPH) on a food-reinforced DRL 45-s schedule were evaluated using both cumulative- and repeated-dosing drug regimens. These two dosing regimens were designed to evaluate sensitization as a shift in the dose-response relationship, inasmuch as a range of doses was imposed within each dosing session. Daily 190-min sessions were composed of five 35-min subsessions separated by 3-min time-out periods. For selected sessions, five cumulative or repeated oral doses of AMPH were administered across the session, with a dose given during each of the time-out periods prior to the start of each subsession. Drug sessions were separated by intervals of 7-l0 days of non-drug sessions. Four cumulative dose-effect functions for AMPH were determined: for each dose-effect determination session, increasing doses (0.5, 1, 2, 4, 8 mg/kg gavage) were successively administered prior to each subsession. Four dose-effect functions were then determined in which a 0.5 mg/kg AMPH dose was repeated for each subsession (repetitive-dose regimen) rather than escalating subsession dose size. Then, four additional functions were determined using a larger repetitive dose of 1 mg/kg AMPH. Cumulative doses resulted in a leftward shift in the inter-response times (IRT) distribution accompanied by dose-dependent increases in subcriterion responses (< 45 s) and decreases in reinforced responses. The repeated doses of 0.5 or 1 mg/kg AMPH also resulted in progressive intrasession increases in subcriterion responses and decreases in reinforced responses. Although intrasession, accumulating dose effects were evident and statistically significant, there was no statistical significance or trend supporting sensitization of differential reinforcement of low-rate (DRL) responding with either cumulative- or repeated-dosing regimens across drugging sessions, unlike a previous, similar study in which oral cocaine resulted in robust sensitization.     

Restoration of latent inhibition by olanzapine but not haloperidol in entorhinal cortex-lesioned rats

RATIONALE: Latent inhibition (LI) refers to the decrease in conditioned response induced by the repeated non-reinforced pre-exposure to the conditioned stimulus before its pairing with the unconditioned stimulus during the conditioning stage. LI has been considered as a relevant animal model for the study of the biological bases of schizophrenia. LI has recently been demonstrated to depend on the integrity of the entorhinal cortex, as lesioning of this area disrupted LI. OBJECTIVES: The present study aimed to verify whether the classical neuroleptic haloperidol and/or the atypical antipsychotic olanzapine would prevent the effect of entorhinal cortex lesioning. METHODS: LI was studied in an off-baseline conditioned emotional response (CER) paradigm in which a tone is paired with a footshock. Entorhinal cortex lesions were produced by the electrolytic method. After a recovery period, both lesioned and control rats received either haloperidol (0.3 mg/kg), olanzapine (0.3 mg/kg) or vehicle before both the pre-exposure and conditioning stages of the experiment. RESULTS: In control rats, pre-exposure to the tone induced LI, which was affected by neither haloperidol nor olanzapine. Lesioning of the entorhinal cortex produced a deficit of LI, which was restored by olanzapine but not by haloperidol. CONCLUSIONS: This result suggests a dissociation of the anatomical and pharmacological targets of the two drugs. The possible involvement of dopamine D3 receptors in the effects of olanzapine is discussed.     

Antagonism of amphetamine-induced disruption of latent inhibition in rats by haloperidol and ondansetron: Implications for a possible antipsychotic action of ondansetron

Latent inhibition (LI) is a behavioural phenomenon whereby preexposure to a stimulus without reinforcement interferes with the formation of subsequent associations to that stimulus. Using preexposure to a tone stimulus which subsequently serves as a conditioned stimulus for suppression of licking, we have confirmed that LI is disrupted by a low dose of amphetamine. Haloperidol was able to prevent this effect of amphetamine. Ondansetron, a selective and potent 5HT₃ receptor antagonist, was also shown to be effective at blocking the amphetamine-induced disruption of LI at a dose of 0.01 mg/kg, but not at 0.1 mg/kg. In addition, it was demonstrated that ondansetron could enhance LI; using only ten preexposures, no LI was obtained in the saline group, but was apparent in animals given ondansetron, an effect which has been previously shown with haloperidol. Haloperidol, at the higher dose used, reduced suppression of licking, however, ondansetron at the effective dose had no such effect. It is concluded that ondansetron is able to attenuate increases in dopamine activity, produced pharmacologically with amphetamine without affecting baseline dopamine activity. The implications of these findings for a possible antipsychotic action of ondansetron are discussed.     

Abnormally persistent latent inhibition induced by MK801 is reversed by risperidone and by positive modulators of NMDA receptor function: differential efficacy depending on the stage of the task at which they are administered

Rationale Latent inhibition (LI) is the poorer conditioning to a stimulus resulting from its nonreinforced preexposure. LI indexes the ability to ignore irrelevant stimuli and is used extensively to model attentional impairments in schizophrenia (SZ). We showed that rats and mice treated with the N-methyl-d-aspartic acid (NMDA) receptor antagonist MK801 expressed LI under conditions preventing LI expression in controls. This abnormally persistent LI was reversed by the atypical antipsychotic drug (APD) clozapine and by compounds enhancing NMDA transmission via the glycineB site, but not by the typical APD haloperidol, lending the MK801 LI model predictive validity for negative/cognitive symptoms. Objective To test additional representatives from the two classes of drugs and show that the model can dissociate between atypical APDs and glycinergic drugs are the objectives of the study. Materials and methods LI was measured in a conditional emotional response procedure. Atypical APD risperidone, selective 5HT2A antagonist M100907, and three glycinergic drugs were administered in preexposure or conditioning. Results Rats treated with MK801 (0.05 mg/kg) exhibited LI under conditions that disrupted LI in controls. This abnormality was reversed by risperidone (0.25 and 0.067 mg/kg) and M100907 (1 mg/kg) given in preexposure. Glycine (0.8 g/kg), d-cycloserine (DCS;15 and 30 mg/kg), and glycyldodecylamide (GDA; 0.05 and 0.1 g/kg.) counteracted MK801-induced LI persistence when given in conditioning. Conclusions These results support the validity of MK801-induced persistent LI as a model of negative/cognitive symptoms in SZ and indicate that this model may have a unique capacity to discriminate between typical APDs, atypical APDs, and glycinergic compounds, and thus, foster the identification of novel treatments for SZ.     

Acute withdrawal from repeated cocaine treatment enhances latent inhibition of a conditioned fear response

Psychostimulant-induced locomotor sensitization and disrupted latent inhibition (LI) of a classically conditioned association are two paradigms that have been widely studied as animal behavioural models of psychosis. In this study we assessed the effects of withdrawal from the repeated intermittent administration of cocaine on LI of a conditioned fear response. Animals which were either preexposed (PE) to a tone conditioned stimulus (CS) or naive to the tone (i.e. non-preexposed: NPE) subsequently experienced 10 pairings of the tone CS with footshock. Afterwards, both groups received five daily injections of cocaine (20 mg/kg, i.p.) or saline. After 3 days of withdrawal from drug treatment, animals were tested for conditioned freezing to the context of the footshock chamber, and 1 day later, for conditioned freezing to the tone CS. Cocaine-sensitized animals exhibited markedly enhanced LI compared to saline-treated animals, due to the fact that NPE-cocaine animals spent more time freezing during the tone CS than NPE-saline animals, whereas PE-cocaine animals showed a tendency toward reduced freezing compared to the saline groups. While these results suggest the presence of increased anxiety in cocaine-withdrawn NPE animals, the absence of this effect in cocaine-withdrawn PE rats indicates that cocaine withdrawal also influences the retrieval of previously learned information.     

Facilitation of latent inhibition by haloperidol in rats

Latent inhibition (LI) is a behavioral paradigm in which prior exposure to a stimulus not followed by reinforcement retards subsequent conditioning to that stimulus when it is paired with reinforcement. Two experiments investigated the effects of 0.1 mg/kg haloperidol administration on LI as a function of number of CS pre-exposures. The investigation was carried out using a conditioned emotional response (CER) procedure consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where LI was indexed by animals' suppression of licking during tone presentation. The three stages were conducted 24 h apart. In Experiment 1, 40 CS pre-exposures were given. LI was obtained in both the placebo and haloperidol conditions, but the effect was much more pronounced under the drug. Experiment 2 used ten CS pre-exposures. LI was not obtained in the placebo animals but was clearly evident in animals injected with haloperidol. The implications of these findings for the effects of neuroleptics on learning are discussed.