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)     

Latent inhibition is not affected by acute or chronic administration of 6 mg/kg dl-amphetamine

Latent inhibition (LI) is a behavioral paradigm in which animals learn to ignore a repeatedly presented stimulus not followed by meaningful consequences. We previously reported that LI was disrupted following the administration of 1.5 mg/kg dl-amphetamine. The present experiments investigated the effects of 6 mg/kg dl-amphetamine administration on LI in 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, the drug was administered in a 2×2 design, i.e. drug-no drug in pre-exposure and drug-no drug in conditioning. LI was obtained in all conditions. In Experiment 2, animals were given either 5 days of 6 mg/kg amphetamine pretreatment and amphetamine in pre-exposure and conditioning or 7 days of saline. LI was not obtained under amphetamine, but this outcome reflected a state-dependency effect. In Experiment 3, animals received either 5 days of amphetamine pretreatment and amphetamine in pre-exposure, conditioning and test or 8 days of saline. LI was obtained in both the placebo and amphetamine conditions. Experiments 4a and 4b compared the effects of two drug doses, 1.5 (4a) and 6 mg/kg (4b), administered in pre-exposure and conditioning. LI was abolished with the 1.5 mg/kg dose but not with the 6 mg/kg dose.     

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.     

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.     

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.     

Effect of the NMDA antagonist MK-801 on latent inhibition of fear conditioning

N-methyl-d-aspartate (NMDA) receptors seem to play a central role in learning and memory processes involved in Latent Inhibition (LI). In fact, MK-801, a non-competitive NMDA receptor antagonist, has proved its effectiveness as a drug for attenuating LI when administered before or after stimulus preexposure and conditioning stages. This paper presents three experiments designed to analyze the effect of MK-801 on LI when the drug is administered before (Experiment 1A) or after (Experiment 1B) preexposure and conditioning stages with a conditioned emotional response procedure. Additionally, we analyze the effect of the drug when it was administered before preexposure, before conditioning or before both phases (Experiment 2). The results show that the effect of the drug varied as a function of the dose (with only the highest dose being effective), the moment of administration (with only the drug administered before the experimental treatments being effective), and the phase of procedure (reducing LI when the drug was administered only at preexposure, and disrupting fear conditioning when administered at conditioning). These differences may be due to several factors ranging from the role played by NMDA receptors in the processing of stimuli of different sensorial modalities to the molecular processes triggered by drug administration.     

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.     

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

The animal amphetamine model of schizophrenia has been based primarily on stereotyped behavior. The present study sought to demonstrate an amphetamine-induced deficit in attentional processes. To this end, the effects of acute and chronic (14 days) 1.5 mg/kg dl-amphetamine administration on the ability of rats to ignore irrelevant stimuli were examined using the paradigm of latent inhibition (LI) in a conditioned emotional response (CER) procedure. The procedure consisted of three stages: pre-exposure, in which the to-be-conditoned stimulus, tone, was presented without being followed by reinforcement; acquisition, in which the pre-exposed tone was paired with shock; and test, in which LI was indexed by animals' suppression of licking during tone presentation. Experiment 1 showed that chronic but not acute treatment abolished LI. Experiment 2 showed that animals receiving chronic amphetamine pretreatment but pre-exposed and conditioned without the drug, exhibited normal LI. In Experiment 3, animals which received chronic amphetamine pretreatment and were pre-exposed under the drug but conditioned without it, also showed normal LI. The implications of these results for the animal amphetamine model of schizophrenia are discussed.     

Latent inhibition in 35-day-old rats is not an "adult" latent inhibition: implications for neurodevelopmental models of schizophrenia

Rationale Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its inconsequential preexposure. Amphetamine-induced disruption of LI and its potentiation by antipsychotic drugs (APDs) in the adult rat are well-established models of schizophrenia and antipsychotic drug action, respectively. It is not clear whether LI can be similarly modulated at prepubertal age.Objectives In view of the notion that schizophrenia is a neurodevelopmental disorder whose overt expression depends on postpubertal brain maturational processes, we investigated whether several manipulations known to modulate LI in adult rats, including systemic administration of amphetamine and the atypical APD clozapine, are capable of producing the same effects in prepubertal (35-day-old) rats.Methods LI was measured in a thirst motivated conditioned emotional response (CER) procedure in which rats received 10 or 40 tone preexposures followed by 2 or 5 tone-footshock pairings.Results Like in adults, LI was present with 40 preexposures and 2 conditioning trials. In contrast to findings in adults, LI was resistant to disruption by amphetamine at a dose (1 mg/kg) that significantly increased locomotor activity, as well as by reducing the number of preexposures to ten, increasing the number of conditioning trials to five, or changing the context between preexposure and conditioning. Clozapine (5 mg/kg) and the selective 5HT2A antagonist M100907 (0.3 mg/kg) administered in conditioning were without an effect on "persistent" LI with extended conditioning, but were capable of disrupting LI when administered in the preexposure stage, as found in adults.Conclusion The results point to functionality within brain systems regulating LI acquisition but not those regulating LI expression in periadolescent rats, further suggesting that postpubertal maturation of the latter systems may underlie schizophrenia-mimicking LI disruption reported in adult rats following perinatal manipulations and possibly disrupted LI observed in schizophrenia.     

Clozapine and haloperidol reinstate latent inhibition following its disruption during amphetamine withdrawal.

Latent inhibition (LI) is a behavioral phenomenon whereby repeated exposure to a non-reinforced stimulus retards subsequent conditioning to that stimulus. Deficits in LI may reflect an inability to ignore irrelevant stimuli and are studied as a model of the cognitive/attentional abnormalities found in schizophrenia. We recently determined that pretreatment with escalating doses of the indirect dopamine agonist amphetamine (AMPH; 3 daily injections ip, 1-5 mg/kg, over 6 days) disrupts LI in rats tested in a 2-way active avoidance paradigm during withdrawal. In the present study, we evaluated the effects of the atypical neuroleptic clozapine and the typical neuroleptic haloperidol on the expression of LI on day 4 of AMPH withdrawal. Neuroleptic injections were given either 45 min prior to each of two tone preexposure sessions and a subsequent tone-shock avoidance test session, or only prior to the test session. As expected, saline-injected control groups showed LI during the test session, as reflected by significantly reduced avoidance in tone preexposed vs. non-preexposed rats. In contrast, animals pretreated with escalating doses of AMPH did not show LI, due to the improved avoidance of the preexposed animals. Both haloperidol (0.03 mg/kg) and clozapine (5 mg/kg) largely reversed the disruptive influence of AMPH on LI regardless of whether these drugs were administered prior to both preexposure and test sessions or only prior to the test session. These results provide pharmacological validation for an AMPH withdrawal model of schizophrenic symptoms.     

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.     

Dopamine in nucleus accumbens: salience modulation in latent inhibition and overshadowing

Latent inhibition (LI) is demonstrated when non-reinforced pre-exposure to a to-be-conditioned stimulus retards later learning. Learning is similarly retarded in overshadowing, in this case using the relative intensity of competing cues to manipulate associability. Electrolytic/excitotoxic lesions to shell accumbens (NAc) and systemic amphetamine both reliably abolish LI. Here a conditioned emotional response procedure was used to demonstrate LI and overshadowing and to examine the role of dopamine (DA) within NAc. Experiment 1 showed that LI but not overshadowing was abolished by systemic amphetamine (1.0 mg/kg i.p.). In Experiment 2, 6-hydroxydopamine (6-OHDA) was used to lesion DA terminals within NAc: both shell- and core- (plus shell-)lesioned rats showed normal LI and overshadowing. Experiment 3 compared the effects of amphetamine microinjected at shell and core coordinates prior to conditioning: LI, but not overshadowing, was abolished by 10.0 but not 5.0 μg/side amphetamine injected in core but not shell NAc. These results suggest that the abolition of LI produced by NAc shell lesions is not readily reproduced by regionally restricted DA depletion within NAc; core rather than shell NAc mediates amphetamine-induced abolition of LI; overshadowing is modulated by different neural substrates.     

Amphetamine increases aversive conditioning to diffuse contextual stimuli and to a discrete trace stimulus when conditioned at higher footshock intensity

Amphetamine can increase conditioning to poor predictors of reinforcement in selective learning tasks (e.g. latent inhibition, LI). In the present study, a noise stimulus was contiguous with footshock or presented at a trace interval. A flashing light background stimulus was used to measure contextual conditioning. Experiment 1 used 1.5 mg/kg and 6 mg/kg dl-amphetamine. Experiments 2 and 3 used 0.5 mg/kg and 1.5 mg/kg d-amphetamine. Unconditioned stimuli parameters (intensity, number, duration) were also manipulated from one experiment to the next. Amphetamine consistently increased conditioning to the background stimulus, and increased conditioning to the trace stimulus at higher footshock intensity (Experiment 3). Thus, amphetamine increased conditioning only to relatively uninformative predictors. The effect on conditioning to trace conditioned stimuli depended on the level of reinforcer but increased conditioning to background did not. Throughout, there was no effect of amphetamine on conditioning of the contiguous stimulus. Thus, the results did not simply arise because amphetamine increased conditioning under any condition in which conditioning without amphetamine was poor. The results are discussed in terms of amphetamine effects on breadth of attention and LI to context.     

The effects of the new antipsychotic, sertindole, on latent inhibition in rats

Latent inhibition (LI) is a measure of retarded conditioning to a previously presented non-reinforced stimulus, that is impaired in schizophrenic patients and in rats treated with amphetamine. Neuroleptic drugs are known to produce two effects in this paradigm: to antagonize amphetamine-induced disruption of LI, and to facilitate the development of LI when administered on their own. The present experiments tested the effects on LI of the new neuroleptic, sertindole. The experiments used a conditioned emotional response procedure in rats licking for water, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus (a tone) was repeatedly presented without being followed by reinforcement; conditioning, in which the pre-exposed stimulus was paired with reinforcement (a foot shock); and test, in which LI was indexed by degree of suppression of licking during tone presentation. In Experiment 1 the effects of 0.31, 1.3 and 5.0mg/kg sertindole were assessed following pre-exposure to 40 non-reinforced tones. Experiment 2 tested the effects of 5mg/kg on LI following pre-exposure to 10 non-reinforced tones. Experiment 3 investigated antagonism of amphetamine-induced disruption of LI by 5.0mg/kg sertindole. The results demonstrated that sertindole (5.0mg/kg) possesses a neuroleptic-like profile in the LI model: it facilitates the development of LI and antagonizes amphetamine-induced disruption of LI.     

Amphetamine-induced disruptions of latent inhibition are reinforcer mediated: implications for animal models of schizophrenic attentional dysfunction

Latent inhibition (LI) is a phenomenon observed when repeated, non-reinforced presentation of a stimulus results in a retardation of subsequent conditioning to that stimulus. Several recent experiments have suggested that LI is abolished in conditioned suppression paradigms following acute, low doses of amphetamine given during pre-exposure and conditioning. Experiment 1 sought to increase the generality of this finding in an appetitive LI paradigm, using a dose of amphetamine previously shown to disrupt the LI effect in an aversive paradigm (Killcross and Robbins 1993). However, no evidence for any disruption of LI was found. Experiment 2 extended this investigation to additional, higher doses ofd-amphetamine, and also examined the role of reinforcer magnitude in the effect. A non-significant trend towards an attenuated LI effect was found, which was reversed by decreases in the concentration of the sucrose reinforcer. Experiments 3 and 4 investigated the influence of systemic amphetamine in aversive paradigms, with specific attention to the increased response to the aversive footshock reinforcer found in amphetamine-treated animals. These experiments revealed that the influence of amphetamine on the LI effect in conditioned suppression paradigms could be reversed by reducing the intensity of footshock used in conditioning, thereby paralleling the effect found in the appetitive paradigm. Therefore it is unlikely that a simple attentional account of the abolition of the LI effect in previous experiments can be sustained.     

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.     

Antagonism of amphetamine-induced disruption of latent inhibition by the atypical antipsychotic olanzapine in rats

The present study aimed at characterising the effects of the new antipsychotic olanzapine in a Latent Inhibition (LI) paradigm. A conditioned emotional response (CER) procedure was used, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus (a tone) was presented six times without being followed by reinforcement; conditioning, in which the pre-exposed stimulus was paired twice with reinforcement (a foot shock); and test, in which LI was assessed by the suppression of licking during the tone presentation. In Experiment I, it was found that pre-treatment with an intermediate dose (0.312mg/kg) of olanzapine, but not with lower (0.003; 0.031mg/kg) or higher doses (0.625; 1.25mg/kg), restored LI in amphetamine-treated (1.5mg/kg) animals. This effect could not be attributed to a disruptive effect of olanzapine on CER learning, as olanzapine per se had no effect on this conditioning (Experiment 2). In Experiment 3, olanzapine did not antagonise the amphetamine-induced locomotor hyperactivity. As olanzapine has not only dopaminergic, but also serotonergic, adrenergic, histaminergic and cholinergic activities, the differential effects of olanzapine on amphetamine-induced disruption of LI and hyperactivity may reflect an action on several pharmacological targets, possibly interacting with one another.     

The role of mesolimbic and nigrostriatal dopamine in latent inhibition as measured with the conditioned taste aversion paradigm

Repeatedly presenting a non-reinforced stimulus normally retards conditioning to this stimulus when it is coupled to a reinforcer. This phenomenon is called latent inhibition. Since latent inhibition is disturbed after systemic administration of amphetamine, the present study investigated the role of the mesolimbic and nigrostriatal dopamine terminal fields in latent inhibition using a conditioned taste aversion (CTA) paradigm. In this paradigm, a 5% sucrose solution was used as the test stimulus and lithium chloride (LiCl) as the CTA inducing drug. The degree of CTA was assessed by measuring the sucrose preference in a two-bottle sucrose/water choice paradigm 24 h after the LiCl injection. Since conditioned taste aversion has so far not been used to evaluate the role of dopamine in latent inhibition, we first studied the effects of systemic application of amphetamine. The results show that intraperitoneal injections of 0.25 or 0.5 mg/kg d-amphetamine sulphate (given at preexposure and conditioning) significantly disrupted latent inhibition, by selectively reducing sucrose preference in the preexposed group. This could not be attributed to a reduced sucrose intake during preexposure or to a conditioned taste aversion effect of amphetamine itself. In experiment 2 local bilateral administration of 10 μg/0.5 μl amphetamine into the nucleus accumbens or the dorsal striatum was given in the pre-exposed and the conditioning phase, after which the rats were allowed to drink for a fixed period of time. The results show a significant reduction in latent inhibition after intrastriatal, but not after intra-accumbens injections of amphetamine. Intra-accumbens injections of amphetamine, however, significantly reduced fluid intake during preexposure and conditioning. In experiment 3, we therefore repeated this experiment, but allowed the animals to drink only a restricted amount of liquid during preexposure and conditioning. Again the results show a disruption of latent inhibition after intrastriatal, but not intra-accumbens injections of amphetamine. These experiments emphasize the importance of the nigrostriatal dopamine system in the disruption of latent inhibition, at least when using the conditioned taste aversion paradigm. A possible mechanism by which the dorsal striatum might influence latent inhibition is discussed. Received: 22 November 1995 /Final version: 20 August 1996     

Clozapine-induced potentiation of latent inhibition is due to its action in the conditioning stage: implications for the mechanism of action of antipsychotic drugs

Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its non-reinforced pre- exposure. LI is impaired in some subsets of schizophrenic patients and in rats treated with amphetamine. Antipsychotic drugs (APDs) potentiate LI under conditions that are insufficient to produce LI in control animals, namely, low number of pre-exposures or high number of conditioning trials. The present experiments tested the proposition that LI potentiation under both conditions stems from the action of APDs in the conditioning stage. Experiments 1-3 used 10 pre-exposures and 2 conditioning trials, and tested the effects of 2.5, 5, and 10 mg/kg clozapine, respectively. Experiments 4-6 used 40 pre-exposures and 5 conditioning trials, with clozapine doses as above. Clozapine was administered in either the pre-exposure, the conditioning stage, or in both. In all the experiments, vehicle controls did not show LI. Overall, clozapine administration in conditioning, irrespective of drug condition in pre-exposure, produced LI. The implications of these results for the mechanism of action of antipsychotic drugs are discussed.     

Latent inhibition is unaffected by direct dopamine agonists.

Latent inhibition (LI) refers to the finding that nonreinforced preexposure to a stimulus retards subsequent conditioning to that stimulus when it is paired with reinforcement. The development of LI reflects a process of learning not to attend, or ignore, irrelevant stimuli. Previous experiments showed that LI was disrupted by low but not high doses of amphetamine, and facilitated by neuroleptic drugs. The present experiments sought to investigate the role of dopamine D1 and D2 receptors in LI disruption. Experiments 1 and 2 showed that the selective D1 agonist, SKF-38393 (1, 5, 10 mg/kg) and the selective D2 agonist, quinpirole (0.1, 0.3, 1.0 mg/kg), did not affect LI. Experiment 3 showed that both low (0.3 mg/kg) and high (1.5 mg/kg) doses of the mixed D1-D2 agonist, apomorphine, failed to affect L1. These results show that L1 is not disrupted by direct stimulation of DA receptors and suggest that the differential effect exerted on this phenomenon by apomorphine (and possibly SKF-38393 and quinpirole) and amphetamine is related to the direct versus the indirect agonist action of these drugs. In addition, apomorphine at the dose of 0.03 mg/kg, which is believed to activate preferentially DA autoreceptors, did not produce neuroleptic-like facilitation of LI. The implications of the results of the involvement of DA mechanisms in L1 are discussed.