Disruption of the US pre-exposure effect and latent inhibition in two-way active avoidance by systemic amphetamine in C57BL/6 mice

RATIONALE: Pre-exposure to either one of the two to-be-associated stimuli alone is known to reduce the efficiency of the learning of their association when they are subsequently paired explicitly. In classical conditioning, pre-exposure to the conditioned stimulus (CS) gives rise to latent inhibition (LI); and pre-exposure to the unconditioned stimulus (US) results in the US pre-exposure effect (USPEE). Considerable evidence supports an important role of central dopamine in the regulation and modulation of LI; it has been suggested that the USPEE may be similarly controlled by dopamine, but this parallelism has only been directly demonstrated in the conditioned taste aversion paradigm. OBJECTIVE: The present study tested this hypothesis by comparing the efficacy of systemic amphetamine treatment to affect the expression of LI and the USPEE in a two-way active avoidance paradigm. METHODS: C57BL/6 male mice were tested in active avoidance using a tone CS and a foot-shock US. Twenty-four hours before, they were pre-exposed to 100 presentations of the CS or the US, or to the test apparatus only. Amphetamine (2.5 mg/kg) or saline was administered before stimulus pre-exposure and conditioned avoidance test, in which the mice learned to avoid the shock by shuttling in response to the tone. RESULTS: Amphetamine disrupted both stimulus pre-exposure effects, thus, lending further support to the hypothesis that the USPEE is similar to LI in its sensitivity to dopamine receptor agonist. Hence, the USPEE paradigm may represent a valuable addition to the study of dopamine-sensitive processes of selective learning currently implicated in LI and Kamin blocking.     

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.     

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.     

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.     

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.     

Nicotine blocks latent inhibition in rats: evidence for a critical role of increased functional activity of dopamine in the mesolimbic system at conditioning rather than pre-exposure

Latent inhibition (LI) is a cognitive process whereby repeated exposure of a stimulus without consequence impedes the formation of subsequent associations with that stimulus. A number of studies in the rat have reported that LI is impaired by moderate systemic doses of amphetamine, an effect believed to be mediated via dopamine (DA) release in the nucleus accumbens. We and others have reported that nicotine has a selective effect in releasing DA in the accumbens rather than the caudate nucleus. We have therefore examined the ability of nicotine to disrupt LI, using a conditioned emotional response paradigm. Pre-exposure of a tone stimulus impaired subsequent conditioning between that stimulus and mild footshock, as indexed by suppression of licking by the tone subsequently presented alone. This LI effect was prevented, by an effect confined to the pre-exposed group, by doses of 0.4 or 0.6 mg/kg nicotine SC, which are accumbens selective, given before pre-exposure and before conditioning. The effect of nicotine in disrupting LI was prevented by prior administration of haloperidol at a dose (0.5 mg/kg) reported to reverse the disruptive effect of amphetamine on LI. Although the amphetamine effect requires two administrations, the effect of two administrations of nicotine was reproduced by a single dose of nicotine given before conditioning, but not by a single dose before pre-exposure. The results are discussed in relation to studies in human control and schizophrenic subjects, which suggest that increased DA activity in humans is also associated with impaired LI. The results indicate that nicotine does indeed increase functional DA activity in the rat accumbens; the consequent disruption of LI critically depends upon an action at the time of conditioning, and is independent of processes which occur during pre-exposure. In more general terms, this indicates the potential of drug experiments to complement behavioural studies on the mechanism of latent inhibition.     

Expression of the CS- and US-pre-exposure effects in the conditioned taste aversion paradigm and their abolition following systemic amphetamine treatment in C57BL6/J mice.

In classical conditioning, pre-exposures to either the to-be-conditioned stimulus (CS) or unconditioned stimulus (US) can retard subsequent conditioning between the CS and US. The present experiment evaluated the expression of these two pre-exposure effects in mice of the C57BL6/J strain, one of the most common background strains for genetically altered mice. We tested whether their expression would be disrupted by amphetamine treatment (2.5 mg/kg, i.p.) in a conditioned taste aversion paradigm with sucrose as the CS and lithium chloride-induced gastric malaise as the US. We found that one pre-exposure (PE) to either the CS or the US reduced aversion to sucrose solution in the controls following conditioning, but no such tendency was evident in the amphetamine-treated mice. The present study represents the first report of amphetamine-induced disruption of the CS-PE effect (ie latent inhibition) in mice, and the first attempt to compare it directly with the US-PE effect in any species. It extended previous reports in rats and humans, suggesting that the sensitivity of latent inhibition to amphetamine is largely comparable across species, thereby lending credence to the use of the latent inhibition effect as a behavioral assay for psychotic-like phenotype in transgenic mice. The parallel observation in the US-PE effect further indicates that its expression, at least in the present conditioned taste aversion paradigm, may also be under similar influence of the dopaminergic system.     

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.     

Provision of cues to signal a withdrawal US prevents the US pre-exposure effect in a diazepam-withdrawal conditioned taste aversion

RATIONALE: Prior experience of withdrawal from chronic diazepam treatment reduces the aversiveness of withdrawal when precipitated withdrawal is made the US in a conditioned taste aversion (CTA) paradigm. Some accounts of US pre-exposure reducing its effectiveness in CTA postulate that US pre-exposure leads to the formation of associations with the environment, resulting in blocking of taste conditioning, but a test of a blocking explanation failed to provide support for such an account. OBJECTIVE: The present experiments tested alternative explanations. METHODS: Male mice (C57BLx129sv derived) made dependent upon diazepam (15 mg/kg per day, SC) were subjected to precipitated withdrawal with IP flumazenil (20 mg/kg) as the unconditioned stimulus (US) in a conditioned taste aversion (CTA) paradigm, in which sucrose was the conditioned stimulus (CS). The conditioning trial took place in either the same or different environment from that in which the mice had received pre-exposure to the withdrawal US. RESULTS: No evidence was found that a place conditioned to withdrawal was capable of supporting a second-order CTA. A second experiment showed that whether withdrawal supported a CTA depended upon whether the previous experience of withdrawal had been predicted by an environmental stimulus. CONCLUSIONS: Prior experience of an unpredictable aversive US disrupts the subsequent formation of a CTA to the same US. Since prior experience of withdrawal, if it was predictable by an environmental event, did not prevent withdrawal from being a US in a subsequent CTA experiment, withdrawal retains its aversive nature even following prior experience. An explanation in terms of the nature of US predictability following repeated withdrawal from diazepam is consistent both with the current data and our previous findings.     

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.     

Previous experience of diazepam withdrawal prevents the formation of a withdrawal-conditioned taste aversion: test of a blocking hypothesis

Prior experience of withdrawal from chronic diazepam treatment reduces the aversiveness of withdrawal when precipitated withdrawal is made the unconditioned stimulus in a conditioned taste aversion (CTA) paradigm. Accounts of the mechanism by which unconditioned stimulus pre-exposure reduces its effectiveness in CTA postulate that unconditioned stimulus pre-exposure leads to the formation of associations with the environment, resulting in blocking of taste conditioning. We tested whether a blocking explanation accounted for the reduced effectiveness of withdrawal as a unconditioned stimulus in a CTA following prior exposure. Mice received chronic diazepam (15mg/kg/day, s.c. in sesame oil), or sesame oil vehicle, for three periods of 7 days, interspersed with 3-day withdrawal periods. The first two withdrawals occurred either in the home cage, or in one compartment of a place-conditioning apparatus (PCA). Animals which experienced withdrawal in the home cage were given equivalent experience of the PCA outside the withdrawal period. The third withdrawal was precipitated by i.p. administration of flumazenil (20mg/kg). Thirty minutes before injection, all animals were placed individually in the compartment of the PCA to which they had been previously exposed, allowed to drink a novel 10% sucrose solution, injected with flumazenil, and replaced in the PCA for 2 h, before being returned to the home cage. When sucrose consumption was measured 24 h later, only that group which had experienced all three withdrawals in the PCA showed evidence of a CTA. These animals (but not those that had experienced withdrawal in the home cage, or vehicle-treated mice) also showed strong avoidance of the chamber in which they had experienced withdrawal. Thus, no evidence was adduced that prior conditioning of an environment-conditioned stimulus to a withdrawal unconditioned stimulus blocked the formation of a CTA. When the CTA conditioning was repeated in the home cage, again only the mice that had experienced withdrawal in the place-conditioning apparatus showed evidence of conditioning. These observations are discussed in the context of blocking explanations of unconditioned stimulus pre-exposure.     

Scopolamine induces disruption of latent inhibition which is prevented by antipsychotic drugs and an acetylcholinesterase inhibitor.

The fact that muscarinic antagonists may evoke a psychotic state ('antimuscarinic psychosis'), along with findings of cholinergic alterations in schizophrenia, have kindled an interest in the involvement of the cholinergic system in this disorder. Latent inhibition (LI) is a cross-species phenomenon manifested as a poorer conditioning of a stimulus seen when the stage of conditioning is preceded by a stage of repeated nonreinforced pre-exposure to that stimulus, and is considered to index the capacity to ignore irrelevant stimuli. Amphetamine-induced LI disruption and its reversal by antipsychotic drugs (APDs) is a well-established model of positive symptoms of schizophrenia. Here, we tested whether the muscarinic antagonist scopolamine would disrupt LI and whether such disruption would be reversed by APDs and by the acetylcholinesterase inhibitor physostigmine. The results showed that scopolamine at doses of 0.15 and 0.5 mg/kg disrupted LI, and that this effect was due to the action of the drug in the pre-exposure stage, suggesting a role of muscarinic transmission in attentional processes underlying LI. Both the typical and the atypical APDs, haloperidol and clozapine, reversed scopolamine-induced LI disruption when given in conditioning or in both stages, but not in pre-exposure, indicating that the mechanism of antipsychotic action in this model is independent of the mechanism of action of the propsychotic drug. Scopolamine-induced LI disruption was reversed by physostigmine (0.05 and 0.15 mg/kg), which was ineffective in reversing amphetamine-induced LI disruption, pointing to distinct mechanisms underlying LI disruption by these two propsychotic drugs. The latter was further supported by the finding that unlike amphetamine, the LI-disrupting doses of scopolamine did not affect activity levels. We propose scopolamine-induced LI disruption as a model of cholinergic-related positive symptoms in schizophrenia.     

Differential effects of intra-accumbens and systemic amphetamine on latent inhibition using an on-baseline,within-subject conditioned suppression paradigm

Latent inhibition (LI) is a phenomenon in which repeated, non-reinforced presentation of a stimulus retards subsequent conditioning to that stimulus. Several recent experiments have suggested that LI is abolished following acute, low doses of amphetamine given during pre-exposure and conditioning, and this effect has been attributed to amphetamine-induced changes in dopamine levels in the nucleus accumbens. Experiments 1 and 2 examined the effects of two doses of intra-accumbensd-amphetamine (10 µg/µl and 3 µg/µl) on LI in an on-baseline, within-subject conditioned suppression paradigm. There was no effect of either dose on LI, but a significant disinhibition of conditioned suppression resulted in a retardation of learning. In experiment 3 the effects of a low dose of systemicd-amphetamine (0.5 mg/kg) on latent inhibition were examined. The results replicated the abolition of LI found in previous studies, and demonstrated enhanced post-shock suppression in amphetamine-treated animals. These data provide no evidence for the involvement of the mesolimbic dopamine system in LI.     

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 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)     

Aversive stimulus properties of the 5-HT2C receptor agonist WAY 161503 in rats

Serotonin2C (5-HT2C) receptors may influence motivation and reward through effects on the mesocorticolimbic dopamine (DA) system. Previous work from this laboratory indicated that 5-HT2C receptor stimulation does not induce place conditioning when animals are tested in a drug-free state, but does result in decreased locomotor activity and increased frequency thresholds for electrical self-stimulation of the ventral tegmental area (VTA). The present study was conducted to determine whether the 5-HT2C receptor agonist WAY 161503 may induce place conditioning in a state-dependent manner and also whether this compound will induce gustatory avoidance conditioning in the conditioned taste aversion (CTA) paradigm. The effects of the 5-HT2C receptor agonist WAY 161503 in the place conditioning and CTA (two-bottle choice test) paradigms were assessed in male Sprague-Dawley rats. Administration of WAY 161503 (3.0 mg/kg) induced a state-dependent conditioned place aversion and a CTA to saccharin. The differential state dependency of 5-HT2C receptor agonists' effects in place conditioning (state dependent) and CTA (non-state dependent) is consistent with the activation of different brain systems in these two paradigms. The state-dependent effects in place conditioning underscore the need to include controls for state dependency in studies of 5-HT receptor related compounds.     

Haloperidol potentiation of latent inhibition in rats: evidence for a critical role at conditioning rather than pre-exposure

Latent inhibition (LI) reflects a cognitive process whereby repeated pre-exposure of a to-be-conditioned stimulus impairs subsequent conditioning. Since it is believed to reflect the ability of an organism to screen out irrelevant stimuli, disrupted LI has been suggested as a model for a cognitive deficit in schizophrenia. Animal studies have previously shown that indirect dopamine (DA) agonists can disrupt LI, an effect which is reversed by neuroleptics. Conversely, neuroleptics given alone potentiate LI. In this study, using pre-exposure to a tone stimulus which is subsequently paired with mild footshock, we have demonstrated that haloperidol given before conditioning only is equally as effective as haloperidol given twice, before pre-exposure and conditioning, in potentiating LI after 10 pre-exposures. This supports our earlier results with nicotine, pointing to conditioning as the critical time for the action of dopaminergic manipulations on LI. The implications for the use of potentiated LI as a screening test for neuroleptic action are discussed.     

Disruption and potentiation of latent inhibition by risperidone: the latent inhibition model of atypical antipsychotic action.

Latent inhibition (LI), that is, retarded conditioning to a stimulus following its nonreinforced pre-exposure, is impaired in some subsets of schizophrenia patients and in amphetamine-treated rats. Potentiation of LI by antipsychotic drugs (APDs) given in conditioning, under conditions that do not lead to LI in controls, is a well-established index of antipsychotic activity. Recently, we have shown that the atypical APD, clozapine, in addition disrupts LI if administered in pre-exposure, under conditions that lead to LI in controls. This study demonstrates the same behavioral profile for the atypical APD risperidone. LI was measured in a thirst-motivated conditioned emotional response procedure by comparing suppression of drinking in response to a tone previously paired with a foot shock in rats that received nonreinforced exposure to the tone prior to conditioning (pre-exposed (PE)) and rats for whom the tone was novel (non-pre-exposed (NPE)). We show that under conditions that did not yield LI in vehicle controls (40 pre-exposures and five conditioning trials), risperidone (0.25, 0.5, and 1.2 mg/kg) led to LI when administered in conditioning. Under conditions that led to LI in vehicle controls (40 pre-exposures and two conditioning trials), risperidone (0.25, 0.5, and 2.5 mg/kg) abolished LI when administered in pre-exposure; the latter effect was not evident with haloperidol. In addition, the effects of risperidone administered in both the pre-exposure and conditioning stages were dose-dependent so that the pre-exposure-based action was manifested at lower but not at higher doses. It is concluded that atypical APDs exert in the LI model a dual pattern of effects, which enables detection of their 'typical' action (conditioning-based LI potentiation) as well as a dissociation from typical APDs by their 'atypical' action (pre-exposure-based LI disruption). It is suggested that the former and latter effects are subserved by D2 and 5HT2A antagonism, respectively.     

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     

Long-term attentional deficit in nonhandled males: possible involvement of the dopaminergic system

Latent inhibition (LI) is a behavioral paradigm in which nonreinforced pre-exposure to a stimulus retards subsequent conditioning to that stimulus. The development of LI is considered to reflect learning not to attend to, or ignore, irrelevant stimuli. In our previous studies investigating the effects of early handling on LI, we have shown that normal LI was obtained in handled males and females, as well as in nonhandled females. In contrast, nonhandled males failed to show LI. This finding pointed to a long-term attentional deficit in nonhandled males. Since there is evidence that the development of LI is mediated by the dopaminergic system, the present experiments tested the possibility that the attentional deficit of nonhandled males may be related to a dopaminergic dysfunction. Experiment 1 tested whether the administration of haloperidol, which was shown to enhance LI in normal animals, would reinstate the LI effect in nonhandled males. Infantile handled (Days 1–22) and nonhandled male and female rats were tested in maturity in the LI paradigm, using a conditioned emotional response procedure. Experiment 2 tested the locomotor response of handled and nonhandled males to 0.3, 1 and 2.5 mg/kg d-amphetamine. Experiment 1 showed that handled males, handled females and nonhandled females showed a normal LI effect, whereas nonhandled males failed to develop LI. Haloperidol enhanced LI in all the groups, but this effect was most dramatic in nonhandled males, in which the drug reinstated LI. Experiment 2 showed that nonhandled males exhibited a reduced locomotor response to d-amphetamine.