Conditioned Emotional Response Procedure Research Articles

Hippocampal Disinhibition Reduces Contextual and Elemental Fear Conditioning While Sparing the Acquisition of Latent Inhibition

Hippocampal neural disinhibition, i.e., reduced GABAergic inhibition, is a key feature of schizophrenia pathophysiology. The hippocampus is an important part of the neural circuitry that controls fear conditioning and can also modulate prefrontal and striatal mechanisms, including dopamine signaling, which play a role in salience modulation. Consequently, hippocampal neural disinhibition may contribute to impairments in fear conditioning and salience modulation reported in schizophrenia. Therefore, we examined the effect of ventral hippocampus (VH) disinhibition in male rats on fear conditioning and salience modulation, as reflected by latent inhibition (LI), in a conditioned emotional response (CER) procedure. A flashing light was used as the conditioned stimulus (CS), and conditioned suppression was used to index conditioned fear. In experiment 1, VH disinhibition via infusion of the GABA-A receptor antagonist picrotoxin before CS pre-exposure and conditioning markedly reduced fear conditioning to both the CS and context; LI was evident in saline-infused controls but could not be detected in picrotoxin-infused rats because of the low level of fear conditioning to the CS. In experiment 2, VH picrotoxin infusions only before CS pre-exposure did not affect the acquisition of fear conditioning or LI. Together, these findings indicate that VH neural disinhibition disrupts contextual and elemental fear conditioning, without affecting the acquisition of LI. The disruption of fear conditioning resembles aversive conditioning deficits reported in schizophrenia and may reflect a disruption of neural processing both within the hippocampus and in projection sites of the hippocampus.

The dopamine D1 receptor agonist SKF81297 has dose-related effects on locomotor activity but is without effect in a CER trace conditioning procedure conducted with two versus four trials

In an appetitively motivated procedure, we have previously reported that systemic treatment with the dopamine (DA) D1 receptor agonist SKF81297 (0.4 and 0.8mg/kg) depressed acquisition at a 2s inter-stimulus-interval (ISI), suitable to detect trace conditioning impairment. However since DA is involved in reinforcement processes, the generality of effects across appetitively- and aversively-motivated trace conditioning procedures cannot be assumed. The present study tested the effects of SKF81297 (0.4 and 0.8mg/kg) in an established conditioned emotional response (CER) procedure. Trace-dependent conditioning was clearly shown in two experiments: while conditioning was relatively strong at a 3-s ISI, it was attenuated at a 30-s ISI. This was shown after two (Experiment 1) or four (Experiment 2) conditioning trials conducted in – as far as possible – the same CER procedure. Contrary to prediction, in neither experiment was there any indication that trace conditioning was attenuated by treatment with 0.4 or 0.8mg/kg SKF81297. In the same rats, locomotor activity was significantly enhanced at the 0.8mg/kg dose of SKF81297. These results suggest that procedural details of the trace conditioning variant in use are an important determinant of the profile of dopaminergic modulation.

Effect of dopamine and serotonin receptor antagonists on fencamfamine-induced abolition of latent inhibition

The purpose of this investigation was to verify the role of dopamine and serotonin receptors in the effect of fencamfamine (FCF) on latent inhibition. FCF is a psychomotor stimulant with an indirect dopaminergic action. Latent inhibition is a model of attention. Latent inhibition is blocked by dopaminergic agents and facilitated by dopamine receptor agonists. FCF has been shown to abolish latent inhibition. The serotonergic system may also participate in the neurochemical mediation of latent inhibition. The selective dopamine D1 receptor antagonist SCH 23390 (7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol), D2 receptor antagonists pimozide (PIM) and methoclopramide (METH), and serotonin 5-HT2A/C receptor antagonist ritanserin (RIT) were used in the present study. Latent inhibition was evaluated using a conditioned emotional response procedure. Male Wistar rats that were water-restricted were subjected to a three-phase procedure: preexposure to a tone, tone-shock conditioning, and a test of the effect of the tone on licking frequency. All of the drugs were administered before the preexposure and conditioning phases. The results showed that FCF abolished latent inhibition, and this effect was clearly antagonized by PIM and METH and moderately attenuated by SCH 23390. At the doses used in the present study, RIT pretreatment did not affect latent inhibition and did not eliminate the effect of FCF, suggesting that the FCF-induced abolition of latent inhibition is not mediated by serotonin 5-HT2A/C receptors. These results suggest that the effect of FCF on latent inhibition is predominantly related to dopamine D2 receptors and that dopamine D2 receptors participate in attention processes.

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.

Discriminated conditioned suppression in rats.

experiment evaluated the effects of superimposing the Estes-Skinner Conditioned Emotional Response (CER) procedure on one of two components of a multiple schedule. The question was whether CER conditioning occurred under contextual control. The procedure had four experimental phases: (1) baseline of operant responding under a two-component multiple schedule (mult VI 30 VI 30), one component correlated with the house light on and the other correlated with the house light off (light/ dark components), (2) introduction of tone-shock pairings during the light component only, (3) return to baseline contingencies, and (4) reintroduction of the tone (but not shock) in the light component. Three Wistar rats showed robust suppression of responding in the light component, and the suppression also partially generalized to the dark component. The suppression was stronger during the pre-aversive stimulus than during the intervals immediately before and after its presentation. Responding partially recovered under baseline contingencies, but response rates remained lower in the light component than in the dark component. Thus, under the present experimental conditions, the context in which CER conditioning occurred (i.e., the house light-illuminated chamber) also produced conditioned suppression, and contextual control of suppressed responding generalized to another context, one that shared some but not all elements of the first context (i.e., the same chamber not illuminated by a house light). These results have direct implications for our understanding of emotional conditioning produced in the laboratory and for analysis of related phenomena addressed in the clinic. Keywords: conditioned suppression; aversive control; contextual control; tone-shock pairings; rats.

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.

Effect of Aripiprazole on Methamphetamine-Induced Disruption of Latent Inhibition in Rats

Objectives: To elucidate the pharmacological profile of aripiprazole, we examined its ameliorating effect on the methamphetamine-induced disruption of latent inhibition (LI) in rats. Method: The effect was measured using a conditioned emotional response procedure. The conditioned stimulus was a tone (2.8 kHz, 90 dB), and the unconditioned stimulus was a mild foot shock delivered through a floor grid. The conditioning procedure was repeated five times. Results: Methamphetamine-induced (1.0 mg/kg, i.p.) disruption of LI was ameliorated by the administration of haloperidol (0.2 mg/kg, i.p.) and by a moderate dose of aripiprazole (0.3 mg/kg, i.p.) but not by a lower or higher dose (0.1 or 3.0 mg/kg, i.p.) of aripiprazole. However, immunohistochemical examination showed increased levels of c-Fos expression in the shell of the nucleus accumbens after the administration of haloperidol (0.2 mg/kg, i.p.) but not of aripiprazole (0.3 mg/kg, i.p.). Conclusions: It is suggested that aripiprazole has an ameliorating effect on methamphetamine-induced disruption of latent inhibition within only a marginal therapeutic window.

Reduced dopamine function within the medial shell of the nucleus accumbens enhances latent inhibition

Latent inhibition (LI) manifests as poorer conditioning to a CS that has previously been presented without consequence. There is some evidence that LI can be potentiated by reduced mesoaccumbal dopamine (DA) function but the locus within the nucleus accumbens of this effect is as yet not firmly established. Experiment 1 tested whether 6-hydroxydopamine (6-OHDA)-induced lesions of DA terminals within the core and medial shell subregions of the nucleus accumbens (NAc) would enhance LI under conditions that normally disrupt LI in controls (weak pre-exposure). LI was measured in a thirst motivated conditioned emotional response procedure with 10 pre-exposures (to a noise CS) and 2 conditioning trials. The vehicle-injected and core-lesioned animals did not show LI and conditioned to the pre-exposed CS at comparable levels to the non-pre-exposed controls. 6-OHDA lesions to the medial shell, however, produced potentiation of LI, demonstrated across two extinction tests. In a subsequent experiment, haloperidol microinjected into the medial shell prior to conditioning similarly enhanced LI. These results underscore the dissociable roles of core and shell subregions of the NAc in mediating the expression of LI and indicate that reduced DA function within the medial shell leads to enhanced LI.

Catecholaminergic depletion within the prelimbic medial prefrontal cortex enhances latent inhibition

Latent inhibition (LI) refers to the reduction in conditioning to a stimulus that has received repeated non-reinforced pre-exposure. Investigations into the neural substrates of LI have focused on the nucleus accumbens (NAc) and its inputs from the hippocampal formation and adjacent cortical areas. Previous work has suggested that lesions to the medial prefrontal cortex (mPFC), another major source of input to the NAc, do not disrupt LI. However, a failure to observe disrupted LI does not preclude the possibility that a particular brain region is involved in the expression of LI. Moreover, the mPFC is a heterogeneous structure and there has been no investigation of a possible role of different regions within the mPFC in regulating LI under conditions that prevent LI in controls. Here, we tested whether 6-hydroxydopamine (6-OHDA)-induced lesions of dopamine (DA) terminals within the prelimbic (PL) and infralimbic (IL) mPFC would lead to the emergence of LI under conditions that do produce LI in controls (weak pre-exposure). LI was measured in a thirst motivated conditioned emotional response procedure with 10 pre-exposures to a noise conditioned stimulus (CS) and two conditioning trials. Sham-operated and IL-lesioned animals did not show LI and conditioned to the pre-exposed CS at comparable levels to the non-pre-exposed controls. 6-OHDA lesions to the PL, however, produced potentiation of LI. These results provide the first demonstration that the PL mPFC is a component of the neural circuitry underpinning LI.

Lesions to the ventral, but not the dorsal, medial prefrontal cortex enhance latent inhibition

The acquisition of a conditioned response to a stimulus when it is paired with a reinforcer is retarded if the stimulus has previously been repeatedly pre-exposed in the absence of the reinforcer. This effect, called latent inhibition, has previously been found to be insensitive to lesions of the medial prefrontal cortex (mPFC) in rats. Using an on-baseline conditioned emotional response procedure, which is especially sensitive to small variations in the absolute magnitude of latent inhibition, we found increased latent inhibition following excitotoxic lesions of the mPFC (Experiment 1) or the ventral mPFC alone (Experiment 2) as compared with sham-operated control rats. Lesions restricted to the dorsal mPFC, however, were without effect (Experiment 2). These results are consistent with those of experiments employing another type of interference procedure, extinction. Together, these findings suggest that when different contingencies between a stimulus and a reinforcer are established in separate learning phases, lesions to the ventral mPFC result in increased interference between first-learned and second-learned contingencies. As a consequence, retrieval of the second-learned contingency is impaired, and performance is dominated by the first-learned contingency. These findings are discussed in light of the use of latent inhibition to model cognitive deficits in schizophrenia.

Dissociating scopolamine-induced disrupted and persistent latent inhibition: stage-dependent effects of glycine and physostigmine

Latent inhibition (LI) is the poorer conditioning to a stimulus seen when conditioning is preceded by repeated non-reinforced pre-exposure to the stimulus. LI indexes the ability to ignore irrelevant stimuli and is used extensively to model attentional impairments in schizophrenia. We showed that the pro-psychotic muscarinic antagonist scopolamine can produce LI disruption or LI persistence depending on dose and stage of administration: low doses disrupt LI acting in the pre-exposure stage of the LI procedure, whereas higher dose produces abnormally persistent LI via action in the conditioning stage. The two LI abnormalities show distinct response to antipsychotic drugs (APDs), with LI disruption, but not LI persistence, reversed by APDs. The objective of this study is to show that both LI abnormalities will be reversed by the cognitive enhancers, glycine and physostigmine, in a stage-specific manner, reversing each abnormality via the stage at which it is induced by scopolamine. LI was measured in a conditioned emotional response procedure. Scopolamine, physostigmine, and glycine were administered in pre-exposure and/or in conditioning. Scopolamine (0.15 mg/kg)-induced disrupted LI was reversed by glycine (800 mg/kg) and physostigmine (0.15 mg/kg) via action in pre-exposure, whereas scopolamine (1.5 mg/kg)-induced persistent LI was reversed by these compounds via action in conditioning. In addition, glycine reversed scopolamine-induced disrupted LI via action in conditioning. Finally, glycine failed to reverse amphetamine-induced disrupted LI. These results extend the pharmacological differentiation between scopolamine-induced disrupted and persistent LI and indicate that the scopolamine LI model may have a unique capacity to discriminate between typical APDs, atypical APDs, and cognitive enhancers.

A new model of the disrupted latent inhibition in C57BL/6J mice after bupropion treatment

Schizophrenia is characterized by disturbances in attention and information processing that can be measured by latent inhibition (LI). Research has implicated significant aberrations in dopaminergic (DA) neurotransmission in this disorder. The objectives of this study were as follows: to probe whether bupropion disrupts LI; to compare its efficacy to the effects of GBR12783 (specific DA uptake inhibitor) and to amphetamine (DA releaser); to test if antipsychotics would reverse LI deficits induced by bupropion, GBR12783, and amphetamine; and to probe if rolipram (phosphodiesterase-4 inhibitor), which increases cyclic AMP (cAMP) similarly to antipsychotics, effectively corrects drug-induced LI deficits. Based on its efficacy in drug addiction, we also asked if bupropion could block the effect of amphetamine. LI was measured in a conditioned emotional response procedure by comparing suppression of drinking in response to a noise in C57BL/6J mice. Mice previously received 0 (nonpreexposed) or 40 noise exposures (preexposed) followed by two or four noise-foot shock pairings. Bupropion abolished LI in mice, which was corrected by rolipram, but not by haloperidol and clozapine. GBR12783 and amphetamine, but not antidepressants, also disrupted LI, and this was reversed by antipsychotics and rolipram. Both bupropion and amphetamine disrupted LI via conditioning session. Paradoxically, bupropion and GBR12783 also blocked the amphetamine-induced LI deficit. Efficacy of rolipram but not antipsychotics to reverse the effects of bupropion suggests novel cAMP-dependent and D(2) receptor-independent mechanisms of the bupropion-induced LI deficit. Further detailed biochemical analysis of bupropion-induced LI deficit might be a fruitful approach in developing new antipsychotics.

Neuromodulatory property of standardized extract Ginkgo biloba L. (EGb 761) on memory: Behavioral and molecular evidence

Although it has been suggested that the standardized Ginkgo biloba leaf extract (Egb 761) may have a beneficial effect on memory, the cellular and molecular changes that underlie this process are not yet well defined. The present study evaluated the effects of acute (one dose) or subacute treatments (one daily dose/seven days) with EGb 761 (0.5 g kg − 1 and 1.0 g kg − 1 ) on rats submitted to a conditioned emotional response (CER) in comparison with positive (4 mg kg − 1 Diazepam) and negative (12%Tween 80) control groups. To this end, eighty ( n = 10/group) adult, male, Wistar rats (± 250–300 g) were used in an off-baseline CER procedure. We here observed that the rats submitted to an acute and subacute EGb 761 treatments had acquisition of fear conditioning. Additionally, we investigate if the expression of genes previously associated with classical conditioning (CREB-1 and GAP-43) and new candidate genes (GFAP) are modulated following EGb 761 acute treatment. CREB-1, GAP-43 and GFAP mRNA and protein expressions were evaluated using both quantitative PCR (qPCR) and immunohistochemical analysis, respectively. We here show, for the first time, that EGb 761 modulated GAP-43, CREB-1 and GFAP expression in the prefrontal cortex, amygdala and hippocampus. We observed an underexpression of GAP-43 in all structures evaluated and over-expression of GFAP in the amygdala and hippocampus following acute G. biloba treatment when compared to control group (Tween; p < 0.01). GAP-43 expression was decreased in prefrontal cortex and hippocampus in the subacute treatment with EGb 761. Subacute treatment with EGb 761 lead to a decreased CREB-1 in mPFC ( p < 0.001) and increased in the hippocampus to 1.0 g kg − 1 G. biloba group ( p < 0.001). The results obtained from immunohistochemical analysis support our aforementioned findings and revealed that the changes in expression occurred within specific regions in the areas evaluated. All together, our findings not only provide new evidence for a role of EGb 761 on memory but also identify molecular changes that underlie the fear memory consolidation.

Pioneer in behavioral pharmacology: a tribute to Joseph V. Brady.

The contributions of Joseph V. Brady to behavioral pharmacology span more than 50 years and range from early studies using the Estes-Skinner (conditioned emotional response) procedure to examine drug effects and various physiological processes in experimental animals to the implementation of mobile methadone treatment services and to small group behavioral analyses in simulated space environments. This expansive range of activities is based on Brady's insight and innovative use of behavioral procedures, his spirited and unabashed enthusiasm for the discipline and its philosophical underpinnings, together with a collegiality and commitment to the experimental analysis of behavior that is both legendary and inspirational. These contributions are summarized and highlighted in this tribute that focuses primarily on Brady's contributions to behavioral pharmacology but which also acknowledges his conceptual and technical contributions spanning multiple disciplines.

Procognitive and antipsychotic efficacy of glycine transport 1 inhibitors (GlyT1) in acute and neurodevelopmental models of schizophrenia: latent inhibition studies in the rat

SSR103800 and SSR504734 are novel glycine transport 1 (GlyT1) inhibitors with therapeutic potential for the treatment of schizophrenia. The present studies investigated the effects of GlyT1 inhibitors in acute pharmacological and neurodevelopmental models of schizophrenia using latent inhibition in the rat; these latent inhibition (LI) models are believed to be predictive for treatments of positive, negative, and cognitive aspects of schizophrenia. LI, the poorer conditioning to a previously irrelevant stimulus, was measured in a conditioned emotional response procedure in male rats. The effects of SSR103800 or SSR504734 (both at 1, 3, and 10 mg/kg, i.p.) were determined on amphetamine-induced disrupted LI, MK-801-induced abnormally persistent LI, and neurodevelopmentally induced abnormally persistent LI in adult animals that had been neonatally treated with a nitric oxide synthase inhibitor. SSR103800 (1 and 3 mg/kg) and SSR504734 (1 and 10 mg/kg) potentiated LI under conditions where LI was not present in nontreated controls and SSR103800 (1 mg/kg) reversed amphetamine-induced disrupted LI while not affecting LI on its own. Additionally, SSR103800 (1 and 3 mg/kg) and SSR504734 (3 and 10 mg/kg) reversed abnormally persistent LI induced by MK-801. In the neurodevelopmental model, SSR504734 (3 and 10 mg/kg) reverted the LI back to control (normal) levels. These preclinical data, from acute and neurodevelopmental models, suggest that GlyT1 inhibition may exhibit activity in the positive, negative, and cognitive symptom domains of schizophrenia.

P.3.b.003 Comprehension of metaphors in patients with schizophrenia

Latent inhibition (LI) refers to retarded conditioning to a stimulus that has been repeatedly presented without reinforcement. LI is impaired in schizophrenic patients and in rats treated with amphetamine. Neuroleptic drugs produce two effects in this test paradigm: antagonism of amphetamine-induced disruption of LI, and enhancement of LI when administered on their own. The present experiments tested the effects of the atypical neuroleptic, clozapine, on LI. The experiments used a conditioned emotional response procedure in rats licking for water, 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 reinforcement (foot shock); and test, in which LI was indexed by animals' degree of suppression of licking during tone presentation. In experiments 1 and 2, the effects of 5.0 and 10.0 mg/kg clozapine on LI were assessed following 20 or 10 tone preexposures, respectively. Experiments 3 and 4 used 40 preexposures and investigated antagonism of amphetamine-induced disruption of LI by 5.0 and 10.0 mg/kg clozapine, respectively. The results demonstrated that clozapine possesses a neuroleptic profile in the LI model, namely, it facilitates the development of LI and antagonizes amphetamine-induced disruption of LI.

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

In order to test the possible role of mGluR5 signaling in the behavioral endophenotypes of schizophrenia and other psychiatric disorders, we used genetic engineering to create mice carrying null mutations in this gene. Compared to their mGluR5(+/+) littermates, mGluR5(-/-) mice have disrupted latent inhibition (LI) as measured in a thirst-motivated conditioned emotional response procedure. Administration of the positive modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPAR), CX546, during the conditioning phase only, improved the disrupted LI in mGluR5 knockout mice and facilitated LI in control C57BL/6J mice, given extended number of conditioning trails (four conditioning stimulus-unconditioned stimulus). Prepulse inhibition (PPI) was impaired in mGluR5(-/-) mice to a level that could not be disrupted further by the antagonist of N-methyl-D-aspartate receptors - MK-801. PPI deficit of mGluR5(-/-) mice was effectively reversed by CX546, whereas aniracetam had a less pronounced effect. These data provide evidence that a potent positive AMPAR modulator can elicit antipsychotic action and represents a new approach for treatment of schizophrenia.

P.3.d.021 Physostigmine reverses MK-801-induced but not amphetamine-induced effects on latent inhibition: focus on cholinergic treatments in schizophrenia

Latent inhibition (LI) refers to retarded conditioning to a stimulus that has been repeatedly presented without reinforcement. LI is impaired in schizophrenic patients and in rats treated with amphetamine. Neuroleptic drugs produce two effects in this test paradigm: antagonism of amphetamine-induced disruption of LI, and enhancement of LI when administered on their own. The present experiments tested the effects of the atypical neuroleptic, clozapine, on LI. The experiments used a conditioned emotional response procedure in rats licking for water, 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 reinforcement (foot shock); and test, in which LI was indexed by animals' degree of suppression of licking during tone presentation. In experiments 1 and 2, the effects of 5.0 and 10.0 mg/kg clozapine on LI were assessed following 20 or 10 tone preexposures, respectively. Experiments 3 and 4 used 40 preexposures and investigated antagonism of amphetamine-induced disruption of LI by 5.0 and 10.0 mg/kg clozapine, respectively. The results demonstrated that clozapine possesses a neuroleptic profile in the LI model, namely, it facilitates the development of LI and antagonizes amphetamine-induced disruption of LI.

Abnormally persistent latent inhibition induced by lesions to the nucleus accumbens core, basolateral amygdala and orbitofrontal cortex is reversed by clozapine but not by haloperidol

Latent inhibition (LI) is the proactive interference of inconsequential preexposure to a stimulus with its ability to signal significant events, and disrupted LI is considered to model positive symptoms of schizophrenia. We have recently shown that lesions of the nucleus accumbens core (NACc), basolateral amygdala (BLA) and orbitofrontal cortex (OFC) produce abnormally persistent LI, and suggested that this phenomenon may model negative symptoms. Here we tested whether NACc, BLA and OFC lesion-induced persistent LI would be reversed by the atypical antipsychotic drug (APD) clozapine but not by the typical APD haloperidol. Because clozapine’s action is likely reflecting its 5HT2A receptor antagonism, we also tested whether NACc lesion-induced persistent LI would be reversed by the selective 5HT2A antagonist M100907. LI was measured in a conditioned emotional response procedure by comparing suppression of drinking in response to a tone in rats receiving 0 (nonpreexposed) or 40 tone presentations (preexposed) followed by five tone-shock pairings. Under these conditions, control rats did not show LI but all lesioned rats persisted in exhibiting LI, and this was reversed by clozapine but not by haloperidol. In addition, M100907 reversed NACc lesion-induced persistent LI. These two novel phenomena, abnormally persistent LI and its selective reversal by an atypical APD, suggest a novel index of schizophrenia relevant behavioral abnormality and of atypical antipsychotic activity in the LI model. The identification of brain regions whose damage leads to persistent LI in the rat may provide valuable cues on dysfunctional brain circuits involved in negative symptoms and in the action of atypical APDs.

Latent inhibition is disrupted by nucleus accumbens shell lesion but is abnormally persistent following entire nucleus accumbens lesion: The neural site controlling the expression and disruption of the stimulus preexposure effect

Latent inhibition (LI) is the proactive interference of repeated nonreinforced preexposure to a stimulus with subsequent performance on a learning task involving that stimulus. The present experiments investigated the role of the nucleus accumbens (NAC) in LI. LI was measured in a thirst motivated conditioned emotional response procedure with low or high number of conditioning trials, and in two-way active avoidance procedure with the stages of preexposure and conditioning taking place in the same or different contexts. Sham-lesioned rats showed LI with low but not high number of conditioning trials and if preexposure and conditioning took place in the same context but not if the context was changed between the stages. Lesion to the shell subregion of the NAC disrupted LI but LI was preserved in rats with a combined lesion to the NAC shell and core subregions. Moreover, rats with a combined shell-core lesion persisted in showing LI in spite of high number of conditioning trials and in spite of context change. These results show that the NAC is not essential for the acquisition of LI but rather plays a key role in regulating the expression of LI. Moreover, they suggest that the two subregions of the NAC contribute competitively and cooperatively to this process, selecting the response appropriate to the stimulus-no event or the stimulus-reinforcement association in conditioning.