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.     

Acoustic startle, prepulse inhibition, locomotion, and latent inhibition in the neuroleptic-responsive (NR) and neuroleptic-nonresponsive (NNR) lines of mice

The acoustic startle reflex (ASR) is inhibited by low intensity acoustic stimuli (prepulse inhibition; PPI) delivered prior to the startle stimulus. PPI may reflect underlying sensorimotor processes involved in the filtering of exteroceptive stimuli for their cognitive or physiological relevance. Latent inhibition (LI) is a cognitive process in which pre-exposure to the conditioned stimulus (CS) produces pro-active interference with the acquisition of an associative learning task. LI is thought to reflect a selective attention mechanism that contributes to an organism’s ability to adjust its behavior to changing contingencies of reinforcement. In the present series of experiments, the ASR, PPI at three prepulse intensities (56, 68, and 80 dB), locomotor activity, and LI using an active avoidance paradigm were assessed in mice bidirectionally selected from a heterogeneous stock for response (NR line) or non-response (NNR line) to neuroleptic-induced catalepsy. A randomly selected line was used as the control. Mice from the NNR line displayed weak startle responses and a complete absence of PPI. In contrast, the NR line displayed the largest ASR and the greatest PPI. The control line displayed ASRs and PPI values intermediate to the selected lines. Locomotor activity which is known to affect LI was lowest in the NR line but was similar in the NNR and control lines. In the LI paradigm, acquisition of the avoidance response was impaired in mice from the NR and control lines that were pre-exposed to the auditory CS (normal response). In contrast, the acquisition of the avoidance response in the NNR line was similar in CS pre-exposed and CS non-pre-exposed animals. Overall, the results demonstrate that some of the same genetic factors which regulate neuroleptic response also play a significant role in PPI and LI. Received: 17 April 1997/Final version: 28 January 1998     

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.     

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.     

7-OH-DPAT effects on latent inhibition: low dose facilitation but high dose blockade: implications for dopamine receptor involvement in attentional processes

7-OH-DPAT is a dopamine D2/D3 agonist, which at low doses acts preferentially on D3 receptors but at high doses it acts on D2 and D3 receptors. The present study investigated the contribution of D3 and D2 receptors on latent inhibition (LI) by using two dose levels of 7-OH-DPAT: a low dose, 0.1 mg/kg (D3 receptor activation) and a high dose, 1.0 mg/kg, (D2/D3 receptor activation) in a conditioned emotional response (CER) paradigm. The LI Protocols included CS pre-exposure (10 or 40 CS alone trials), CER induction and a non-drug CER test phase. Additionally, the drug effects upon CER acquisition without LI were assessed using the same treatments and test environment pre-exposure protocols but without the tone CS. The effects of 7-OH-DPAT on crossing, rearing and grooming were also measured in an open field 1 day after the CER test phase. The results showed that the low dose 7-OH-DPAT treatment potentiated LI at 10 but not at 40 CS pre-exposures. The high dose 7-OH-DPAT treatment blocked LI at both the 10 and 40 stimulus pre-exposures; and it also induced hyperactivity. Thus, D3 stimulation induced by a low dose of 7-OH-DPAT can facilitate LI but these effects are contingent upon and are specific to the number of stimulus presentations. Altogether, these findings indicate that D3 stimulation can enhance attentional processes, but D2 stimulation can impair attentional processes.     

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.     

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.     

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)     

Facilitation of latent inhibition by the atypical antipsychotic risperidone

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

Effects of the noncompetitive NMDA receptor antagonist MK-801 on classical eyeblink conditioning in mice

N-methyl-D-aspartate (NMDA) receptors are involved in synaptic plasticity and play a critical role in learning and memory. We investigated the effects of the noncompetitive NMDA receptor antagonist (+)MK-801 on classical eyeblink conditioning of mice, using various interstimulus intervals between the conditioned stimulus (CS) and unconditioned stimulus (US). A tone was used for the CS and a periorbital shock was used for the US. In the delay paradigm, in which the US coterminated with the CS or started immediately after CS offset, the effect of (+)MK-801 (0.1mg/kg, i.p.) was a slight impairment in the acquisition of the conditioned response (CR). During subsequent CS-alone trials, the responses of (+)MK-801-injected mice were extinguished as easily as those of saline-injected mice. In the trace paradigm, (+)MK-801 impaired acquisition of the CR with a trace interval of 250 ms more than it did with a trace interval of 100 ms, and more than in the delay paradigm. (+)MK-801 injected after acquisition of 250-ms trace conditioning did not impair expression or extinction of the CR. These results suggest that NMDA receptors are involved in acquisition of the CR during longer trace interval conditioning more than during shorter trace interval conditioning or delay conditioning, and that their contribution to extinction is much smaller than their contribution to acquisition in mouse eyeblink conditioning.     

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.     

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.     

A comparison of the effects of amphetamine, strychnine and caffeine on prepulse inhibition and latent inhibition

Sensorimotor gating deficits characterize several neuropsychiatric disorders, including schizophrenia. Prepulse inhibition (PPI) and latent inhibition (LI) are measures that are used to assess sensorimotor gating and have been found to be reduced in schizophrenia patients. In PPI, a weak stimulus presented immediately prior to a startling stimulus attenuates the startle response. In LI, pre-exposure to a stimulus retards the subsequent association of that stimulus with a consequence (e.g. footshock). In rats, indirect dopamine (DA) agonists such as amphetamine disrupt both PPI and LI. Amphetamine has also been reported to increase exploratory locomotion at doses that decrease PPI and LI. Such behavioral activation might complicate the interpretation of amphetamine-induced changes in measures of sensorimotor gating. The present study was conducted in order to compare the effects of three behaviorally activating drugs on PPI, LI and locomotor activity. Separate groups of rats were treated with either vehicle, the DA releaser amphetamine (1.5mg/kg), the glycine antagonist strychnine (0.75mg/kg), or the adenosine receptor antagonist caffeine (10mg/kg) and then tested in either startle chambers (for PPI) or an active avoidance chamber (for LI). Locomotion was measured by inter-trial crossing in the avoidance chamber. Amphetamine stimulated locomotion and disrupted both PPI and LI, but did not elevate startle amplitude. In contrast, caffeine increased locomotion, but had no effect on PPI or LI. Strychnine did not increase locomotion significantly, but did increase startle amplitude and disrupt PPI and LI. Hence, neither increased startle amplitude nor locomotor activation are necessary or sufficient conditions for disruption of sensorimotor gating as measured by PPI and LI.     

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.     

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.     

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.     

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.     

Differential effects of intraventricular administration of 6-hydroxydopamine on behavior of rats in approach and avoidance procedures: Reversal of avoidance decrements by diazepam.

The administration of 6-hydroxdopamine (6-HD) and pargyline to rats produced similar selective decreases in responding during the conditioned stimulus (CS) on a discriminated avoidance test where the unconditioned stimulus (US) was shock and on an analogous conditioned approach test where the US was water. Approach behavior during the CS generally recovered, however, while avoidance decrements in the same rats remained for the duration of testing. This suggested that 6-HD-induced avoidance decrement was a result of two independent but interacting processes: (1) a decrease in conditioned behavior as reflected by the similar decrease in responding on both tests; and (2) a hyper-reaction to aversive stimuli that resulted in a tendency to selectively suppress avoidance behavior after the animal received shock. In support of this hypothesis, it was found that 6-HD-induced avoidance decrements could be reversed (1) by treatment with diazpam, a drug that releases suppressed responses; or (2) by delaying avoidance testing until conditioned responding had recovered, thus minimizing the interaction of the two processes.     

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.