Deficits In Latent Inhibition Research Articles

Ras and Rab interactor 1 controls neuronal plasticity by coordinating dendritic filopodial motility and AMPA receptor turnover.

Ras and Rab interactor 1 (RIN1) is predominantly expressed in the nervous system. RIN1-knockout animals have deficits in latent inhibition and fear extinction in the amygdala, suggesting a critical role for RIN1 in preventing the persistence of unpleasant memories. At the molecular level, RIN1 signals through Rab5 GTPases that control endocytosis of cell-surface receptors and Abl nonreceptor tyrosine kinases that participate in actin cytoskeleton remodeling. Here we report that RIN1 controls the plasticity of cultured mouse hippocampal neurons. Our results show that RIN1 affects the morphology of dendritic protrusions and accelerates dendritic filopodial motility through an Abl kinase-dependent pathway. Lack of RIN1 results in enhanced mEPSC amplitudes, indicating an increase in surface AMPA receptor levels compared with wild-type neurons. We further provide evidence that the Rab5 GEF activity of RIN1 regulates surface GluA1 subunit endocytosis. Consequently loss of RIN1 blocks surface AMPA receptor down-regulation evoked by chemically induced long-term depression. Our findings indicate that RIN1 destabilizes synaptic connections and is a key player in postsynaptic AMPA receptor endocytosis, providing multiple ways of negatively regulating memory stabilization during neuronal plasticity.

Prepulse inhibition and latent inhibition deficits in Roman high-avoidance vs. Roman low-avoidance rats: Modeling schizophrenia-related features

The aim of the present study was to obtain further evidence supporting the validity of a new genetically-based rat model for the study of schizophrenia-relevant symptoms. The Roman high- (RHA-I) and low-avoidance (RLA-I) inbred rats have been psychogenetically selected for their rapid versus extremely poor acquisition of the two-way avoidance task in the shuttle box and present two well-differentiated profiles regarding several traits related to anxiety, impulsivity and sensitivity to (dopaminergic) psychostimulants. In this study we have tested animals from both strains in two behavioral paradigms that are related to schizophrenia, i.e. prepulse inhibition (PPI) and latent inhibition (LI) of fear-potentiated startle (FPS). The results show that while RLA-I rats display good PPI and LI to the context, RHA-Is show an impairment of PPI and no sign of an LI effect, which goes in the direction of the results obtained in schizophrenic patients. Therefore, although further behavioral and psychopharmacological work needs to be done, the present findings and previous studies carried out in our laboratory and others allow us to propose the RHA-I rat strain as a putative genetic rat model of differential schizophrenia-related features.

Recreational cocaine use is associated with attenuated latent inhibition

IntroductionEvidence has linked chronic cocaine use with various cognitive deficits; however few studies have investigated the effects of recreational (non-dependent) use. The present study aimed to assess whether recreational users show deficits in latent inhibition (LI: a measure of delayed learning of an association between 2 stimuli, one of which has been previously exposed (PE) without consequence and thus deemed irrelevant). MethodsUsing a quasi-experimental between groups design, recreational cocaine users (n=21), poly-drug users (n=17) and drug-naive controls (n=18) were compared on a LI task. Questionnaires assessing psychological health and drug use were also completed. ResultsThere was a statistically significant interaction between condition (PE vs non PE) and group (cocaine, polydrug and control); cocaine users scored lower in the PE condition compared to polydrug users and controls, indicating quicker learning. ConclusionsRecreational cocaine users show attenuated LI reflecting reduced ability to filter out irrelevant stimuli enabling faster learning of a PE irrelevant and novel stimuli association. This does not appear to be a result of schizotypy and/or other drug use. Thus even at recreational levels, cocaine use may be sufficient to affect inhibitory attentional processes.

Ketamine administration during the second postnatal week induces enduring schizophrenia-like behavioral symptoms and reduces parvalbumin expression in the medial prefrontal cortex of adult mice

Dysfunctions in the GABAergic system are considered a core feature of schizophrenia. Pharmacological blockade of NMDA receptors (NMDAR), or their genetic ablation in parvalbumin (PV)-expressing GABAergic interneurons can induce schizophrenia-like behavior in animals. NMDAR-mediated currents shape the maturation of GABAergic interneurons during a critical period of development, making transient blockade of NMDARs during this period an attractive model for the developmental changes that occur in the course of schizophrenia's pathophysiology. Here, we examined whether developmental administration of the non-competitive NMDAR antagonist ketamine results in persistent deficits in PFC-dependent behaviors in adult animals. Mice received injections of ketamine (30mg/kg) on postnatal days (PND) 7, 9 and 11, and then tested on a battery of behavioral experiments aimed to mimic major symptoms of schizophrenia in adulthood (between PND 90 and 120). Ketamine treatment reduced the number of cells that expressed PV in the PFC by ∼60% as previously described. Ketamine affected performance in an attentional set-shifting task, impairing the ability of the animals to perform an extradimensional shift to acquire a new strategy. Ketamine-treated animals showed deficits in latent inhibition, novel-object recognition and social novelty detection compared to their SAL-treated littermates. These deficits were not a result of generalized anxiety, as both groups performed comparably on an elevated plus maze. Ketamine treatment did not cause changes in amphetamine-induced hyperlocomotion that are often taken as measures for the positive-like symptoms of the disorder. Thus, ketamine administration during development appears to be a useful model for inducing cognitive and negative symptoms of schizophrenia.

Genetic Rat Models of Schizophrenia-Relevant Symptoms

It is recognized that developing valid animal models is essential for the research on the neurobiological mechanisms of (and treatments for) psychiatric disorders, even when these are as complex as schizophrenia. To be considered a valid analogue of the disorder, a given model should present good face validity (i.e. similarity of symptoms), good predictive validity (i.e. similarity of treatment effects and potential for discovering novel treatments) and enough construct validity (i.e. the model should help discover neurobiological mechanisms underlying the disorder or some relevant symptoms). The complexity of symptoms (positive, negative and cognitive) of schizophrenia makes it a very difficult task for a model to mimic all the main features of the disorder, but some rodent (mouse and rat) models have behavioural and even neurobiological phenotype characteristics resembling positive-like symptoms, cognitive symptoms and some neurochemical features of schizophrenia. As several recent works have already reviewed the main behavioural and developmental models, as well as the most used drug-induced, lesion-induced and genetic mouse models, the present review focuses on describing the most relevant genetically-based rat models of schizophrenia-relevant symptoms. Thus, we discuss several selective breeding programs leading to rat lines/strains which present impaired prepulse inhibition (PPI) of the acoustic startle response and (in some cases) latent inhibition deficits (both of which may be considered as endophenotypes of schizophrenia related with pre-attentive processes and attention, respectively), as well as other schizophrenia-relevant symptoms (e.g. learning deficits). Evidence is presented for the effects of genetic background on PPI (and other symptoms/phenotypes), as well as for environmental influences on genetic predisposition to enhanced apomorphine (mixed dopamine receptor agonist) effects. Some of the described rat models appear to present face validity and, to a certain extent, construct validity. While efforts should be made to evaluate the predictive validity of these genetic rat models, we propose that they have the advantage (over mouse knockouts, for example) of better representing “normal” genetic, neurobiological and phenotype variation, thus allowing the study of associations among them by means of genetic mapping or gene expression studies.

Deficits in latent inhibition induced by estradiol replacement are ameliorated by haloperidol treatment

There are sex differences in the symptomatology of schizophrenia, and in the response to antipsychotic treatments. One hallmark symptom of schizophrenia is a deficit in selective attention. Selective attention can be measured using a latent inhibition (LI) paradigm in humans; LI can be measured in rodents, and is used as an animal model of the selective attention deficits observed in schizophrenia. In the current experiments LI was used to clarify whether selective attention differs between male rats and ovariectomized (OVX) female rats receiving different estradiol (E2) replacement regimens. An additional aim was to determine whether haloperidol’s (HAL) facilitation of LI is enhanced by E2. Males and OVX female rats were trained in a conditioned emotional response LI paradigm. Females received no E2 replacement, a chronic low dose of E2 via silastic capsule, or a high phasic dose of E2 via silastic capsule accompanied by E2 (10 µg/kg subcutaneous (SC)) injections every 4th day. Actual plasma levels of E2 were determined using an enzyme linked immunosorbent assay. Rats were also administered a vehicle treatment, a 0.05 mg/kg, or a 0.1 mg/kg IP injection of HAL. Males and OVX females that did not receive E2 replacement both exhibited LI, but LI was not observed in the low and high E2 replacement groups. HAL restored LI at a lower dose in the females receiving high E2 replacement compared to females receiving low E2 replacement, indicating that E2 replacement facilitates HAL in restoring LI.

Neonatal domoic acid treatment produces alterations to prepulse inhibition and latent inhibition in adult rats

Schizophrenia is a complex and severe mental disorder characterized by positive, negative and cognitive symptoms. Characteristic behavioral alterations reflecting these categories of symptoms have been observed in many animal models of this disorder, and are consistent with those manifested in the clinical population. The purpose of this study was to determine whether early alterations in glutamate signaling would result in alterations to prepulse inhibition (PPI) and latent inhibition (LI); two assessments used for evaluating putative novel animal models with relevance to schizophrenia. In the present experiment, daily subcutaneous (s.c.) injections of 20μg/kg of domoic acid (DOM) were administered to rat pups from postnatal days (PND) 8–14. When tested as adults, DOM treated rats displayed deficits in PPI that were dependant on both sex and time of day. No differences in startle amplitude, habituation, or movement were found during any test, indicating that the PPI deficits seen could not be attributed to baseline startle differences. Deficits in LI were also apparent when adult rats were tested using a conditioned taste aversion task, with DOM-treated animals displaying a significantly suppressed LI. These results suggest that early treatment with DOM may serve as a useful tool to model schizophrenia which in turn may lead to a better understanding of the contribution of glutamate, and in particular, kainate receptors, to the development and/or manifestation of schizophrenia or schizophrenia-like symptoms in the clinical population.

Prenatal immune challenge in rats: Altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route‐based learning as a function of maternal body weight gain after prenatal exposure to poly IC

Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic acid (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into those that lost or gained the least weight, Poly IC (L), versus those that gained the most weight, Poly IC (H), following treatment. The study design controlled for litter size, litter sampling, sex distribution, and test experience. We found no effects of Poly IC on elevated zero maze, open-field activity, object burying, light-dark test, straight channel swimming, Morris water maze spatial acquisition, reversal, or shift navigation or spatial working or reference memory, or conditioned contextual or cued fear or latent inhibition. The Poly IC (H) group showed a significant decrease in the rate of route-based learning when visible cues were unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males. The Poly IC (L) group exhibited altered responses to acute pharmacological challenges: exaggerated hyperactivity in response to (+)-amphetamine and an attenuated hyperactivity in response to MK-801. This model did not exhibit the cognitive, or latent inhibition deficits reported in Poly IC-treated rats but showed changes in response to drugs acting on neurotransmitter systems implicated in the pathophysiology of schizophrenia (dopaminergic hyperfunction and glutamatergic hypofunction).

Intact neurobehavioral development and dramatic impairments of procedural-like memory following neonatal ventral hippocampal lesion in rats

Neonatal ventral hippocampal lesions (NVHL) in rats are considered a potent developmental model of schizophrenia. After NVHL, rats appear normal during their preadolescent time, whereas in early adulthood, they develop behavioral deficits paralleling symptomatic aspects of schizophrenia, including hyperactivity, hypersensitivity to amphetamine (AMPH), prepulse and latent inhibition deficits, reduced social interactions, and spatial working and reference memory alterations. Surprisingly, the question of the consequences of NVHL on postnatal neurobehavioral development has not been addressed. This is of particular importance, as a defective neurobehavioral development could contribute to impairments seen in adult rats. Therefore, at several time points of the early postsurgical life of NVHL rats, we assessed behaviors accounting for neurobehavioral development, including negative geotaxis and grip strength (PD11), locomotor coordination (PD21), and open-field (PD25). At adulthood, the rats were tested for anxiety levels, locomotor activity, as well as spatial reference memory performance. Using a novel task, we also investigated the consequences of the lesions on procedural-like memory, which had never been tested following NVHL. Our results point to preserved neurobehavioral development. They also confirm the already documented locomotor hyperactivity, spatial reference memory impairment, and hyperresponsiveness to AMPH. Finally, our rseults show for the first time that NVHL disabled the development of behavioral routines, suggesting dramatic procedural memory deficits. The presence of procedural memory deficits in adult rats subjected to NHVL suggests that the lesions lead to a wider range of cognitive deficits than previously shown. Interestingly, procedural or implicit memory impairments have also been reported in schizophrenic patients.

Genetic and pharmacological evidence for schizophrenia‐related Disc1 interaction with GSK‐3

Recent studies have identified disrupted-in-schizophrenia-1 (DISC1) as a strong genetic risk factor associated with schizophrenia. Previously, we have reported that a mutation in the second exon of the DISC1 gene [leucine to proline at amino acid position 100, L100P] leads to the development of schizophrenia-related behaviors in mice. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase that interacts with the N-terminal region of DISC1 (aa 1-220) and has been implicated as an important downstream component in the etiology of schizophrenia. Here, for the first time, we show that pharmacological and genetic inactivation of GSK-3 reverse prepulse inhibition and latent inhibition deficits as well as normalizing the hyperactivity of Disc1-L100P mutants. In parallel to these observations, interaction between DISC1 and GSK-3α and β is reduced in Disc1-L100P mutants. Our data provide genetic, biochemical, and behavioral evidence for a molecular link between DISC1 and GSK-3 in relation to psychopathology and highlights the value of missense mutations in dissecting the underlying and complex molecular mechanisms of neurological disorders.

Antipsychotic drugs dose-dependently suppress the spontaneous hyperactivity of the chakragati mouse

The chakragati ( ckr) mouse has been proposed as a model of aspects of schizophrenia. The mice, created serendipitously as a result of a transgenic insertional mutation, exhibit spontaneous circling, hyperactivity, hypertone of the dopamine system, reduced social interactions, enlarged lateral ventricles, deficits in pre-pulse inhibition of acoustic startle and deficits in latent inhibition of conditioned learning. In this study, the dose-dependent effects of antipsychotic drugs (haloperidol, pimozide, risperidone, clozapine, olanzapine, ziprasidone, quetiapine and aripiprazole) on the spontaneous hyperactivity of the mice were investigated. All the antipsychotic drugs tested dose-dependently suppressed spontaneous hyperactivity. Aripriprazole, which is known to be a dopamine D2 receptor partial agonist, exhibited a tri-phasic dose-response, initially suppressing hyperactivity at low doses, having little effect on hyperactivity at intermediate doses, and suppressing activity again at high doses. These data suggest that the spontaneous circling and hyperactivity of the ckr mouse may allow screening of candidate antipsychotic compounds, distinguishing compounds with aripriprazole-like profiles.

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.

The chakragati mouse shows deficits in prepulse inhibition of acoustic startle and latent inhibition

The chakragati ( ckr) mouse, which was serendipitously created as a result of a transgenic insertional mutation, has been proposed as a model of aspects of schizophrenia. The mice exhibit circling, hyperactivity, reduced social interactions, and enlarged lateral ventricles, which parallel aspects of the pathophysiology of schizophrenia. Deficits in sensorimotor gating and processing of the relevance of stimuli are core features of schizophrenia, which underlie many of the symptoms presented. Measures of prepulse inhibition (PPI) and latent inhibition (LI) can assess sensorimotor gating and processing of relevance in both humans and animal models. We investigated PPI of acoustic startle and LI of aversive conditioning in wild-type, heterozygous, and ckr mice. The ckr mice, which are homozygous for the transgene insertion, but not heterozygous littermates, showed impaired PPI in the absence of any difference in acoustic startle amplitude and showed deficits in LI of conditioning of a light stimulus to footshock, measured as suppression of licking for water in water-restricted mice. Together with the previous evidence for hyperactivity, reduced social interactions, and enlarged lateral ventricles, these data lend further support to the suggestion that the ckr mouse has utility as an animal model of aspects of schizophrenia.

Cognitive Deficits Caused by Late Gestational Disruption of Neurogenesis in Rats: a Preclinical Model of Schizophrenia

Late gestational disruption of neurogenesis in rats has been shown to induce behavioral abnormalities thought to mimic aspects of positive and negative symptoms of schizophrenia. Furthermore, it has been shown that the morphological changes produced by the perturbation are relevant to schizophrenia with reduced thickness of the hippocampus, thalamus, and cortical regions. In addition to the positive and negative symptoms, schizophrenia is associated with deficits in a wide variety of cognitive domains. In the present studies, we assessed whether the cognitive deficits are modeled by disruption of neurogenesis late during gestation (gestational day 17) in the rat. In the battery of tests utilized, we describe that rats in which neurogenesis was disrupted have deficits in a reversal-learning paradigm of the Morris water maze and in object recognition, and that they exhibit perseveration in the Porsolt forced swimming test. Additionally, we found deficient associative learning in an acquisition of an active avoidance paradigm and deficits in latent inhibition. No deficits were observed in the reference memory version of the Morris water maze and in a non-match-to position experiment, showing that the deficits are limited to certain aspects of cognition.

Suppressing unwanted thoughts in schizophrenia: Its relation to thought control strategies and schizotypal traits

Two experiments examined the visual search analog of latent inhibition (LI) and the novel popout (NPO) effect in healthy humans. In Experiments 1 (n=48) and 2 (n=180), subjects judged the positions (left or right side of a computer screen) of a unique target amongst a field of homogeneous distractors. In both experiments, there was a strong LI effect, as indicated by longer response times (RT) to those displays in which the target was previously a distractor and the distractors were previously the target, as compared with displays in which the target was novel and the distractors were previously the target. NPO, faster RT to a display in which the target was novel on a background of familiar distractors than to a display in which both target and distractors were novel, was not obtained. In Experiment 1, LI magnitude was not affected by gender. In Experiment 2, LI magnitude was larger for low schizotypal females than for high schizotypal females, a result not obtained for males. This pattern is similar to one reported for medicated schizophrenic out-patients (Lubow, R.E., Kaplan, O., Abramovich, P., Rudnick, R., Laor, N., 2000. Visual search in schizophrenics: latent inhibition and novel popout effects. Schizophr. Res., in press). Together, these data suggest that the LI deficits found in high schizotypal healthy subjects and in schizophrenic patients represent a dysfunction that is characterized by an inability to reduce attention allocated to irrelevant stimuli, and that this may serve as a trait marker for some subtypes of schizophrenia, particularly those associated with female gender.

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.

Performance on the visual search analog of latent inhibition is modulated by an interaction between schizotypy and gender

Two experiments examined the visual search analog of latent inhibition (LI) and the novel popout (NPO) effect in healthy humans. In Experiments 1 ( n=48) and 2 ( n=180), subjects judged the positions (left or right side of a computer screen) of a unique target amongst a field of homogeneous distractors. In both experiments, there was a strong LI effect, as indicated by longer response times (RT) to those displays in which the target was previously a distractor and the distractors were previously the target, as compared with displays in which the target was novel and the distractors were previously the target. NPO, faster RT to a display in which the target was novel on a background of familiar distractors than to a display in which both target and distractors were novel, was not obtained. In Experiment 1, LI magnitude was not affected by gender. In Experiment 2, LI magnitude was larger for low schizotypal females than for high schizotypal females, a result not obtained for males. This pattern is similar to one reported for medicated schizophrenic out-patients (Lubow, R.E., Kaplan, O., Abramovich, P., Rudnick, R., Laor, N., 2000. Visual search in schizophrenics: latent inhibition and novel popout effects. Schizophr. Res., in press). Together, these data suggest that the LI deficits found in high schizotypal healthy subjects and in schizophrenic patients represent a dysfunction that is characterized by an inability to reduce attention allocated to irrelevant stimuli, and that this may serve as a trait marker for some subtypes of schizophrenia, particularly those associated with female gender.

Nicotine enhances latent inhibition and ameliorates ethanol-induced deficits in latent inhibition

Nicotine enhances latent inhibition and ameliorates ethanol-induced deficits in latent inhibition

Nicotine enhances latent inhibition and ameliorates ethanol-induced deficits in latent inhibition

Alcohol and nicotine are drugs of abuse that are used frequently together. One possible explanation for this co-administration is that nicotine prevents or lessens alcohol-associated impairments. The present study examined the dose-dependent effects of acute administration of nicotine, alcohol, or alcohol plus nicotine on latent inhibition as measured by lick suppression in C57BL/6 mice. Alterations in a lick suppression ratio were measured by assessing the effects of 10 pre-exposures to an auditory conditioned stimulus (CS) on formation of subsequent CS-shock unconditioned stimulus (US) associations. Mice pre-exposed to the CS were expected to develop a weaker CS-US association. Nicotine administered prior to pre-exposure to the CS produced increased suppression ratios, ethanol given prior to pre-exposure to the CS decreased suppression ratios, and nicotine reversed the effects of ethanol when the two drugs were co-administered. These opposing actions of nicotine and ethanol may have relevance to the high incidence of smoking and drinking in humans.

Simulation of psychosis by continuous delivery of phencyclidine from controlled-release polymer implants

To simulate psychosis in rats we have developed a method for the continuous delivery of phencyclidine (PCP) using implantable controlled-release polymers. PCP polymer implants produced deficits in latent inhibition which do not occur after repeated bolus injections. PCP implanted rats were also devoid of any anxiogenic signs, motoric hyperactivity and learning acquisition which can be seen in rats receiving daily bolus injections of a comparable PCP dose. This behavioral double-dissociation of the two modes of PCP application was accompanied by respective neurochemical changes. PCP binding sites were reduced in both striatum and hippocampus, but in the hippocampus, loss of PCP binding sites was more severe following pulsatile PCP administration. Morphological assessment revealed a significant shrinkage of the CA3 region in hippocampus in both groups. Pharmacokinetic analysis showed that the maximum PCP concentration in the brain after bolus injections was 10-fold above the PCP implants.