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.     

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 haloperidol and clozapine on the disruption of sensorimotor gating induced by the noncompetitive glutamate antagonist MK-801

The amplitude of the acoustic startle response in rats is decreased if the startle stimulus is preceded by a nonstartle-eliciting auditory stimulus. This sensory gating phenomenon, known as prepulse inhibition, is diminished in schizophrenic individuals. In rats, the noncompetitive glutamate antagonist MK-801 disrupts prepulse inhibition. The present study examined whether the disruption by MK-801 is reversible in rats pretreated with the classical antipsychotic haloperidol or the atypical antipsychotic clozapine. Male Sprague-Dawley rats were placed into a startle chamber and presented with auditory stimuli consisting of either 95 or 105 dB tones presented alone or preceded by a 70 dB tone. Rats treated with 0.1 mg/kg MK-801 demonstrated a significant disruption of prepulse inhibition. Haloperidol (0.1 and 0.5 mg/kg) and clozapine (1.0 and 5.0 mg/kg) each consistently failed to antagonize the MK-801-induced blockade of prepulse inhibition. The effects of haloperidol and clozapine on prepulse inhibition were also examined in saline-treated rats. Clozapine and, to some extent, haloperidol produced a dose-related facilitation of prepulse inhibition. Although preliminary, this finding raises the possibility that the enhancement of prepulse inhibition by antipsychotics might provide a useful rodent model for screening potential antipsychotic drugs.     

Apomorphine-induced disruption of prepulse inhibition that can be normalised by systemic haloperidol is insensitive to clozapine pretreatment

Rationale Prepulse inhibition (PPI) of startle refers to the phenomenon in which a weak prepulse attenuates the startle response to a succeeding intense stimulus. PPI can be disrupted by systemic apomorphine in animals, and reduced PPI has been consistently reported in schizophrenia patients. The ability of the atypical antipsychotic clozapine to reverse apomorphine-induced PPI deficit has been demonstrated in the rat, but has not yet been tested in the mouse. The present study was designed to fill this gap.Objective and results We investigated the efficacy of clozapine in reversing apomorphine-induced (2.0 or 2.5 mg/kg, SC) PPI deficit in C57BL6 mice. Clozapine failed to restore PPI disruption in apomorphine-treated mice in two independent laboratories across two dose ranges (1–3 mg/kg, IP, or 3–30 mg/kg, PO), whereas the typical antipsychotic haloperidol (1 mg/kg,IP) completely normalised PPI performance.Conclusions Unlike the rat, apomorphine-induced PPI disruption in mice might be instrumental in distinguishing between typical and atypical antipsychotic drugs. This also lends further support to the suggestion that the neuropharmacology of PPI is not identical in the two rodent species.     

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.     

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.     

Effects of antipsychotic drugs on MK-801-induced attentional and motivational deficits in rats

Background

Attentional deficits that accompany schizophrenia are not effectively treated by available antipsychotic medications. Disruption of NMDA receptor function is often used to model aspects of this disorder in rodents. We used the 5-choice serial reaction time task (5CSRTT) to characterize attentional deficits caused by acute administration or withdrawal from chronic administration of the NMDA receptor antagonist MK-801, and determine if they are ameliorated by haloperidol or clozapine.

Methods

Acute studies involved tests in the presence of MK-801: rats were administered haloperidol (0.008-0.125 mg/kg, SC) or clozapine (0.16-2.5 mg/kg, SC) in combination with MK-801 (0.25 mg/kg, IP) prior to daily test sessions. Chronic studies involved tests in the absence of MK-801: following daily tests, rats were administered MK-801 (0.5 mg/kg, IP) and tested 24 h later in the absence or presence of haloperidol or clozapine.

Results

Acute MK-801 disrupted performance: it decreased accuracy while increasing omissions, premature responses, and magazine entries. Haloperidol reduced disruptive effects associated with increased activation, whereas it exacerbated other deficits. Clozapine dose-dependently attenuated several of the MK-801-induced performance deficits. Withdrawal from chronic MK-801 progressively increased omissions and response latencies and decreased premature responding, suggesting an amotivational state. Neither haloperidol nor clozapine ameliorated these performance deficits.

Discussion

Acute administration and withdrawal from chronic MK-801 administration produced distinct behavioral profiles in the 5CSRTT. Acute MK-801 impaired attention and impulse control whereas chronic MK-801 withdrawal caused signs consistent with amotivation. Haloperidol and clozapine were more effective at attenuating deficits caused by acute MK-801 administration.     

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

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

Parametric and pharmacological modulations of latent inhibition in mouse inbred strains

Latent inhibition (LI) is a cross species selective attention phenomenon, which is disrupted by amphetamine and enhanced by antipsychotic drugs (APDs). Accumulating data of LI in gene-modified mice as well as in mouse inbred strains suggest genetic component of LI. Here we study modulation of LI in mouse inbred strains with spontaneously disrupted LI by parametric manipulations (number of pre-exposures and conditioning trials) and pharmacological treatments with antipsychotics and NMDA modulator, D-serine. C3H/He and CBA/J inbred mice showed disrupted LI under conditions with 40 pre-exposures (PE) and 2 trials of the conditioned stimulus-unconditioned stimulus (CS-US) due to either loss of the pre-exposure effect or a ceiling effect of poor learning, respectively. The increased number of pre-exposures and/or number of conditioning trials corrected expression of LI in these inbred mice. The disrupted LI was also reversed by haloperidol in both inbred strains at 1.2 mg/kg but not at 0.4 mg/kg, as well as by clozapine (at 3 mg/kg in C3H/He and at 9 mg/kg in CBA/J mice). D-serine potentiated LI in C3H/He mice at 600 mg/kg, but not in the CBA/J at both studied doses (600 and 1800 mg/kg). Desipramine (10 mg/kg) had no effect on LI in both inbred mouse strains. Our findings demonstrated some resemblance between the effects of parametric and pharmacological manipulations on LI, suggesting that APDs may affect the capacity of the brain processes environmental stimuli in LI. Taken together, LI may offer a translational strategy that allows prediction of drug efficacy for cognitive impairments in schizophrenia.     

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.     

Chronic treatment with caffeine blunts the hyperlocomotor but not cognitive effects of the<Emphasis Type="Italic"> N</Emphasis>-methyl-<Emphasis Type="SmallCaps">d</Emphasis>-aspartate receptor antagonist MK-801 in mice

Rationale. Administration of N-methyl-d-aspartate (NMDA) receptor antagonists produce hyperlocomotion and cognitive deficits in rodents. Activation of NMDA receptors promotes adenosine release, and adenosine agonists prevent central effects of NMDA receptor antagonists. We hypothesized that if NMDA receptor antagonists require adenosine to produce behavioral effects, mice tolerant to the adenosine receptor antagonist caffeine would have a diminished response to NMDA receptor antagonists. Objectives. To evaluate MK-801-induced hyperlocomotion and cognitive deficits after chronic caffeine treatment in mice. Methods. Locomotor activity was analyzed in a computerized system, spontaneous alternation was assessed in the Y-maze and long-term memory was assessed with the inhibitory avoidance task in mice. Results. Mice chronically treated with caffeine in drinking solution (1 mg/ml for 7 days) presented normal habituation and substantial tolerance to acute caffeine (30 mg/kg, i.p.) locomotor effects. MK-801 (0.25 mg/kg, i.p.) produced pronounced hyperlocomotion in water-treated mice, but this effect was abolished in caffeine-drinking mice. Chronic caffeine treatment had no influence on either normal or MK-801-induced deficits in spontaneous alternation and inhibitory avoidance tasks. Conclusion. Hyperlocomotion induced by MK-801 may be mediated by reduced adenosinergic activity. These results also suggest that locomotor and cognitive effects of MK-801 can be dissociated and are distinctly modulated. Finally, these findings agree with the adenosine hypofunction model of schizophrenia, since NMDA receptor antagonists are a pharmacological model for this disorder. Electronic Publication     

Abnormally persistent latent inhibition induced by MK801 is reversed by risperidone and by positive modulators of NMDA receptor function: differential efficacy depending on the stage of the task at which they are administered

Rationale Latent inhibition (LI) is the poorer conditioning to a stimulus resulting from its nonreinforced preexposure. LI indexes the ability to ignore irrelevant stimuli and is used extensively to model attentional impairments in schizophrenia (SZ). We showed that rats and mice treated with the N-methyl-d-aspartic acid (NMDA) receptor antagonist MK801 expressed LI under conditions preventing LI expression in controls. This abnormally persistent LI was reversed by the atypical antipsychotic drug (APD) clozapine and by compounds enhancing NMDA transmission via the glycineB site, but not by the typical APD haloperidol, lending the MK801 LI model predictive validity for negative/cognitive symptoms. Objective To test additional representatives from the two classes of drugs and show that the model can dissociate between atypical APDs and glycinergic drugs are the objectives of the study. Materials and methods LI was measured in a conditional emotional response procedure. Atypical APD risperidone, selective 5HT2A antagonist M100907, and three glycinergic drugs were administered in preexposure or conditioning. Results Rats treated with MK801 (0.05 mg/kg) exhibited LI under conditions that disrupted LI in controls. This abnormality was reversed by risperidone (0.25 and 0.067 mg/kg) and M100907 (1 mg/kg) given in preexposure. Glycine (0.8 g/kg), d-cycloserine (DCS;15 and 30 mg/kg), and glycyldodecylamide (GDA; 0.05 and 0.1 g/kg.) counteracted MK801-induced LI persistence when given in conditioning. Conclusions These results support the validity of MK801-induced persistent LI as a model of negative/cognitive symptoms in SZ and indicate that this model may have a unique capacity to discriminate between typical APDs, atypical APDs, and glycinergic compounds, and thus, foster the identification of novel treatments for SZ.     

Blockade of acquisition of one-way conditioned avoidance responding by haloperidol and metoclopramide but not by thioridazine or clozapine: implications for screening new antipsychotic drugs

The classical neuroleptic drugs haloperidol and pimozide have a strong disruptive effect on the acquisition of conditioned avoidance responding (CAR), yet have relatively little impact on the performance of previously acquired responses. Separate experiments compared the effects of haloperidol, two atypical neuroleptics, thioridazine and clozapine, and a substituted benzamide, metoclopramide, on one-way avoidance by rats. Thioridazine (10–50 mg/kg) and clozapine (1.25–10.0 mg/kg) disrupted both acquisition and performance of CAR. In contrast, haloperidol (0.075–0.150 mg/kg) and metoclopramide (5.0–7.5 mg/kg) completely blocked the acquisition of CAR, yet initially produced only a slight disruption in the performance of a previously acquired response. The ineffectiveness of the atypical neuroleptics in producing a complete disruption of acquisition of CAR may be due to the anticholinergic properties of these drugs. Alternatively, the differences between metoclopramide and the atypical neuroleptics may be due to a preferential effect of metoclopramide on striatal or amygdaloid dopamine neurotransmission. These results suggest that caution should be exercised in using CAR as an animal model for assessing the antipsychotic potential of new pharmacological agents.A preliminary report of these findings was presented at the June 1987 meeting of the Canadian Psychological Association in Vancouver, B.C. (Blackburn et al. 1987)     

mGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition

Hypoglutamatergic theory of schizophrenia is substantiated by observation that high affinity uncompetitive antagonists of NMDA receptors such as PCP can induce psychotic symptoms in humans. Recently, metabotropic glutamate receptors of the mGluR5 type have also been discussed as possible players in this disease. However, less is known about the potential contribution of mGluR1 in schizophrenia. Therefore, the aim of the present study was to compare the effect of selective mGluR1 antagonist EMQMCM, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) and mGluR5 antagonist (MTEP ([(2-methyl-1, 3-thiazol-4-yl) ethynyl] pyridine) either alone or in combination with (+)MK-801 in a prepulse inhibition (PPI) model and locomotor activity tests. Additionally, the effect of both mGluR1 and mGluR5 antagonists on (+)MK-801-evoked ataxia was tested. In contrast to (+)MK-801, which induced disruption of PPI, neither MTEP (1.25-5 mg/kg) nor EMQMCM (0.5-4 mg/kg) altered the PPI. However, MTEP, but not EMQMCM, enhanced disruption of PPI induced by (+)MK-801. Although neither mGluR1 nor mGluR5 antagonists given alone changed locomotor activity of rats, MTEP at 5 mg/kg potentiated the effect of (+)MK-801 while EMQMCM (up to 4 mg/kg) turned out to be ineffective. On the other hand, EMQMCM, but not MTEP, enhanced ataxia evoked by MK-801. The present results demonstrate that blockade of mGluR1 and mGluR5 evokes different effects on behavior induced by NMDA receptor antagonists.     

Towards an animal model of an antipsychotic drug-resistant cognitive impairment in schizophrenia: scopolamine induces abnormally persistent latent inhibition, which can be reversed by cognitive enhancers but not by antipsychotic drugs

Schizophrenia symptoms segregate into positive, negative and cognitive, which exhibit differential sensitivity to drugs. Recent efforts to identify treatments targeting cognitive impairments in schizophrenia have directed attention to the cholinergic system for its well documented role in cognition. Relatedly, muscarinic antagonists (e.g. scopolamine) produce an 'antimuscarinic syndrome', characterized by psychosis and cognitive impairments. Latent inhibition (LI) is the poorer conditioning to a stimulus resulting from its non-reinforced pre-exposure. LI indexes the ability to ignore irrelevant stimuli and aberrations of this capacity produced by pro-psychotic agents (e.g. amphetamine, MK-801) are used extensively to model attentional impairments in schizophrenia. We recently showed that LI was disrupted by scopolamine at low doses, and this was reversed by typical and atypical antipsychotic drugs (APDs) and the acetylcholinesterase inhibitor physostigmine. Here, at a higher dose (1.5 mg/kg), scopolamine produced an opposite pole of attentional impairment, namely, attentional perseveration, whereby scopolamine-treated rats persisted in expressing LI under strong conditioning that prevented LI expression in controls. Scopolamine-induced persistent LI was reversed by cholinergic and glycinergic cognitive enhancers (physostigmine and glycine) but was resistant to both typical and atypical APDs (haloperidol and clozapine). The latter sets scopolamine-induced persistent LI apart from scopolamine- and amphetamine-induced disrupted LI, which are reversed by both typical and atypical APDs, as well as from other cases of abnormally persistent LI including MK-801-induced persistent LI, which is reversed by atypical APDs. Thus, scopolamine-induced persistent LI may provide a pharmacological LI model for screening cognitive enhancers that are efficient for the treatment of APD-resistant cognitive impairments in schizophrenia.     

Disruption of latent inhibition induced by ovariectomy can be reversed by estradiol and clozapine as well as by co-administration of haloperidol with estradiol but not by haloperidol alone

Introduction

Epidemiological and clinical life cycle studies have indicated that the more favorable illness course and the better response to antipsychotic drugs (APDs) in women with schizophrenia correlate with high levels of estrogen, whereas increased vulnerability to exacerbation and relapse and reduced sensitivity to treatment are associated with low estrogen levels. Accordingly, the estrogen hypothesis of schizophrenia proposes that estrogen has a neuroprotective effect in women vulnerable to schizophrenia.

Materials and methods

Latent inhibition (LI), the capacity to ignore stimuli that received nonreinforced preexposure prior to conditioning, is disrupted in acute schizophrenia patients and in rats and humans treated with the psychosis inducing drug amphetamine. Disruption of LI is reversible by typical and atypical APDs. The present study tested whether low levels of estrogen induced by ovariectomy (OVX) would lead to disruption of LI in female rats and whether such disruption would be normalized by estrogen replacement treatment and/or APDs.

Results

Results showed that OVX led to LI disruption, which was reversed by 17β-estradiol (150 μg/kg) and the atypical APD clozapine (5 mg/kg), but not by the typical APD haloperidol (0.1, 0.2, 0.3 mg/kg). Haloperidol regained efficacy when administered with 17β-estradiol (50 μg/kg).

Discussion

These results provide the first demonstration in rats that low levels of hormones can induce a pro-psychotic state that is resistant to at least typical antipsychotic treatment. This constellation may mimic states seen in schizophrenic women during periods associated with low levels of hormones such as the menopause.     

Reversal of phencyclidine-induced prepulse inhibition deficits by clozapine in monkeys

Rationale Prepulse inhibition (PPI) of the acoustic startle reflex is a measure of sensorimotor gating, which occurs across species and is deficient in severe neuropsychiatric disorders such as schizophrenia. In monkeys, as in rodents, phencyclidine (PCP) induces schizophrenia-like deficits in PPI. In rodents, in general, typical antipsychotics (e.g. haloperidol) reverse PPI deficits induced by dopamine (DA) agonists (e.g. apomorphine), but not those induced by N-methyl-d-aspartate (NMDA) receptor antagonists [e.g. phencyclidine (PCP)], whereas atypical antipsychotics (e.g. clozapine) reverse PPI deficits induced by DA agonists and NMDA antagonists. However, some discrepancies exist with some compounds and strains of rodents.Objectives This study investigated whether a typical (haloperidol, 0.035 mg/kg) and an atypical (clozapine, 2.5 mg/kg) antipsychotic could be distinguished in their ability to reverse PCP-induced deficits in PPI in eight monkeys (Cebus apella).Methods First, haloperidol dose was determined by its ability to attenuate apomorphine-induced deficits in PPI. Then, haloperidol and clozapine were tested in eight monkeys with PCP-induced deficits of PPI. Experimental parameters were similar to standard human PPI procedures, with 115 dB white noise startle pulses, either alone or preceded by 120 ms with a prepulse 16 dB above the 70 dB background noise.Results Clozapine reversed PCP-induced PPI deficits. In contrast, haloperidol did not significantly attenuate PCP-induced PPI deficits even at doses that significantly attenuated apomorphine effects.Conclusions In this primate model, clozapine was distinguishable from haloperidol by its ability to attenuate PCP-induced deficits in PPI. The results provide further evidence that PPI in nonhuman primates may provide an important animal model for the development of novel anti-schizophrenia medications.     

Naltrexone-precipitated morphine withdrawal in infant rat is attenuated by acute administration of NOS inhibitors but not NMDA receptor antagonists

Rationale: Intermittent footshock reinstates drug-taking behavior in rats, but not behaviors previously maintained by food reinforcers. Here we tested further the generality of this phenomenon by determining whether restraint and food deprivation stressors would reinstate heroin seeking, whether the environment in which footshock is given modulates footshock-induced reinstatement, and whether footshock would reinstate operant responding previously maintained by brain stimulation reward (BSR). Methods: Groups of rats were trained to self-administer for 10 days either heroin (0.05–0.1 mg/kg/infusion, IV, three 3-h sessions/day) or brain stimulation into the septal area (trains of monopolar cathodal pulses of 100 μs for 500 ms, one 60-min session/day). After extinction of the heroin-reinforced behavior (10–13 days), the rats were tested for reinstatement after exposure to food deprivation (1 and 21 h), restraint given outside the self-administration environment (5, 15 and 30 min), or intermittent footshock (0.8 mA, 15 min) given in the self-administration environment or in a novel (non-drug) environment. For BSR-trained rats, the effect of footshock on reinstatement after extinction (6–10 days) was compared with that induced by non-contingent brain stimulation (three or six discrete stimulations at the start of the test sessions). Results: Food deprivation reinstated heroin seeking. Footshock reliably reinstated heroin seeking when given in the drug environment, but not when given in a non-drug environment. Similarly, restraint given outside the self-administration environment failed to reinstate heroin seeking. In addition, footshock was as effective as priming brain stimulation in reinstating operant responding previously maintained by BSR. Conclusions: The effect of footshock on reinstatement of heroin seeking generalizes to food deprivation, and appears to be dependent on the environment in which the stressor is given. The data with BSR indicate that the phenomenon of footshock-induced reinstatement is not selective for drug reinforcers. Electronic Publication     

Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats

Rationale Neurodevelopmental deficits of parvalbumin-immunoreactive γ-aminobutyric acid (GABA)ergic interneurons in prefrontal cortex have been reported in schizophrenia. Glutamate influences the proliferation of this type of interneuron by an N-methyl-d-aspartate (NMDA)-receptor-mediated mechanism. The present study hypothesized that prenatal blockade of NMDA receptors would disrupt GABAergic neurodevelopment, resulting in differences in effects on behavioral responses to a noncompetitive NMDA antagonist, phencyclidine (PCP), and a dopamine releaser, methamphetamine (METH). Methods GABAergic neurons were immunohistochemically stained with parvalbumin antibody. Psychostimulant-induced hyperlocomotion was measured using an infrared sensor. Results Prenatal exposure (E15–E18) to the NMDA receptor antagonist MK-801 reduced the density of parvalbumin-immunoreactive neurons in rat medial prefrontal cortex on postnatal day 63 (P63) and enhanced PCP-induced hyperlocomotion but not the acute effects of METH on P63 or the development of behavioral sensitization. Prenatal exposure to MK-801 reduced the number of parvalbumin-immunoreactive neurons even on postnatal day 35 (P35) and did not enhance PCP-induced hyperlocomotion, the acute effects of METH on P35, or the development of behavioral sensitization to METH. Conclusions These findings suggest that prenatal blockade of NMDA receptors disrupts GABAergic neurodevelopment in medial prefrontal cortex, and that this disruption of GABAergic development may be related to the enhancement of the locomotion-inducing effect of PCP in postpubertal but not juvenile offspring. GABAergic deficit is unrelated to the effects of METH. This GABAergic neurodevelopmental disruption and the enhanced PCP-induced hyperlocomotion in adult offspring prenatally exposed to MK-801 may prove useful as a new model of the neurodevelopmental process of pathogenesis of treatment-resistant schizophrenia via an NMDA-receptor-mediated hypoglutamatergic mechanism.     

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.