Neurochemical,behavioral and architectural changes after chronic inactivation of NMDA receptors in mice

Schizophrenia is a psychotic illness characterized by problems in perception, learning, and memory. Post-mortem clinical data revealed abnormalities in neuronal organization, reduced soma and dendritic tree size. In rodents, reduction of glutamatergic neurotransmission by NMDA receptor antagonists mimics symptoms of schizophrenia. However, the dosage, treatment and species used in previous studies have not been consistent, leading to a lack of correlation between the findings reported in low-dose, long-term treatment models and the results in acute or chronic high dose administration. Thus, the present study investigates whether long-term, low-dose blockade of NMDA receptors with MK-801 in the early postnatal period results in molecular, cellular, morphological and behavioral changes in the mouse, alterations that have been singly described by using different drugs and dosages in either mice or rats. We found that early postnatal administration of 0.1 mg/kg MK-801 for 15 days altered protein translation, synapse formation, hippocampus-dependent learning and neuronal development, resembling findings reported in schizophrenia. These results suggest that there are strong parallels between this animal model and schizophrenia, which validates it as an animal model for this condition and lends further strength of the NMDA receptor hypofunction as a useful model for the study of psychosis.     

Behavioral Analysis of the Consequences of Chronic Blockade of NMDA-Type Glutamate Receptors in the Early Postnatal Period in Rats

Considering data on the possible glutamatergic nature of the pathogenesis of schizophrenia, we attempted to model cognitive derangements in animals by chronic blockade of NMDA glutamate receptors. Wistar rats received daily s.c. injections of the non-competitive NMDA glutamate receptor antagonist MK-801 (0.05 mg/kg) from days 7 to day 49 of postnatal life. One day after the antagonist injections given on days 27 and 28 of life, animals of the experimental group showed decreased levels of spontaneous movement and orientational-investigative activity as compared with controls, where there was no change in the elevated locomotor reaction produced in response to the direct action of MK-801. These animals showed decreases in the level of anxiety (on day 40 of life) and derangement in spatial learning with food reinforcement (days 50–54 of life). It is suggested that early neonatal blockade of NMDA glutamate receptors leads to the development in animals of disturbances to situational perception and assessment of incoming sensory information.     

Chronic exposure to typical or atypical antipsychotics in rodents: temporal effects on central alpha7 nicotinic acetylcholine receptors

A decrease in alpha7 nicotinic acetylcholine receptors in the hippocampus has been hypothesized to contribute to alterations in auditory gating and other behavioral impairments in schizophrenia. However, while both typical and atypical neuroleptics are routinely used in the therapeutics of schizophrenia, little is known about their effects on auditory gating or alpha7 nicotinic acetylcholine receptor expression particularly when they are administered for extended periods of time (which is common in the clinical setting). In the present study in normal rats, the residual effects of prior chronic treatment (90 or 180 days) with representative typical and atypical neuroleptics (oral haloperidol, 2.0 mg/kg/day; chlorpromazine, 10.0 mg/kg/day, risperidone, 2.5 mg/kg/day; or olanzapine, 10.0 mg/kg/day) on prepulse inhibition of the auditory gating response were investigated. The densities of alpha7 nicotinic acetylcholine receptors were subsequently measured using [125I]-alpha-bungarotoxin autoradiography. The results indicated that none of the compounds significantly altered the startle amplitude or prepulse inhibition response either during drug treatment (day 60) or after 90 or 180 days of treatment (i.e. during a drug free washout). However, prior exposure to chlorpromazine, risperidone and olanzapine for 90 days resulted in modest but significant (P<0.01) decreases in [125I]-alpha-bungarotoxin binding sites in some brain regions (e.g. posterior cortical amygdala). After 180 days of treatment, decreases in [(125I]-alpha-bungarotoxin binding ranging from approximately 12% (lateral dentate gyrus) up to 24% (e.g. CA1 hippocampal region) were evident in the risperidone group in 13 of the 36 regions analyzed while decreases associated with the other neuroleptics agents were still present, but not statistically significant. These data indicate that the commonly used atypical neuroleptic, risperidone is associated with time dependent and persistent negative effects on an important biological substrate of memory (i.e. the alpha7 nicotinic receptor), but that the magnitude of the deficits was not sufficient to impair auditory gating.     

Sleep deficits in rats after NMDA receptor blockade.

N-Methyl-D-aspartate (NMDA) receptor blockade disrupts a variety of functions associated with neural plasticity, including acquisition of learned responses and long-term potentiation. Deficits in memory are significantly correlated with deficits in measures of paradoxical sleep in several amnesic populations. The present experiment therefore assessed whether NPC 12626, a competitive NMDA receptor antagonist, also disrupts sleep. NPC 12626 (1, 10, 50, and 100 mg/kg) or saline was administered to Sprague-Dawley rats 30 min prior to 3-h daytime recording periods. Paradoxical sleep was selectively impaired at all but the highest dose, which prevented all sleep during the recording period. Some deficits in nonparadoxical sleep first appeared at the 10 mg/kg dose but did not became prominent until the 50 mg/kg dose. The results thus show that NPC 12626 impairs sleep states in rats and demonstrate that paradoxical sleep is particularly susceptible to the effects of NMDA receptor blockade. These findings, along with previous evidence that NMDA antagonists impair waking measures of arousal, provide evidence that all sleep-wake states are impaired by NMDA receptor blockade. More generally, the results suggest that some brain mechanisms underlying sleep and memory may share common elements.     

Effect of paliperidone and risperidone on extracellular glutamate in the prefrontal cortex of rats exposed to prenatal immune activation or MK-801

The NMDA glutamate hypofunction model of schizophrenia is based in part upon acute effects of NMDA receptor blockade in humans and rodents. Several laboratories have reported glutamate system abnormalities following prenatal exposure to immune challenge, a known environmental risk factor for schizophrenia. Here we report indices of NMDA glutamate receptor hypofunction following prenatal immune activation, as well as the effects of treatment during periadolescence with the atypical antipsychotic medications risperidone and paliperidone. Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or saline on gestational day 14. Male offspring were treated orally via drinking water with vehicle, risperidone (0.01mg/kg/day), or paliperidone (0.01mg/kg/day) between postnatal days 35 and 56 (periadolescence) and extracellular glutamate levels in the prefrontal cortex were determined by microdialysis at PD 56. Consistent with decreased NMDA receptor function, MK-801-induced increases in extracellular glutamate concentration were markedly blunted following prenatal immune activation. Further suggesting NMDA receptor hypofunction, prefrontal cortex basal extracellular glutamate was significantly elevated (p<0.05) in offspring of poly I:C treated dams. Pretreatment with low dose paliperidone or risperidone (0.01mg/kg/day postnatal days 35-56) normalized prefrontal cortical basal extracellular glutamate (p<0.05 vs. poly I:C vehicle-treatment). Pretreatment with paliperidone and risperidone also prevented the acute MK-801-induced increase in extracellular glutamate. These observations demonstrate decreased NMDA receptor function and elevated extracellular glutamate, two key features of the NMDA glutamate receptor hypofunction model of schizophrenia, during periadolescence following prenatal immune activation. Treatment with the atypical antipsychotic medications paliperidone and risperidone normalized basal extracellular glutamate. Demonstration of glutamatergic abnormalities consistent with the NMDA glutamate receptor hypofunction model of schizophrenia as an early developmental consequence of prenatal immune action provides a model to identify novel early interventions targeting glutamatergic systems which play an important role in both positive and negative symptoms of schizophrenia.     

Lack of task specificity and absence of posttraining effects of atropine on learning

Three experiments are reported whose purpose was to examine the effect of the cholinergic antagonist atropine on the acquisition of different learning tasks known to be sensitive or insensitive to impairment by hippocampal lesions; on the retention of performance acquired in the absence of the drug; and on memory consolidation immediately after daily training trials. In Experiment 1, atropine sulfate (10 or 50 mg/kg, ip), injected 30 min prior to training, severely impaired learning of both spatial and nonspatial discrimination tasks when compared with saline or atropine methylnitrate (50 mg/kg). In Experiment 2, atropine sulfate (50 mg/kg) also impaired spatial discrimination accuracy in rats previously trained to asymptote under drug-free conditions. These deficits were not due to either peripheral drug effects or gross sensorimotor impairments. In Experiment 3, daily posttraining injections of atropine sulfate (50 mg/kg) failed to influence either learning or subsequent retention of place navigation in rats that were trained to find a single hidden escape platform. The data confirm that profound learning deficits occur when training is conducted under atropine but offer no support to the hypothesis that cholinergic neurons play an important role in memory consolidation or other posttraining processes. Furthermore, these results point to dissimilarities between the behavioral impairments induced by cholinergic blockade and hippocampal lesions under appropriate test regimes.     

Dissociation of cholinergic function in spatial and procedural learning in rats

The cholinergic system has long been known for its role in acquisition and retention of new information. Scopolamine, a muscarinic acetylcholine receptor antagonist impairs multiple memory systems, and this has promoted the notion that drug-induced side effects are responsible for diminished task execution rather than selective impairments on learning and memory per se. Here, we revisit this issue with the aim to dissociate the effects of scopolamine (0.2-1.0 mg/kg) on spatial learning in the water maze. Experiments 1 and 2 showed that acquisition of a reference memory paradigm with constant platform location is compromised by scopolamine independent of whether the animals are pre-trained or not. Deficits were paralleled by drug induced side-effects on sensorimotor parameters. Experiment 3 explored the role of muscarinic receptors in acquisition of an episodic-like spatial delayed matching to position (DMTP) protocol, and scopolamine still caused a learning deficit and side-effects on sensorimotor performance. Rats extensively pre-trained in the DMTP protocol with 30 s and 1 h delays over several months in experiment 4 and tested in a within-subject design under saline and scopolamine had no sensorimotor deficits, but spatial working memory remained compromised. Experiment 5 used the rising Atlantis platform in the DMTP paradigm. Intricate analysis of the amount of dwelling and its location revealed a clear deficit in spatial working memory induced by scopolamine, but there was no effect on sensorimotor or procedural task demands. Apart from the well-known contribution to sensorimotor and procedural learning, our findings provide compelling evidence for an important role of muscarinic acetylcholine receptor signaling in spatial episodic-like memory.     

Spatial working memory deficits in schizophrenia patients and their first degree relatives from Palau,Micronesia

Spatial working memory deficits associated with dorsolateral prefrontal dysfunction have been found in Caucasian samples of schizophrenia patients and their first‐degree relatives. This study evaluated spatial working memory function in affected and unaffected members of multiplex schizophrenia families from the Republic of Palau to determine whether the spatial working memory deficits associated with schizophrenia extend to this non‐Caucasian population. Palau is an isolated island nation in Micronesia with an elevated prevalence of schizophrenia and an aggregation of cases in large multigenerational families. Our objective was to evaluate the potential for spatial working memory function to serve as one of multiple endophenotypes in a genetic linkage study of these Palauan schizophrenia families. A spatial delayed response task requiring resistance to distraction and a sensorimotor control task were used to assess spatial working memory in 32 schizophrenia patients, 28 of their healthy first‐degree relatives, and 19 normal control subjects. Schizophrenia patients and their relatives were significantly less accurate than normal control subjects on the spatial delayed response task but not on the sensorimotor control task. On both tasks, patients and relatives were slower to respond than the normal controls. There were no age or gender effects on accuracy, and working memory performance in schizophrenia patients was not significantly correlated with medication dosage. In summary, spatial working memory deficits that have been found in Caucasian schizophrenia patients and relatives were confirmed in this isolated Pacific Island family sample. These results suggest that spatial working memory deficits may be a potentially useful addition to the endophenotypic characterization of family members to be used in a comprehensive genome wide linkage analysis of these Palauan families. © 2002 Wiley‐Liss, Inc.     

Chronic intracerebroventricular exposure to β-amyloid(1–40) impairs object recognition but does not affect spontaneous locomotor activity or sensorimotor gating in the rat

This study examined the cognitive effects of chronic in vivo exposure to beta-amyloid(1-40) via the intracerebroventricular route on two distinct paradigms. The first test evaluated a form of early attentional control referred to as sensorimotor gating in which an antecedent weak prepulse stimulus modulates the reactivity to a subsequent startle-eliciting stimulus. The second test utilized the spontaneous preference for a novel object over that of a familiar one in rats as a measure of object recognition memory. We found that beta-amyloid exposure leads to a severe deficit in the object memory test but spares sensorimotor gating. Moreover, unlike the water maze deficit induced by beta-amyloid (Nag et al., in preparation), the deficit on object recognition was resistant to amelioration by systemic physostigmine treatment at a dose of 0.06 mg/kg per day intraperitoneally. The present results add to previous reports that beta-amyloid exposure can lead to deficits on hippocampal lesion sensitive tasks, suggesting that dysfunction of the rhinal cortices in addition to that of the septohippocampal system is implicated in beta-amyloid-induced behavioral impairments. It therefore lends support to the hypothesis that beta-amyloid exposure can lead to severe impairment across multiple memory systems.     

Spatial working memory deficits in schizophrenia patients and their first degree relatives from Palau,Micronesia

Spatial working memory deficits associated with dorsolateral prefrontal dysfunction have been found in Caucasian samples of schizophrenia patients and their first-degree relatives. This study evaluated spatial working memory function in affected and unaffected members of multiplex schizophrenia families from the Republic of Palau to determine whether the spatial working memory deficits associated with schizophrenia extend to this non-Caucasian population. Palau is an isolated island nation in Micronesia with an elevated prevalence of schizophrenia and an aggregation of cases in large multigenerational families. Our objective was to evaluate the potential for spatial working memory function to serve as one of multiple endophenotypes in a genetic linkage study of these Palauan schizophrenia families. A spatial delayed response task requiring resistance to distraction and a sensorimotor control task were used to assess spatial working memory in 32 schizophrenia patients, 28 of their healthy first-degree relatives, and 19 normal control subjects. Schizophrenia patients and their relatives were significantly less accurate than normal control subjects on the spatial delayed response task but not on the sensorimotor control task. On both tasks, patients and relatives were slower to respond than the normal controls. There were no age or gender effects on accuracy, and working memory performance in schizophrenia patients was not significantly correlated with medication dosage. In summary, spatial working memory deficits that have been found in Caucasian schizophrenia patients and relatives were confirmed in this isolated Pacific Island family sample. These results suggest that spatial working memory deficits may be a potentially useful addition to the endophenotypic characterization of family members to be used in a comprehensive genome wide linkage analysis of these Palauan families.     

Effects of excessive glucocorticoid receptor stimulation during early gestation on psychomotor and social behavior in the rat

Severe psychological stress in the first trimester of pregnancy increases the risk of schizophrenia in the offspring. To begin to investigate the role of glucocorticoid receptors in this association, we determined the effects of the glucocorticoid dexamethasone (2 mg/kg), administered to pregnant rats on gestation days 6–8, on maternal behaviors and schizophrenia‐relevant behaviors in the offspring. Dams receiving dexamethasone exhibited increased milk ejection bouts during nursing. Offspring of dexamethasone‐treated dams (DEX) showed decreased juvenile social play and a blunted acoustic startle reflex in adolescence and adulthood, effects that were predicted by frequency of milk ejections in the dams. DEX offspring also showed increased prepulse inhibition of startle and reduced amphetamine‐induced motor activity, effects not correlated with maternal behavior. It is postulated that over‐stimulation of receptors targeted by glucocorticoids in the placenta or other maternal tissues during early gestation can lead to psychomotor and social behavioral deficits in the offspring. Moreover, some of these deficits may be mediated by alterations in postnatal maternal behavior and physiology produced by early gestational exposure to excess glucocorticoids. © 2010 Wiley Periodicals, Inc. Dev Psychobiol 52:121–132, 2010     

Mice deleted for the DiGeorge/velocardiofacial syndrome region show abnormal sensorimotor gating and learning and memory impairments.

Del22q11 syndrome is caused by heterozygous deletion of an approximately 3 Mb segment of chromosome 22q11.2. Children diagnosed with del22q11 syndrome commonly have learning difficulties, deficits of motor development, cognitive defects and attention deficit disorder. They also have a higher than normal risk for developing psychiatric disorders, mainly schizophrenia, schizoaffective disorder and bipolar disorder. Here, we show that mice that are heterozygously deleted for a subset of the genes that are deleted in patients have deficits in sensorimotor gating and learning and memory. The finding of sensorimotor gating deficits is particularly significant because patients with schizophrenia and schizotypal personality disorder show similar deficits. Thus, our deletion mouse models at least two major features of the del22q11-associated behavioral phenotype, and as such, represents an animal model of this complex behavioral phenotype. These findings not only open the way to pharmacological analyses that may lead to improved treatments, but also to the identification of gene/s that modulate these specific behaviors in humans.     

Water T-maze,an improved method to assess spatial working memory in rats: Pharmacological validation

The present study was performed to validate a spatial working memory task using pharmacological manipulations. The water escape T-maze combines the advantages of the Morris water maze and the T-maze while minimizing the disadvantages. Scopolamine (1 mg/kg), a drug that affects cognitive function in spatial working memory tasks, significantly decreased the rats’ performance in the present delayed alternation task. Glutamate neurotransmission plays an important role in the maintenance of working memory; rats treated with dizocilpine (MK-801; 0.125–0.25 mg/kg), a N-methyl-d-aspartate (NMDA) receptor antagonist, were impaired in this task. In agreement with evidence showing a functional interaction between ionotropic and metabotropic glutamatergic receptors, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a mGlu₅ receptor antagonist, at a dose (1 mg/kg) which by itself had no significant effects, enhanced MK-801-induced impairments of spatial working memory. These evidences suggest that the water escape T-maze might be a valid method to assess spatial working memory, sensitive to pharmacological manipulations.     

N-methyl-D-aspartate antagonists and working memory performance: comparison with the effects of scopolamine, propranolol, diazepam, and phenylisopropyladenosine.

The effects of the competitive N-methyl-D-aspartate (NMDA) antagonists CPP (5 & 10 mg/kg) and NPC 12626 (25 & 40 mg/kg) and the noncompetitive NMDA antagonists phencyclidine (1, 3, & 6.25 mg/kg) and MK 801 (0.1 & 0.2 mg/kg) on performance of rats on a nonspatial delayed matching-to-sample working memory task were evaluated. At the highest dose, each NMDA antagonist reduced choice accuracy at all retention intervals. In contrast, the reference anticholinergic agent scopolamine selectively reduced accuracy at long retention intervals, suggesting that scopolamine but not the NMDA antagonists directly interfered with time-dependent working memory retention. Propranolol, diazepam, and phenylisopropyladenosine had little or no effect on choice accuracy, suggesting that noradrenergic, gamma-aminobutyric acid-diazepam, and adenosine receptors may be relatively unimportant for working memory performance as assessed in this task. The NMDA antagonists also differed from scopolamine in that doses of NMDA antagonists that reduced response accuracy also reduced response probability, altered bias (competitive antagonists only), and increased intertrial interval responding (noncompetitive antagonists only). It was concluded that NMDA antagonists disrupt cognitive functions including, but not limited to, those required for accurate working memory performance.     

Effect of subchronic phencyclidine administration on sucrose preference and hippocampal parvalbumin immunoreactivity in the rat

Persistent blockade of NMDA receptor function by repeated phencyclidine dosing produces pathophysiological changes that model deficits observed in schizophrenia. The present study investigates the effects of subchronic phencyclidine administration (PCP; 2 or 5 mg/kg bi-daily for 7 days followed by a drug-free period) on sucrose choice, a measure of anhedonia. Sucrose preference in a two-bottle sucrose–water choice test was assessed 1 and 2 weeks after PCP. Results showed no differences in sucrose intake between PCP rats and controls, nor a difference in water intake or total volume of liquid consumed at either time-point. Six weeks post-PCP, analysis of brains showed a reduction in expression of parvalbumin immunoreactive neurons in the hippocampus with significant reductions localised to the CA1 and CA2/3 regions. These results demonstrate that while subchronic PCP may not be a valid model for the negative symptom of anhedonia observed in schizophrenia, it induces pathology in the brain in hippocampal subregions that are reminiscent of changes observed in schizophrenia.     

Strain-Specificity in Nicotine Attenuation of Phencyclidine-Induced Disruption of Prepulse Inhibition in Mice: Relevance to Smoking in Schizophrenia Patients

Schizophrenia patients may exhibit high tobacco smoking rates in part to self-medicate sensory gating deficits with nicotine contained in tobacco. To test this hypothesis, we induced sensori-motor gating deficits in four mouse strains with phencyclidine, a noncompetitive antagonist of glutamatergic N -methyl-d-aspartate receptors. Nicotine attenuated the disruption in prepulse inhibition induced by phencyclidine in DBA/2J and C3H/HeJ but not in C57BL/6J or 129T2/SvEmsJ mice. These results highlight genetic variations in the regulation by nicotinic cholinergic systems of the dysfunction in glutamatergic transmission contributing to gating deficits in schizophrenia. Further, these findings support the hypothesis of self-medication of gating deficits in schizophrenia through tobacco smoking, and suggest that treatments targeting genetic dysfunctions in nicotinic-glutamatergic interactions that would treat cognitive deficits will assist schizophrenia patients in minimizing tobacco smoking.     

Long-lasting auditory gating deficit accompanied by GABA(B) receptor dysfunction in the hippocampus after early-life limbic seizures in rats

In a previous study, we reported a rat model of early-life limbic seizures which resulted in a loss of GABA(B) receptor inhibition in the hippocampus. Since gating of auditory evoked potentials in the hippocampus (auditory gating) requires GABA(B) receptors and spatial behaviors depend on the hippocampus, we hypothesize that rats with early-life limbic seizures manifest deficits of auditory gating and spatial behaviors. Seizure rats were given a single injection of GABA(B) receptor antagonist CGP56999A (1-1.2 mg/kg i.p.) on postnatal day (PND) 15, which induced multiple limbic seizures in 8h; control rats were given saline injection. When tested at 3-9 weeks after seizure/control treatment, seizure as compared to control rats showed no difference in finding a hidden platform in the water maze, but were deficient in learning and maintaining consecutive criterion performance in the 8-arm radial arm maze. Auditory gating, as measured by paired-click (conditioning followed by test click) average auditory evoked potentials in the hippocampus, revealed a significant difference between seizure rats and controls. Seizure as compared to control rats showed an increased ratio of the test to conditioning click response as adolescents (50 days old) or adults (70 days old). Heterosynaptic electric paired-pulse depression of hippocampal population excitatory postsynaptic potential in freely moving rats, a measure of hippocampal GABA(B)-receptor mediated inhibition, was decreased in seizure as compared to control rats. Seizure as compared to control rats showed increased locomotor activity in a novel open field for the first 10 min, and decreased activity at 15-60 min. However, auditory prepulse inhibition, a measure of sensorimotor gating, revealed no difference between seizure and control rats. In conclusion, early-life limbic seizures induced a long-lasting deficit in auditory gating, likely caused by GABA(B) receptor-mediated inhibition loss in the hippocampus. Auditory gating loss is a symptom of schizophrenia, and thus GABA(B) receptor inhibition loss in the hippocampus provides a mechanism linking early-life seizures to a psychiatric symptom.     

Alpha-1-adrenergic receptors mediate sensorimotor gating deficits produced by intracerebral dizocilpine administration in rats.

Prepulse inhibition refers to the inhibition by a weak prepulse of the startle response to an intense stimulus. Prepulse inhibition is thought to provide an operational measure of sensorimotor gating, a putative central inhibitory process by which an organism filters information from its environment. Prepulse inhibition deficits are observed in schizophrenia patients and in rats treated with psychotomimetic compounds, such as the non-competitive N-methyl-D-aspartate antagonists phencyclidine or dizocilpine maleate. In rats, phencyclidine-induced prepulse inhibition deficits are blocked by clozapine, olanzapine and quetiapine, which are multireceptor antagonists and atypical antipsychotics, or by prazosin, which is a selective alpha1-adrenergic antagonist. The dorsal hippocampus and amygdala are two of the brain regions shown to contribute to the disruption of prepulse inhibition produced by non-competitive N-methyl-D-aspartate antagonists. The present study tested the hypotheses that quetiapine or prazosin would prevent deficits in prepulse inhibition produced by dizocilpine infusion into the dorsal hippocampus or amygdala. In separate groups of rats, either quetiapine (0 or 5.0 mg/kg, s.c.) or prazosin (0 or 1.0 mg/kg, i.p.) was administered 15 min prior to bilateral infusion of dizocilpine (0 or 6.25 microg/0.5 microl/side) into either the dorsal hippocampus or amygdala. Rats were placed into startle chambers immediately after intracerebral drug infusion and prepulse inhibition was assessed. Confirming previous studies, prepulse inhibition was decreased after either intra-dorsal hippocampus or intra-amygdala infusions of dizocilpine. Both quetiapine and prazosin blocked the prepulse inhibition deficits produced by intracranial dizocilpine administration. Startle reactivity was increased by dizocilpine infusion into either region; these effects were not blocked by either quetiapine or prazosin. These results indicate that non-competitive N-methyl-D-aspartate antagonists may disrupt sensorimotor gating via actions within the dorsal hippocampus or amygdala, and that alpha1-adrenergic receptors distal to these sites might mediate this effect.     

A study of a topiramate pre-treatment on the effects induced by a subanaesthetic dose of ketamine on human reaction time

Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, impairs reaction time performance and interacts with foreperiod duration, thereby suggesting that ketamine alters motor preparation. These effects can be attributed either to the blockade of NMDA receptors or to the stimulation of alpha-amino-3-hydroxy-5-methylisoxasole-4-proprionic acid (AMPA) and kainate receptors. The purpose of the present study was: (i) to replicate previous findings and (ii) to study the effect of a pre-treatment with topiramate, an AMPA/kainate antagonist, on the impairments induced by ketamine on RT. Thirty six healthy subjects (3 groups of 12) performed a two-choice RT task in which the foreperiod was manipulated. All subjects performed the task under perfusion of ketamine (intravenous bolus of 0.12 mg followed by a perfusion of 0.5 mg/kg over 60 mn) or placebo (saline). Depending on the group, an oral dose of topiramate (50 mg) or placebo (lactose) was administered 2 h before ketamine infusion (randomised, double-blind, double-dummy, parallel-group design). At the dose studied, topiramate exerted no detectable effect on RT. The results relative to ketamine corroborate previous findings and suggest that this molecule affects motor preparation through the blockade of NMDA receptors.     

Selective Breeding of Reduced Sensorimotor Gating in Wistar Rats

Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating that is reduced in some neuropsychiatric disorders (e.g. schizophrenia). Animal models have revealed insight into the neuronal and pharmacological underpinnings of PPI-deficits. Recent work has shown that a PPI-deficit can be selectively bred in Wistar rats and is already stable in the second filial generation. We here report on developmental and parametric characteristics of sensorimotor gating deficits in the 4th and 6th filial generation of male rats selectively bred for low PPI (low PPI) compared to rats with normal levels of PPI (high PPI). Low PPI rats showed significantly reduced PPI and variable startle magnitude (in pulse alone trials) along with reduced short-term habituation of startle as adults. Reduced PPI in the low PPI rats was found throughout development (tested on postnatal days 21, 35, 49, 70). PPI-deficits in the low PPI rats were evident at prepulse intensities ranging from 62–86 dB and for interstimulus intervals ranging between 30–1000 ms. These behavioral data add to a growing body of knowledge about the genetic basis of sensorimotor gating deficits and suggest that low PPI rats have potential use as an intermediate phenotype in schizophrenia research. The stable phenotype of breeding-induced PPI-deficits and reduced startle habituation indicates that PPI has strong genetic determinants and that selectively bred rats can be used for future neurophysiological, anatomical, pharmacological, and genomic analyses. Edited by Stephen Maxson.