Remediation of attentional dysfunction in rats with lesions of the medial prefrontal cortex by intra-accumbens administration of the dopamine D2/3 receptor antagonist sulpiride

Rationale

Anti-psychotic drugs are widely recognised to produce beneficial effects on impaired cognition in schizophrenia but their mechanism of action is poorly understood. The prefrontal cortex (PFC) and nucleus accumbens (NAC) are key brain loci considered to mediate many of the cognitive deficits associated with schizophrenia and related disorders.

Objectives

To investigate (1) the effects of selective damage to the PFC on visuo-spatial attention and cognition in the rat and (2) the ability of the anti-psychotic drug sulpiride after its intra-NAC administration to ameliorate cognitive and behavioural deficits produced by lesions of the PFC.

Methods

Selective lesions of the medial PFC were made using quinolinic acid in rats previously trained on a five-choice serial reaction time task of sustained visual attention (n = 7). Sham rats received phosphate-buffered saline infusions (n = 7). Following a period of recovery, low doses of sulpiride (0.5ng or 1ng) were infused into the core sub-region of the NAC of sham and lesioned rats immediately prior to testing on the five-choice task.

Results

Lesions of the medial PFC produced a range of impairments on the five-choice task, including decreased attentional accuracy, slower latencies to respond correctly and increased omissions and premature responses, the latter an operational measure of impulsivity. Intra-NAC sulpiride dose-dependently ameliorated the increased impulsivity and attentional impairment present in PFC-lesioned rats.

Conclusions

These findings suggest that attentional and cognitive impairment in schizophrenia may be determined in part by a dysregulation of the subcortical dopamine systems occurring as a consequence of damage to the PFC.     

A neurocognitive animal model dissociating between acute illness and remission periods of schizophrenia

Rationale

The development and validation of animal models of the cognitive impairments of schizophrenia have remained challenging subjects.

Objective

We review evidence from a series of experiments concerning an animal model that dissociates between the disruption of attentional capacities during acute illness periods and the cognitive load-dependent impairments that characterize periods of remission. The model focuses on the long-term attentional consequences of an escalating-dosing pretreatment regimen with amphetamine (AMPH).

Results

Acute illness periods are modeled by the administration of AMPH challenges. Such challenges result in extensive impairments in attentional performance and the “freezing” of performance-associated cortical acetylcholine (ACh) release at pretask levels. During periods of remission (in the absence of AMPH challenges), AMPH-pretreated animals’ attentional performance is associated with abnormally high levels of performance-associated cortical ACh release, indicative of the elevated attentional effort required to maintain performance. Furthermore, and corresponding with clinical evidence, attentional performance during remission periods is exquisitely vulnerable to distractors, reflecting impaired top-down control and abnormalities in fronto–mesolimbic–basal forebrain circuitry. Finally, this animal model detects the moderately beneficial cognitive effects of low-dose treatment with haloperidol and clozapine that were observed in clinical studies.

Conclusions

The usefulness and limitations of this model for research on the neuronal mechanisms underlying the cognitive impairments in schizophrenia and for drug-finding efforts are discussed.     

The association between CYP2D6 genotype and switching antipsychotic medication to clozapine

Purpose

Genetic variation in the cytochrome P450 2D6 (CYP2D6) enzyme is responsible for interindividual differences in the metabolism of many antipsychotic drugs, but the clinical relevance of polymorphisms in CYP2D6 for response to antipsychotic treatment is relatively unknown. In the Netherlands, clozapine is prescribed only when patients are non-responsive to or intolerant of at least two different antipsychotics. The aim of our study was to determine the association of the CYP2D6 genotype with switching to clozapine, which served as a surrogate outcome marker for treatment response to antipsychotics.

Methods

CYP2D6 genotype was assessed in patients who had been switched to clozapine and compared with antipsychotic users whose treatment regimen included no more than two different antipsychotic drugs and no clozapine. We also performed the analysis in patients who only used CYP2D6-dependent antipsychotics.

Results

A total of 528 patients were included in the study (222 cases, 306 controls). No statistically significant differences were found in the distribution of the polymorphisms among the case and control groups, both in all patients and in only those patients using CYP2D6-dependent antipsychotics. However, a trend was observed, suggesting an inverse association between CYP2D6 genotype and the switch to clozapine. (9.5 vs. 5.1 % poor metabolisers and 1.3 vs. 2.6 % ultrarapid metabolisers in cases vs. controls, respectively).

Conclusions

Although the results of our study suggest that the CYP2D6 phenotype is not a major determining factor for patients to be switched to clozapine treatment, larger studies are warranted with a focus on the clinical consequences of the CYP2D6 ultrarapid metaboliser and poor metaboliser phenotypes.     

Socio-demographic and clinical characteristics of heavy and non-heavy smokers among schizophrenia inpatients in a Chinese Han population

Objective

Despite higher smoking rates in schizophrenia, few studies have explored the clinical–demographic correlates of different amounts of smoking exposure. Little is known about the association between smoking severity and clinical phenotypes in Chinese patients with schizophrenia.

Materials and methods

We investigated differences between heavy (≥1 pack/day) and non-heavy (<1 pack/day) smoking in 550 male inpatients with schizophrenia using clinician-administered questionnaires and the Fagerstrom Test for Nicotine Dependence. They also were rated on the Positive and Negative Symptom Scale (PANSS), the Simpson and Angus Extrapyramidal Symptom Rating Scale (SAES), and the Abnormal Involuntary Movement Scale (AIMS), as well as were assayed with laboratory tests and an electrocardiogram.

Results

Heavy smoking prevalence was approximately 31 %. Compared to the non-heavy smokers, the heavy smokers were younger, more with paranoid subtype but less with disorganized subtype schizophrenia, smoked at an earlier age, fewer getting clozapine or all atypical antipsychotics together, and were taking larger doses of antipsychotic drugs. The heavy smokers scored significantly lower on the PANSS negative symptom subscore and total score, and also on the SAES and AIMS scores than the non-heavy smokers. In addition, heavy smokers displayed longer rate-corrected electrocardiographic QT intervals, but without any significant differences in other laboratory tests.

Conclusion

Our results suggest several clinical or demographic differences between the heavy and non-heavy smoking patients with schizophrenia in a Chinese population. Heavy smoking remains a general health risk for schizophrenia.     

A study of antioxidant activity in patients with schizophrenia taking atypical antipsychotics

Introduction

Atypical antipsychotics have significantly improved the quality of life for schizophrenic patients. Despite their beneficial effects, these antipsychotics induce weight gain, diabetes, and dyslipidemia. The aims of this study were to investigate the antioxidative activity of paraoxonase and assess lipid profile as a cardiovascular risk factor in patients with schizophrenia under long-term clozapine or risperidone treatment.

Methods

The study included 66 patients with schizophrenia under clozapine or risperidone treatment and 19 healthy control subjects. Serum paraoxonase activities against paraoxon (PON(PO)), phenylacetate (PON(PA)), dihydrocoumarin (PON(DHC)), serum Trolox equivalent antioxidant activity (TEAC), antioxidant gap (GAP), and lipid profile were determined.

Results

PON(DHC) activity was reduced in both antipsychotic drug-treated groups (clozapine 43.46?±?1.06 U/ml, p?p?Conclusions In patients with schizophrenia, clozapine or risperidone treatment had different effects on various paraoxonase activities. The results of the present study suggest that patients with schizophrenia might be at increased risk for metabolic and cardiovascular disease related to reduced PON(DHC), TEAC, and GAP.     

Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice

Rationale

In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity.

Objective

This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT_2A receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis.

Method

Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [³H]Ketanserin binding and 5-HT _2A mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-fos, which is induced by all 5-HT_2A agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed.

Results

Head-twitch response was decreased and [³H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT _2A mRNA was reduced 1 day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day).

Conclusion

Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT_2A receptor as a potential mechanism involved in these persistent therapeutic-like effects.     

Reversal of cognitive deficits by an ampakine (CX516) and sertindole in two animal models of schizophrenia—sub-chronic and early postnatal PCP treatment in attentional set-shifting

Rationale

Therapies treating cognitive impairments in schizophrenia especially deficits in executive functioning are not available at present.

Objective

The current study evaluated the effect of ampakine CX516 in reversing deficits in executive functioning as represented in two animal models of schizophrenia and assessed by a rodent analog of the intradimensional–extradimensional (ID–ED) attentional set-shifting task. The second generation antipsychotic, sertindole, provided further validation of the schizophrenia-like disease models.

Methods

Animals were subjected to (a) sub-chronic or (b) early postnatal phencyclidine (PCP) treatment regimes: (a) Administration of either saline or PCP (5 mg/kg, intraperitonally b.i.d. for 7 days) followed by a 7-day washout period and testing on day 8. (b) On postnatal days (PNDs) 7, 9, and 11, rats were subjected to administration of either saline or PCP (20 mg/kg, subcutaneously (s.c.)) and tested on PNDs 56–95, after reaching adulthood. The single test session required rats to dig for food rewards in a series of discriminations following acute administration of either vehicle, or CX516 (5–40 mg/kg, s.c.), or sertindole (1.25 mg/kg, perorally).

Results

The specific extradimensional deficits produced by sub-chronic or early postnatal PCP treatment were significantly attenuated by sertindole and dose-dependently by CX516.

Conclusion

Findings here further establish PCP treatment as model of executive functioning deficits related to schizophrenia and provide evidence that direct glutamatergic interventions could improve these, when assessed in the ID–ED attentional set-shifting task.     

Alcohol-related stimuli reduce inhibitory control of behavior in drinkers

Rationale

Poor behavioral control and heightened attentional bias toward alcohol-related stimuli have independently received considerable attention in regard to their roles in alcohol abuse. Theoretical accounts have begun to speculate as to potential reciprocal interactions between these two mechanisms that might promote excessive alcohol consumption, yet experimental evidence is lacking.

Objectives

The objective of the study was to integrate these two lines of research through the development of a novel laboratory task that examines the degree to which alcohol cues serve to disrupt mechanisms of behavioral control.

Methods

Fifty adult drinkers were recruited to perform the attentional bias?Cbehavioral activation (ABBA) task. The ABBA task, an adaptation of traditional cued go/no-go tasks, is a reaction time model that measures the degree to which alcohol-related stimuli can increase behavioral activation of a drinker and reduce the ability to inhibit inappropriate responses. Participants also completed a novel measure of attentional bias, the scene inspection paradigm (SIP), that measures fixation time on alcohol content imbedded in complex scenes.

Results

As hypothesized, the proportion of inhibitory failures on the ABBA task was significantly higher following alcohol images compared to neutral images. Correlational analyses showed that heightened attentional bias on the SIP was associated with greater response activation following alcohol images on the ABBA task.

Conclusions

These findings suggest that alcohol stimuli serve to disrupt mechanisms of behavioral control, and that heightened attentional bias is associated with greater disruption of control mechanisms following alcohol images.     

Recent advances in treating cognitive impairment in schizophrenia

Introduction

Schizophrenia is often associated with chronic disability and poor outcome. In addition to positive symptoms, such as hallucinations and delusions, and negative symptoms including poverty of speech and blunted affect, schizophrenia is also associated with deficits in cognitive function. It has been increasingly recognized that the severity of cognitive impairment is a major determinant of outcome. Therefore, interventions to improve cognitive function also have the capacity to improve quality of life and social and occupational outcomes. Whilst some of the antipsychotic drugs have shown some selective benefits, there is some controversy about the extent of these benefits.

Objectives

This article provides an overview of research into drugs that might enhance cognition in schizophrenia.

Conclusion

Drugs such as modafanil and galantamine are being evaluated, and a number of new drugs are currently in development. Standardized cognitive assessment measures are being developed so studies can be compared more easily. This field is advancing rapidly, but as yet, no widely applicable, evidence-based treatments are available to the clinician.     

Preclinical assessment of an adjunctive treatment approach for cognitive impairment associated with schizophrenia using the alpha7 nicotinic acetylcholine receptor agonist WYE-103914/SEN34625

Rationale

??7 nicotinic acetylcholine receptor (nAChR) agonists are proposed as candidate agents for the adjunctive treatment of cognitive deficits associated with schizophrenia. Despite the pursuit of such an approach clinically, it is surprising that the preclinical profile of pro-cognitive agents in conjunction with antipsychotic drugs is currently unexplored.

Objectives

We determined if the memory-enhancing effects of the selective ??7 nAChR agonist WYE-103914 were preserved in the presence of the atypical antipsychotic drug risperidone, and if the antipsychotic-like profile of risperidone was preserved in the presence of WYE-103914.

Methods

Using the rat novel object recognition (NOR) paradigm, the maintenance of memory-enhancing activity of the ??7 nAChR agonist WYE-103914 in the presence of risperidone was examined. Similarly, in the standard tests of antipsychotic-like activity, apomorphine-induced climbing (AIC) in mice and conditioned avoidance responding (CAR) in rats, the preservation of antipsychotic-like activity of risperidone was evaluated in the presence of WYE-103914.

Results

WYE-103914 exhibited memory-enhancing activity in rat NOR, and this effect of WYE-103914 was retained in the presence of risperidone. In AIC, the atypical antipsychotic profile of risperidone was not significantly altered by WYE-103914. In contrast, WYE-103914 moderately potentiated the efficacy profile of risperidone in CAR, an effect that did not appear to be convincingly linked to a pharmacokinetic interaction.

Conclusions

These data underscore the value of a preclinical evaluation of the adjunctive profile of a memory-enhancing agent in combination with antipsychotics and provide further support to augmentation with ??7 nAChR agonists to address the cognitive deficits associated with schizophrenia.     

Outcome definitions and clinical predictors influence pharmacogenetic associations between HTR3A gene polymorphisms and response to clozapine in patients with schizophrenia

Rationale

Pharmacogenetics of schizophrenia has not yet delivered anticipated clinical dividends. Clinical heterogeneity of schizophrenia contributes to the poor replication of the findings of pharmacogenetic association studies. Functionally important HTR3A gene single-nucleotide polymorphisms (SNPs) were reported to be associated with response to clozapine.

Objective

The aim of this study was to investigate how the association between HTR3A gene SNP and response to clozapine is influenced by various clinical predictors and by differing outcome definitions in patients with treatment-resistant schizophrenia (TRS).

Methods

We recruited 101 consecutive patients with TRS, on stable doses of clozapine, and evaluated their HTR3A gene SNP (rs1062613 and rs2276302), psychopathology, and serum clozapine levels. We assessed their socio-demographic and clinical profiles, premorbid adjustment, traumatic events, cognition, and disability using standard assessment schedules. We evaluated their response to clozapine, by employing six differing outcome definitions. We employed appropriate multivariate statistics to calculate allelic and genotypic association, accounting for the effects of various clinical variables.

Results

T allele of rs1062613 and G allele of rs2276302 were significantly associated with good clinical response to clozapine (p?=?0.02). However, varying outcome definitions make these associations inconsistent. rs1062613 and rs2276302 could explain only 13.8?% variability in the responses to clozapine, while combined clinical predictors and HTR3A pharmacogenetic association model could explain 38?% variability.

Conclusions

We demonstrated that the results of pharmacogenetic studies in schizophrenia depend heavily on their outcome definitions and that combined clinical and pharmacogenetic models have better predictive values. Future pharmacogenetic studies should employ multiple outcome definitions and should evaluate associated clinical variables.     

Developmental vitamin D deficiency alters dopamine-mediated behaviors and dopamine transporter function in adult female rats

Rationale

Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. DVD deficiency in neonatal rats is associated with alterations in cellular development, dopamine metabolism, and brain morphology. DVD-deficient adult rats show novelty-induced hyperlocomotion and an enhanced locomotor response to MK-801, which can be ameliorated by pretreatment with the antipsychotic drug haloperidol.

Objectives

In this study, we examined locomotor responses of male and female juvenile and adult rats to a dose range of amphetamine. We also measured dopamine receptor and monoamine transporter densities in adult brain.

Results

Female DVD-deficient adult rats displayed an enhanced sensitivity to amphetamine-induced locomotion, an increased dopamine transporter density in the caudate–putamen and increased affinity in the nucleus accumbens compared with control females. By contrast, there were no differences between control and DVD-deficient male rats.

Discussion

Taken together, this suggests an alteration in the development of the dopamine system and on dopamine-mediated behaviors in female DVD-deficient rats, and this may be relevant to the underlying neurobiology of schizophrenia.     

Long-term neurocognitive effects of antipsychotics in schizophrenia: a network meta-analysis

Purpose

Most schizophrenic patients have mild to moderate cognitive impairment in the early stages of schizophrenia. The aim was to compare the long-term effects of various antipsychotic drugs on overall cognition and on specific cognitive domains in patients with schizophrenia or related disorders.

Methods

We searched MEDLINE and EMBASE for randomized controlled trials in which oral formulations of second-generation antipsychotic drugs were compared head-to-head or against placebo or against haloperidol. Trials had to be of at least 6 months duration to be included. We used a network meta-analysis to combine direct and indirect comparisons of the cognitive effects between antipsychotics.

Results

Nine studies were eligible. The median trial duration was 52 weeks. Quetiapine, olanzapine and risperidone had better effects on global cognitive score than amisulpride (p?<?0.05) and haloperidol (p?<?0.05). When memory tasks were considered, ziprasidone had better effect than amisulpride (0.28 [0.02–0.54]) and haloperidol (0.32 [0.09–0.55]). Quetiapine was better than other drugs (p?<?0.001) on attention and processing speed tasks, followed by ziprasidone (p?<?0.05) and olanzapine (p?<?0.05). The effects of quetiapine, risperidone and olanzapine were better than those of amisulpride (p?<?0.05) on executive functions.

Conclusions

Our results suggest differences between antipsychotics in their effect on the overall cognitive score in schizophrenia. Quetiapine and olanzapine had the most positive effects, followed by risperidone, ziprasidone, amisulpride and haloperidol in that order. Significant differences were also observed according to specific cognitive tasks.     

Relationship between alcohol dependence,escape drinking,and early neural attention to alcohol-related cues

Rationale

Previous work has indicated that implicit attentional biases to alcohol-related cues are indicative of susceptibility to alcohol dependence and escape drinking, or drinking to avoid dysphoric mood or emotions.

Objective

The goal of the current study was to examine whether alcohol dependence and escape drinking were associated with early neural attentional biases to alcohol cues.

Methods

Electroencephalography data were recorded from 54 college students who reported that they regularly drank alcohol, while they viewed alcohol and control pictures that contained human content (active) or no human content (inactive).

Results

Those who were alcohol dependent showed more neural attentional bias to the active alcohol-related stimuli than to the matched control stimuli early in processing, as indicated by N1 amplitude. Escape drinkers showed greater neural attention to the active alcohol cues than non-escape drinkers, as measured by larger N2 amplitudes.

Conclusions

While alcohol dependence is associated with enhanced automatic attentional biases early in processing, escape drinking is associated with more controlled attentional biases to active alcohol cues during a relatively later stage in processing. These findings reveal important information about the time-course of attentional processing in problem drinkers and have important implications for addiction models and treatment.     

Amphetamine as a social drug: effects of d-amphetamine on social processing and behavior

Rationale

Drug users often report using drugs to enhance social situations, and empirical studies support the idea that drugs increase both social behavior and the value of social interactions. One way that drugs may affect social behavior is by altering social processing, for example by decreasing perceptions of negative emotion in others.

Objectives

We examined effects of d-amphetamine on processing of emotional facial expressions and on the social behavior of talking. We predicted amphetamine would enhance attention, identification, and responsivity to positive expressions, and that this in turn would predict increased talkativeness.

Methods

Over three sessions, 36 healthy normal adults received placebo, 10, and 20 mg d-amphetamine under counterbalanced double-blind conditions. At each session, we measured processing of happy, fearful, sad, and angry expressions using an attentional visual probe task, a dynamic emotion identification task, and measures of facial muscle activity. We also measured talking.

Results

Amphetamine decreased the threshold for identifying all emotions, increased negative facial responses to sad expressions, and increased talkativeness. Contrary to our hypotheses, amphetamine did not alter attention to, identification of, or facial responses to positive emotions specifically. Interestingly, the drug decreased the threshold to identify all emotions, and this effect was uniquely related to increased talkativeness, even after controlling for overall sensitivity to amphetamine.

Conclusions

The results suggest that amphetamine may encourage sociability by increasing sensitivity to subtle emotional expressions. These findings suggest novel social mechanisms that may contribute to the rewarding effects of amphetamine.     

An early attentional bias to BEGIN-stimuli of the smoking ritual is accompanied with mesocorticolimbic deactivations in smokers

Rationale

Biased processing of drug-associated stimuli is believed to be a crucial feature of addiction. Particularly, an attentional bias seems to contribute to the disorder's maintenance. Recent studies suggest differential effects for stimuli associated with the beginning (BEGIN-smoking-stimuli) or the terminal stage of the smoking ritual (END-smoking-stimuli), with the former but not the later evoking high cue-reactivity.

Objective

The current study investigated the neuronal network underlying an attentional bias to BEGIN-smoking-stimuli and END-smoking-stimuli in smokers and tested the hypothesis that the attentional bias is greater for BEGIN-smoking-stimuli.

Methods

Sixteen non-deprived smokers and 16 non-smoking controls participated in an fMRI study. Drug pictures (BEGIN-smoking-stimuli, END-smoking-stimuli) and control pictures were overlaid with geometrical figures and presented for 300?ms. Subjects had to identify picture content (identification-task) or figure orientation (distraction-task). The distraction-task was intended to demonstrate attentional bias.

Results

Behavioral data revealed an attentional bias to BEGIN-smoking-stimuli but not to END-smoking-stimuli in both groups. However, only smokers showed mesocorticolimbic deactivations in the distraction-task with BEGIN-smoking-stimuli. Importantly, these deactivations were significantly stronger for BEGIN- than for END-smoking-stimuli and correlated with the attentional bias score.

Conclusions

Several explanations may account for missing group differences in behavioral data. Brain data suggest smokers using regulatory strategies in response to BEGIN-smoking-stimuli to prevent the elicitation of motivational responses interfering with distraction-task performance. These strategies could be reflected in the observed deactivations and might lead to a performance level in smokers that is similar to that of non-smokers.     

Effects of mu opioid receptor antagonism on cognition in obese binge-eating individuals

Rationale

Translational research implicates the mu opioid neurochemical system in hedonic processing, but its role in dissociable high-level cognitive functions is not well understood. Binge-eating represents a useful model of ??behavioural addiction?? for exploring this issue.

Objective

The aim of this study was to objectively assess the cognitive effects of a mu opioid receptor antagonist in obese individuals with binge-eating symptoms.

Methods

Adults with moderate to severe binge-eating and body mass index ??30?kg/m² received 4?weeks of treatment with a mu opioid receptor antagonist (GSK1521498) 2 or 5?mg per day, or placebo, in a double-blind randomised parallel design. Neuropsychological assessment was undertaken at baseline and endpoint to quantify processing bias for food stimuli (visual dot probe with 500- and 2,000-ms stimulus presentations and food Stroop tasks) and other distinct cognitive functions (N-back working memory, sustained attention, and power of attention tasks).

Results

GSK1521498 5?mg/day significantly reduced attentional bias for food cues on the visual dot probe task versus placebo (p?=?0.042), with no effects detected on other cognitive tasks (all p?>?0.10). The effect on attentional bias was limited to the longer stimulus duration condition in the higher dose cohort alone.

Conclusions

These findings support a central role for mu opioid receptors in aspects of attentional processing of food cues but militate against the notion of major modulatory influences of mu opioid receptors in working memory and sustained attention. The findings have implications for novel therapeutic directions and suggest that the role of different opioid receptors in cognition merits further research.     

Chronic clozapine treatment improves prenatal infection-induced working memory deficits without influencing adult hippocampal neurogenesis

Background

Converging evidence indicates that prenatal exposure to immune challenge can induce long-term cognitive deficits relevant to schizophrenia. Such cognitive impairments may be related to deficient hippocampal neurogenesis at adult age.

Objectives

In the present study, we sought evidence for the possibility that chronic treatment with the reference atypical antipsychotic drug clozapine may improve prenatal infection-induced cognitive dysfunctions by stimulating adult hippocampal neurogenesis.

Methods

This hypothesis was tested in a well-established mouse model of prenatal immune challenge which is based on prenatal administration of the viral mimic, polyriboinosinic–polyribocytidilic acid (PolyI:C).

Results

We found that maternal PolyI:C (5 mg/kg, i.v.) exposure on gestation day 17 led to significant spatial working memory impairment and reduced hippocampal neurogenesis in the resulting offspring at adult age. The latter effect was apparent in postmortem immunohistochemical analyses of the cell proliferation marker bromodeoxyuridine and the microtubule-associated protein doublecortin, a marker of newborn neuronal cells. Chronic (3 weeks) administration of clozapine (5 mg/kg/day, i.p.) significantly improved the prenatal PolyI:C-induced working memory deficits, while at the same time, it negatively affected working memory performance in adult offspring born to control mothers. These bidirectional cognitive effects of clozapine were not paralleled by concomitant effects on adult hippocampal neurogenesis.

Conclusions

Our findings do not support the hypothesis that the atypical antipsychotic drug clozapine may influence cognitive functions by acting on adult neurogenesis in the hippocampus, regardless of whether the drug is administered to subjects with or without a neurodevelopmental predisposition to adult neuropathology.     

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.