Effects of clozapine on behavioral and metabolic traits relevant for schizophrenia in two mouse strains

Zarate, Jean Mary; Boksa, Patricia; Baptista, Trino; Joober, Ridha

doi:10.1007/s00213-003-1553-4

Cited by 22 publications

(13 citation statements)

References 67 publications

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“…Interestingly, a number of studies which have directly compared acute vs chronic treatment with both typical and atypical antipsychotics have demonstrated that acute may be more effective than chronic administration at reducing PPI deficits induced by pharmacological or environmental manipulations (Andersen and Pouzet, 2001). Thus, in rodents, chronic administration of antipsychotics may induce long-term changes that counteract the PPI-enhancing effects of clozapine (Zarate et al, 2004), and in some cases may not be as useful in assessing clinical properties.…”

Section: Discussionmentioning

confidence: 99%

Prepulse Inhibition Deficits in GAD65 Knockout Mice and the Effect of Antipsychotic Treatment

Heldt

Green

Ressler

2004

Neuropsychopharmacol

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Recent postmortem studies in humans suggest that defects in GABAergic neurotransmission might contribute to the neuropathology associated with schizophrenia. Disturbances in GABAergic systems may also contribute to the sensorimotor gating deficits classically observed in schizophrenic patients, including deficits in prepulse inhibition (PPI). To explore the relationship, the current study examined the integrity of PPI and startle habituation in knockout (KO) mice that lack the GABA synthesizing enzyme glutamic acid decarboxylase 65 (GAD 65). GAD65 KO mice displayed normal baseline and habituated startle responses, which did not differ from GAD65 wild-type (WT) or heterozygous (HET) mice. However, GAD65 KO mice showed robust deficits in PPI which were reversed by the atypical antipsychotic agent clozapine. These results lend support to the view that abnormalities in GABAergic systems might contribute to the basic pathophysiological mechanisms in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Prepulse Inhibition Deficits in GAD65 Knockout Mice and the Effect of Antipsychotic Treatment

Heldt

Green

Ressler

2004

Neuropsychopharmacol

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“…Recent studies have shown that weight gain can also be induced in rodents by other APDs including haloperidol (Fell et al 2004b;Pouzet et al 2003), clozapine (Kaur and Kulkarni 2002;Zarate et al 2004), olanzapine (Arjona et al 2004;Fell et al 2004a;Goudie et al 2002;Pouzet et al 2003) and risperidone (Baptista et al 2002a(Baptista et al , 2004bFell et al 2004b;Ota et al 2002). Some effects on body weight in rodents are sex-dependent, weight gain being seen only in female rats.…”

Section: Introductionmentioning

confidence: 94%

A parametric analysis of olanzapine-induced weight gain in female rats

et al. 2005

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These data suggest that aspects of olanzapine-induced weight gain and metabolic abnormalities can possibly be modelled in female rats. It is suggested that olanzapine-induced hyperphagia acts as an initial stimulus which leads to weight gain, enhanced visceral adiposity and subsequent insulin resistance, although the latter may be ameliorated by compensatory responses in adiponectin levels. Prolactin elevation appears likely not to be involved in the weight gain, adiposity and metabolic changes seen in this model.

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“…The hypothesis was that we would be able to reproduce an interesting association often noted with clozapine treatment, that of favorable clinical response and weight gain [Meltzer et al, 2003]. In the two parental strains of mice, weight gain under clozapine treatment was examined to investigate its relation with PPI and AMPH-induced locomotion [Zarate et al, 2003]. We found that clozapine had a significant effect on weight gain in both strains.…”

Section: Beyond Endophenotypesmentioning

confidence: 97%

“…In recent work in our laboratory, we have investigated the genetic control of therapeutic response to an atypical AP, clozapine, using mouse models [Zarate et al, 2003]. To do so, we have studied the differential modulation of the PPI and AMPH-induced locomotion endophenotypes by clozapine in the two parental strains of mice used to generate the RCLs.…”

Section: Beyond Endophenotypesmentioning

confidence: 99%

Pharmacogenomics and animal models of schizophrenia

Klink

Boksa

Joober

2003

Drug Development Research

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Schizophrenia is a syndromal brain disease of largely unknown pathophysiology and most likely heterogeneous etiology in which genetic predisposition constitutes the major risk factor. In recent years, a shift from a monolithic view of the disorder is leading to its dissection into component phenotypic modules or endophenotypes that may differ in pathophysiology, underlying genetic diathesis, or treatment response. Reducing phenotypic heterogeneity by focusing on endophenotypes will facilitate the production of valid animal models to be used in experimental approaches, improve our chances of uncovering genes predisposing to the disease in linkage or association approaches, and simplify generation of novel molecular targets for the drug discovery process. We hereby review some recently generated mouse models that replicate specific endophenotypes observed in schizophrenia and that implicate putative contributing genes that may be exploited to explore novel drug targets. These are derived from opposing but complementary perspectives. One approach developed in our work begins with mouse models of schizophrenia traits to uncover candidate schizophrenia genes. Another approach followed by several other groups begins with putative schizophrenia vulnerability genes to investigate the corresponding endophenotype in mouse models. Combined with global analysis of gene expression, these mouse models offer the hope that the disease-causing and treatment pathways implicated in schizophrenia will finally be unraveled. Drug Dev. Res. 60:95-103, 2003.

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Effects of clozapine on behavioral and metabolic traits relevant for schizophrenia in two mouse strains

Cited by 22 publications

References 67 publications

Prepulse Inhibition Deficits in GAD65 Knockout Mice and the Effect of Antipsychotic Treatment

Prepulse Inhibition Deficits in GAD65 Knockout Mice and the Effect of Antipsychotic Treatment

A parametric analysis of olanzapine-induced weight gain in female rats

Pharmacogenomics and animal models of schizophrenia

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