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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

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Abstract

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.

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Acknowledgments

Authors wish to thank the Joseph Sagol Fellowship Program in Humanities and Social Sciences at Tel Aviv University for their funding (M.A). We also would like to thank Novartis, Switzerland, for their generous gifts of clozapine and Johnson & Johnson, Belgium, for their generous gifts of haloperidol.

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  1. Department of Psychology, Tel Aviv University, Tel Aviv, 69978, Israel

    Michal Arad & Ina Weiner

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Correspondence to Ina Weiner.

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Arad, M., Weiner, I. 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. Psychopharmacology 206, 731–740 (2009). https://doi.org/10.1007/s00213-009-1464-0

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