Modeling Antipsychotic-Induced Weight Gain in Rats

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DESCRIPTION (provided by applicant): This revised Exploratory/Developmental grant application seeks funding through an NIMH R21mechanism (PA- 00-073) to conduct exploratory experiments to determine if the chronic delivery to rat, of antipsychotic drugs by constant infusion, to achieve sustained, therapeutic plasma concentrations (for humans) will (a) cause body weight gain (primary aim), and/or (b) modify neuropeptide neurons in hypothalamic appetite control circuitry suggestive of appetite stimulation (secondary aim). Antipsychotic drugs cause significant weight gain in schizophrenic humans, but in almost all cases examined to date, not in rats. This surprising species dichotomy may be due to the manner used to deliver antipsychotics to rats, chronically (single, daily injections) and the more rapid metabolic rate in rats than in humans, such that rats are exposed only a few hours each day to therapeutic plasma drug levels. In this project, adult male and female rats will be implanted with Osmette minipumps to deliver a constant infusion of each of several antipsychotic drugs (haloperidol, clozapine, olanzapine, risperidone, sulpiride, ziprasidone) for 28 days. Food intake, body weight, and blood and brain drug levels will be monitored. Drug dose will be adjusted to set plasma concentrations in the clinically effective range to optimize the chance of observing weight gain. This paradigm will then be used to explore for changes, using in situ mRNA analysis, in the activity of neuropeptide neurons embedded in hypothalamic appetite control circuitry (arcuate neuropeptide-Y and proopiomelanocortin/alphaMSH, paraventricular corticotropin releasing hormone, and lateral hypothalamic orexin). The successful identification of an experimental paradigm in rats that cause, antipsychotics to induce weight gain would allow its application to the study of the underlying mechanisms causing this unwanted side-effect, and could then be applied to the development of adjunct or new treatments that would minimize weight gain, while maintaining antipsychotic efficacy.