Project Summary

James R. Fadel, Ph.D. (Young Investigator 2002) of University of South Carolina, will attempt to characterize the functional interactions between orexin and dopamine (DA) systems in the rat by measuring the effect of orexin A administered into the ventral tegmental area (VTA) on locomotor activity and DA release in forebrain regions implicated in schizophrenia, such as the prefrontal cortex, amygdala, and nucleus accumbens.  Abnormal forebrain DA function is thought to be a crucial factor in the pathophysiology of schizophrenia.  However, the hypothalamus has been shown to provide a strong projection to the midbrain ventral tegmental area (VTA), the source of mesocorticolimbic DA projections.  Cells of the hypothalamus containing the recently discovered neuropeptides orexin A and orexin B, in particular, may be functionally and anatomically well-situation to regulate the release of DA in forebrain regions.  These peptides potently regulate arousal and feeding, and orexin cells are activated by certain antipsychotic drugs (APDs) with clinically-significant weight-gain liability.  The results of this study will provide new information on the neuropharmacological and anatomical substrates underlying hypothalamic-VTA interactions.  Interactions between these two systems may be a critical component of both the pathophysiology of schizophrenia and the response to antipsychotic drug treatment.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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