Knowledge concerning the pharmacology, biochemistry, physiology and regulatory control of mesotelencephalic dopamine (DA) neurons is crucial for obtaining a better understanding of their role in both normal and abnormal behavior and the mechanisms through which antipsychotic drugs (APDs) partially ameliorate psychotic symptoms. Both the therapeutic and neurological side effects of APDs are believed to be due, in part, to actions on mesotelencephalic DA systems. We will therefore continue our studies which have focused on the biochemical, anatomical, and pharmacological heterogeneity of the mesotelencephalic neurons, with particular emphasis on the mesoprefrontal cortical DA system. This cortical DA system has a number of unique properties, and has been hypothesized to be critically involved in the pathogenesis of schizophrenia. We will examine the involvement of DA autoreceptors in the regulation of different DA systems. We will also investigate the modulation of specific DA neurons by heteroceptors (e.g. benzodiazepine/GABA, excitatory amino acid, neuropeptide, serotonin) responding to specific afferents to midbrain DA neurons; these studies will utilize both in vivo and ex vivo biochemical methods, and histochemical approaches. A particular focus will be the investigation of the role of neurotensin in the regulation of mesoprefrontal DA neurons. We will determine whether the activation of the mesoprefrontal DA system by various behavioral stressors and anxiogenic beta-carboline treatment are mediated by similar or divergent mechanisms. The adaptive responses of meso-corticolimbic DA neurons to prolonged or repeated stressors will be evaluated in normal rats and rats in which DA function has been altered by perinatal diazepam exposure. In addition, we will investigate the biochemical effects of stress on DA systems following acute and chronic treatment with typical and atypical APDs. Since the extrapyramidal side effects as well as therapeutic actions of APDs are thought to be related to the induction of depolarization block (DPB) following chronic administration of APDs, we will examine the biochemical correlates of DPB, using post-mortem and in vivo dialysis methods. In light of the importance of relating our findings to man, we plan to extend our rodent findings to the primate. We will investigate the role of autoreceptors in regulation of DA function in a primate species. We will also evaluate which central catecholamine systems are functionally influenced by anxiogenic beta-carbolines, using biochemical and histochemical measurements of monoamine function and c-fos expression.
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