This proposal will explore the mechanisms of regulation and signal transduction, as well as the pharmacology and physiological significance of dopamine (DA) neurons innervating the amygdaloid nuclear complex. Several hypotheses will be tested: 1) that there is a microheterogeneity of DA projection fields in the amygdaloid nuclear complex; 2) that mesoamygdaloid DA neurons exhibit characteristics of presynaptic regulation and postsynaptic signal transduction which are different from other DA systems; 3) that a subset of these populations of DA neurons fulfill criteria supporting their role in mediating the action of antipsychotic drugs, and in modulating the stress response mediated by amygdaloid mechanisms; and 4) that neurotensin (NT) is involved in the regulation and pharmacology of mesoamygdaloid DA neurons. Isolated explants of mesoamygdaloid DA neurons will be used to assess the role of impulse-regulating somatodendritic or release- regulating terminal autoreceptors. The DA receptor-mediated feedback activation of populations of mesoamygdaloid DA neurons will be examined as an additional regulatory variable. The topographic distribution of DA receptor subtypes, and their association with high affinity GTPase activity, specific GTP binding, and DARPP-32 or other DA and/or cAMP-regulated phosphoproteins in the amygdaloid complex will be mapped. Biochemical estimates of DA neuronal activity will be used to compare the administration of typical and atypical antipsychotic drugs. The response of mesoamygdaloid DA neurons to graded stress, distinct types of stressors, and the administration of carboline inverse agonists will be determined. The modulatory influence of NT on mesoamygdaloid DA neurons will be assessed using isolated neuronal explants and the site specific microinjection of fragments (Fab's) of NT antibodies. Immunoneutralization techniques will be further used to investigate the role of NT in the adaptive response of mesoamygdaloid DA neurons to chronic antipsychotic drug administration and their stress-induced activation. Quantitative autoradiographic techniques will be used to map the distribution and cellular localization of NT receptors in the amygdaloid complex. The effects of chronic antipsychotic drugs administration on the density and functional state of amygdaloid NT receptors will be determined.
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