The amygdala is a collection of anatomically, biochemically and functionally heterogeneous nuclei and is a major component of the limbic system. This proposal will test two general hypotheses: that different amygdaloid nuclei have markedly different roles in mediating the actions of antipsychotic drugs and; that the dopamine (DA) neurons terminating in these nuclei, and their postsynaptic elements, exhibit characteristics unusual to neurons of other DA systems. While DA will be the primary neurochemical focus, emphasis will be placed on the role of interactions between DA and norepinephrine (NE) and DA and neurotensin in the expression of antipsychotic drug effects on DA synthesis or turnover in the individual amygdaloid nuclei and other brain nuclei. The role of end-product inhibition and presynaptic DA autoreceptors in regulating the synthesis of DA in mesoamygdaloid neurons will be determined, and the functional significance of conventional postsynaptic DA mechanisms (e.g., adenylate cyclase) will also be assessed. The biochemically estimated in vivo synthesis and turnover of DA in amygdaloid neurons and midbrain cell bodies will be examined as relates to the compensatory response to DA receptor blockade by acute and chronic administration of """"""""typical"""""""" and """"""""atypical"""""""" antipsychotics. The role of selective dosage regimen and drug subclass differences on NE and neurotensin mechanisms in influencing drug effects on DA function will be determined, and the significance of static or dynamic (drug-induced) bilateral asymmetries of amygdaloid DA, NE or neurotensin will be examined. The tools to be used include tissue micropunching from coronal brain slices, sensitive trace enrichment HPLC with electrochemical detection, in vitro adenylate cyclase and radioligand binding techniques optimized for microdeterminations and radioimmunoassay of neurotensin. To complement these methods, site specific microinjections, selective brain lesions and the administration of antipsychotics with differentiated neuropharmacological properties will be used. From these experiments a further understanding of the role of DA, perhaps as a function of interrelated neuromodulators, in the neurobiology and pharmacotherapy of schizophrenia will be obtained.
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