This project continues basic studies of the pharmacology of synaptic neurotransmission systems in brain mediated by dopamine (DA). Brain DA systems are a key component in the brain's ability to link decision-making and perhaps emotions with initiation of behaviors, as well as having a more traditional role in control of movement. It is the critical site of action of virtually all antipsychotic agents and is of intense interest due to its implication in sometimes limiting side effects of such drugs, the pathophysiology of extrapyramidal neurological diseases, and possibly as a biological substrate of psychotic and manic features of major idiopathic psychiatric disorders. DA systems support appetitive-rewarded behaviors and so also are implicated in the neurobiology of addition. Much is known of the neurobiology of central DA systems, particularly from recent explosive advances through techniques of molecular genetics and cell biology. Yet, many questions remain, including details of the molecular physiology of DA receptors, mechanisms underlying control of the synthesis, release and inactivation of DA, as well as the behavioral physiology and pharmacology of new receptors. New advances make such questions very timely. This project continues studies of both basic neuroscientific interest and potential clinical significance; it is based in a psychiatric neuroscience laboratory working in this field for a quarter-century, in collaboration with a leading medicinal chemistry laboratory. New work will pursue rare leads to principles for innovative antipsychotic agents that may avoid problems of standard drugs. These include use of weak partial agonists as functional DA antagonists which minimize compensatory reactions implicated in serious neurological side effects of current treatments, and agents targeted at new, limbic- selective, D3 or D4 receptors. Some agents of this type, including novel S(+)-aporphines, are selective for DA receptors in emotional or limbic forebrain areas while sparing the extrapyramidal motor system, perhaps by interacting with type D4 receptors. The partial-agonist can be extended to limbic type D3 receptors as well. New work is stimulated by recent discoveries of lead compounds, such as R(+)-7-hydroxyaminotetralins with high D3-selectivity. New aminotetralins and aporphines will facilitate extensive characterizations of the pharmacology and functioning of D3 receptors and initiate studies of D4 receptors in rat brain. This project continues to contribute to basic understanding of DA neuropharmacology, developing novel agents, chemical tools, and neurochemical, neurohistological, and behavioral methods for scientific study, with potential clinical utility of new principles of drug action.
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