This project continues a broad attach on topics pertinent to a better understanding of the organization and function of cerebral dopamine (DA) systems and their receptors, through a collaboration between neuropharmacology and medicinal chemistry programs. Proposed studies seek to continue contributing to a better understanding of the basic neuropharmacology of DA receptors as well as developing principles and lead agents with therapeutic potential for major psychiatric- neuropsychiatric disorders. Approaches continue those proved productive in past years of the project, with additions arising from new methods in DA receptor pharmacology, as well as some attempts to push into unexplored areas. New proposals include greater attention to the role of specific putative DA receptor subtypes D1 and D2 and new agents selective for them. Aporphine and benzazepine systems are used as steroselective, rigid template-probes with which to define chemical features of DA receptor surfaces. In addition, they are yielding novel agents with high affinity and selectivity for D2 or D1 receptors useful as functional probes of receptor mechanisms, including the study of receptor-based regulation of Da metabolism, for labeling specific receptor sites in vitro and histologically, and as leads to potential new medicinal agents. Studies include a developmental perspective on the regulation of DA metabolism and seek to clarify striking changes in the receptor-related regulation of DA metabolism during maturation in rat. Critical attempts are made to separate receptor-mediated from direct biochemical actions of DA agonists on DA metabolism by use of novel monohydroxy D2 agonists, and development of similar agents for D1 receptors, Further attempts will be made to understand the basis on which novel S(+) aporphines exert apparently limbic-selective anti-DA activity and so suggest themselves as potential antipsychotic agents with a low risk of acute extrapyramidal side effects. Leads include recent observations of steroselective neurotensin-elevating effects in limbic cerebral cortex not shared with current typical neuroleptics. An alternative strategy that may lead to functionally anti-DA agents with a reduced risk of neurological side effects is the development of mixed agonist-antagonists, including partial-ergoline aporphine analogs. Other work continues on the discovery that a clinically used anti-inflammatory agent may stabilize DA and adrenergic receptors and so modify their super- or subsensitization by prolonged antipsychotic or antidepressant treatment-a suspected source of late side effects or loss of efficacy. Finally, new consideration is given to the possibility that """"""""transporter"""""""" macromolecules associated with monoamine uptake across neuronal membranes may share some plastic- adaptive characteristics with receptors, such as in response to prolonged treatment with mood-elevating or other psychotropic agents.
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