The aims of this proposal are to enhance the candidate's development as an independent investigator in the field of membrane receptors and intracellular signalling within the brain. The candidate's immediate goals are to develop a research program investigating the mechanisms by which muscarinic receptor signalling mechanisms interact with other receptor systems in various regions of the brain and how psychiatric drugs interfere or modulate these interactions. The long range goals of the candidate are to establish the functional significance of interactions between receptor signalling mechanisms in the brain, how these mechanisms influence neuronal excitability, learning, memory and behavior. The financial support of a Research Career Development award will enable the principal investigator to spend more time doing research and learning new techniques to achieve his long range goals. As a member of the Department of Pharmacology at the University of California, Irvine, the candidate will have ample opportunity to collaborate with other established investigators within the field of neuroscience and cardiovascular pharmacology.
The specific aims of the candidate's research proposal are to investigate the influence of muscarinic receptor activation on the ability of other receptor systems to stimulate adenylate cyclase activity in intact cell preparations of the parotid gland and various regions of the brain. The contribution of direct muscarinic receptor-mediated inhibition of adenylate cyclase activity via the inhibitory guanine nucleotide binding protein will be assessed using pertussis toxin to prevent this effect. The pharmacological subtypes of the muscarinic receptor mediating phosphoinositide hydrolysis and inhibition of adenylate cyclase activity will be defined in identical preparations of the corpus striatum and parotid gland using pharmacological null methods and radioligand binding methods to analyze the properties of selective muscarinic agonists and antagonists. Similar methods will be used to identify the subtype of the muscarinic receptor involved in cross-talk with other receptors that stimulate adenylate cyclase activity. Finally, the mechanisms by which various drugs of psychopharmacological interest (neuroleptics, tricyclic antidepressants, lithium) interfere with muscarinic receptor coupling mechanisms will be investigated. The results of these studies may reveal new cholinergic mechanisms in the brain which may be compromised in Alzheimer's disease and other mental disorders of cholinergic hypofunction.
