The focus of Project 2 will continue to be the investigation of aging- related changes in adrenergic receptor subtypes and their signaling systems. Where changes have already been identified, the goal will be to determine mechanisms responsible for these differences. The first set of experiments, carried out in collaboration with Project 1, will test two hypotheses: First that changes in coupling if beta1-adrenergic receptors to adenylate cyclase activation in rat cerebellum and hippocampus contribute to aging-related decreases in noradrenergic function (electrophysiological responsiveness and behavioral performance) and second. That reductions in receptor mRNA levels underlie the loss of specific beta-adrenergic receptor subtypes observed with aging in these brain regions. A number of neurotransmitter receptors, including alpha1- adrenergic receptors, use inositol 1,4,5-triphosphate (IP3) as their second messenger. We have observed a diminished efficacy of IP3 to promote Ca2+ release, which is restricted to the aged cerebral cortex. The second set of experiments will test the idea that this aging-related decrease in IP3 efficacy is due to a loss of IP3 receptors. Subtypes of alpha2-adrenergic receptors have recently been identified, but little is known concerning their involvement in aging-related deficits in central noradrenergic transmission. the third set of experiments will use quantitative autoradiography (QUAR) to identify changes in alpha2A and alpha2B- adrenergic receptors in rat cerebral cortex, hippocampus and locus coeruleus (LC) as a function of aging. We will also investigate functional changes in these receptors related to aging by measuring modulation by these receptors of evoked norepinephrine release from cerebral cortical and hippocampal slices from rats of different ages. The fourth set of experiments is proposed in collaboration with Project 4. these experiments will measure adrenergic receptor subtypes with QAR and related second messengers in single and double in oculo rat allograft (cerebellum, hippocampus and LC). Several different grafts and host ages will be studied. The results will provide evidence as to the importance of intrinsic or extrinsic determinants in aging-induced changes in adrenergic receptors and should help identify mechanism(s) underlying aging-related functional changes. In the fifth set of experiments, we proposed, in collaboration with Project 6, to test the hypotheses that aging-related differences in expression of beta=adrenergic receptors are limited to innervated receptors. beta-adrenergic receptor density and beta-adrenergic receptor-stimulated cyclic AMP generation will be compared in subpopulations of mononuclear leukocytes and in adipocytes isolated from young and elderly healthy volunteers. Potential differences in drug- induced regulation of human adipocyte beta-adrenergic receptors in response to administration of the beta-adrenergic receptor antagonist timolol will also be determined as a function of age. Taken together, the results of the proposed experiments should further our understanding of when alterations in adrenergic receptors and/or their coupling to signal transduction system contribute to changes in noradrenergic responsiveness that occur with aging.
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