The overall goal of this program is to investigate the biology of serotonergic neurotransmission. 5-hydroxytryptamine (5-HT; serotonin) modulates many important behaviors. Abnormalities in 5-HT neurotransmission have been implicated in the pathogenesis of diverse psychiatric disorders, and various classes of psychotherapeutic agents have prominent effects of different aspects of synaptic transmission mediated by 5-HT. Studies specially focus on the function of 5-HT(1A) receptors because of their role in mediating the effects of serotonergic antidepressant and antianxiety drugs. A multidisciplinary approach has been developed utilizing a variety of tools and techniques to study this important receptor at multiple levels. In particular, we have attempted to facilitate interactions between investigators studying behavioral and functional effects of serotonin and those interested in the biochemical and molecular aspects of signal transduction. Thus, studies will be carried out at behavioral, biochemical, molecular biological, chemical, anatomical and physiological levels. Investigation of important unresolved questions relating to the function of 5-HT(1A) receptors and its regulation by psychotherapeutic drugs and stress is a major theme of this proposal. Pharmacological investigations of 5-HT(1A) receptors by all projects in the Program will be facilitated by utilizing new selective 5-HT(1A) receptor agonists and antagonists and radioligands developed by this Program. Proposed studies include investigations of the control of the release of 5-HT by 5-HT(1A) receptors in awake behaving rats in vivo by microdialysis and its modulation by psychotherapeutic drugs. The interactive regulation of 5-HT(1A) and glucocorticoid receptors on neuroendocrine responses to stress will be studied, using molecular changes in individual neurons to establish the mechanistic linkage between these receptors. The involvement of 5-HT(1A) and 5-HT(1B) receptors in antidepressant and anxiolytic behavioral effects in mice will be examined using a variety of gene knockout strategies. The regulation of 5-HT(1A) receptors will be studied in brain and in model systems, including clonal cell lines and transfected cells, in order to identify cell signalling pathways that are associated with the desensitization of functional effects mediated by 5-HT(1A) receptors. The linkage of 5-HT(1A) receptors with subunits of guanine nucleotide-binding regulatory proteins responsible for many of the physiological responses elicited by 5-HT will be studied. The results of the proposed work should have important implications for our understanding of synaptic transmission in the brain and of the effects of psychotherapeutic drugs.
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