The focus in on two central 5HT receptor (5HT2 and 5HT1c) that are coupled to inositol lipid metabolism, the physiological functions of these receptors and the mechanisms by which they are regulated. These problems will be addressed at all levels, from molecular studies of gene expression to cellular studies of receptor-mediated biochemical and physiological responses to whole animal studies of behavioral and physiological functions. Specific questions are: (1) What is the mechanism of the down- regulation of 5HT2 receptor density and loss of responsiveness after antagonist administration? These studies will focus on the atypical antidepressant - 5HT antagonist, mianserin. (2). What is the relationship between 5HT2 behavioral sensitivity and the dual regulatory mechanisms (changes in 5HT2 receptor recognition site and in 5HT2-mediated PI hydrolysis). These studies will compare the two biochemical measures of the 5HT2 receptor state with a unique behavioral model that is bidirectionally sensitive to changes in functionally relevant 5HT2 receptors. (3) What is the explantation for the failure of denervation to elicit, 5HT2 receptor up-regulation and increased responsiveness? A working hypothesis is that 5HT2 receptors on neurons and glia are regulated by distinct mechanisms that mask adaptive changes in neuronal 5HT2 receptor. (4) What is the physiological role of 5HT1c receptors? The working hypothesis is that 5HT1c receptors mediate a trophic effect of 5HT. 5HT-induced elevation of protein synthesis in choroid plexus epithelial cells in primary culture will be used as a model. (5) How are 5HT1c receptors regulated? The mechanism of agonist-induced subsensitivity and of antagonist-induced down-regulation will be explored, including possible effects on the expression of the 5HT1c receptor gene. The key concept that underlies all of this work that it is imperative that biochemical studies in cells and tissues be related to function in the living animal. This approach is essential to the attainment of the ultimate goal of bridging the gap between laboratory studies of psychoactive drugs and clinical treatment of mental illness.
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