REGULATION OF SEROTONIN-1 RECEPTORS

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Serotonin (5HT) is an important neurotransmitter in the central nervous system and is thought to be involved in a variety of mental disorders. The recent proliferation of 5HT receptor subtypes provides a unique opportunity to study the involvement of these subtypes in mental disorders and to develop subtype-specific drugs for the treatment of these disorders. The long-term objective of this application is to understand the regulation of the various 5HT, receptor subtypes on two levels. The first is regulation at the level of the receptor protein in the membrane and its relationship to adenylate cyclase; the second is the genetic regulation of the expression of the receptor. We propose to use the 5HT(1B) receptor in the OK cell line as a model system to study the 5HT(1) receptors in the CNS. Homologous down-regulation and desensitization of the 5HT(1B) receptor in the OK cell line will be studied by a variety of assays including radioligand binding and cyclic AMP production assays. We propose to clone the 5HT(1B) receptor from the OK cell and the 1B and/or 1D receptor from rat brain. These clones will be used as tools in the proposed studies of the regulation of the receptor system. We also plan to define the tissue distribution and level of expression of 5HT(1) receptors in the rat brain by Northern blot analysis and in situ hybridization.