Altered sensitivity of brain secrotonin receptors has been hypothesized in the etiology and/or treatment of depression, sleep disorders, and phychosis. The neuronal biochemical intracellular mechanisms through which serotonin receptor stimulation elicit cellular responses are still unknown. To better understand the nature of the brain's serotonin receptors and the mechanisms regulating their activity radioreceptor assays for brain 5-HT1 and 5-HT2 receptors will be utilized. 3H-ketanserin, an antagonist radiolabel, and 3H-DOB, putatively the first specific HT2 receptor agonist ligand will be used to label the 5-HT2 receptors in rat brain homogenates. 3H-Dihydroergocryptine (DHEC) will be used for the first time to label 5-HT1 receptors; heretofore this radioligand had been used to label adrenergic and dopamine receptors. 3H-DHEC, presumably an antagonist radioligand, is the first receptor radioligand possessing binding properties permitting its use to study the detailed properties of the 5-HT1 receptor both in the presence and absence of the important receptor regulator GTP. In order to determine if the 5-HT1 and/or 5-HT2 receptors interact with an N-protein (a moiety that often mediates receptor-adenylate cyclase coupling) and if so determine if the N-protein is an Ni (inhibitory N-protein) or Ns (stimulatory N-protein), the effects of guanyl nucleotides, divalent cations, monovalent cations, monovalent cations, N- ethylmaleimide, cholera toxin, and pertussis toxin on the radiolabelled receptors will be observed. These agents are known to regulate the interaction of receptors with N subunits. As the free receptor generally has different agonist binding properties from the complexed receptor, the presence of the N-subunit may be inferred from specific alterations in the agonist binding propeties of the radiolabelled receptors. In order to determine the susceptibility of the 5-HT1 and 5-HT2 receptor-N subunit interactions to drug-induced alterations, rats will be acutely and chronically treated with serotonin receptor antagonists, agonists, and various types of antidepressants. Alterations in the amount of 5-HT1 and 5-HT2 receptors and the ability of receptor regulators to interact with the radiolabelled receptors after drug treatments will be determined.
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