PHARMACOLOGY OF FOREBRAIN SEROTONIN RECEPTORS

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Progress has been made in molecular, cellular and biochemical pharmacology of serotonin (5-HT) receptors yet their functional significance is uncertain. The GENERAL OBJECTIVE is to use selective pharmacologic agents to assess forebrain 5-HT receptor subtypes in vivo. The HYPOTHESIS is that selective activation of blockade of 5-HT receptor subtypes in discrete brain regions will elicit unique patterns of autonomic, hemodynamic and neuroendocrine responses to affect cardiovascular function. The SPECIFIC AIMS are to microinject drugs into the anterior hypothalamus, paraventricular nucleus, the medial preoptic area and central amygdala in conscious, unrestrained rats to: 1) DESCRIBE ROLES FOR FOREBRAIN 5-HT1A,5-HT2, and 5-HT3 RECEPTORS IN CARDIOVASCULAR FUNCTION, AND 2) DETERMINE NEURAL AN/OR HORMONAL MEDIATORS OF THE RESPONSES. The 5-HT agonists to be used primarily are 8-OH-DPAT [8- hydroxy-2-di-nu-propylamino) tetralin] for 5-HT1A receptors, DOI [(plus/minus)-1-(2-5-dimethoxy-4-iodophenyl)-2-aminopropane HC1] for 5- HT2/1C receptors and 2-methyl 5-HT for 5-HT3 receptors. Other agonists to provide more detailed receptor characterizations may include flesinoxan and 5-carboxamidotryptamine (5-HT1A), DOB [(plus/minus)-1-(2- 5-dimethoxy-4-bromophenyl)-2-aminopropane HBr] (5-HT2/1C) and phenylbiguanide(5-HT3). The antagonists to be used primarily are spiperone for 5-HT1A receptors, ketanserin for 5-HT2 receptors, and ICS 205-930 for 5-HT3 receptors. Again, more detailed characterizations may include the use of (-)pindolol, (+) pindolol, and methiothepin (5-HT1A), LY 53857 and spiperone (5-HT2/1C, and MDL 72222 and ondansetron (5-HT3). The appropriate use of these drugs in conjunction with a description of diffusional distances using autoradiographic techniques as well as the ability of autonomic and hormone antagonists to alter responses will allow an quantitative in vivo assessment of mechanisms by which 5-HT receptor subtypes in the forebrain regulate arterial pressure, heart rate, cardiac output and renal, iliac and superior mesenteric blood flows. To separate reflex from direct responses the serotonergic drugs will be microinjected following chronic surgical baroreceptor deafferentation. Overall, the experiments will provide detailed information on brain regions, receptor subtypes and neurohumoral mechanisms by which 5-HT receptors regulate cardiovascular homeostasis. These studies will provide significant in vivo data regarding the function of 5-HT receptor subtypes in discrete forebrain areas as an extension of the in vitro biochemical, cellular and molecular pharmacology.