Abstract

The goal of this project will be to identify and characterize serotonin (5-hydroxytryptamine; 5-HT) receptor subtypes in the central nervous system using a combination of molecular pharmacological and biochemical techniques. The project will focus on three major areas. First, an extremely detailed comparative pharmacological characterization will be made of all known 5-HT binding site subtypes using currently available radioligands. The goal is to determine a specific """"""""pharmacological profile"""""""" for each 5-HT receptor subtype so that each subtype can be more easily identified in functional assays. Secondly, novel radioligands will be synthesized in collaboration with other investigators and an attempt will be made to either identify previously undescribed 5-HT binding site subtypes or to improve upon the methodology currently available to characterize known populations of 5-HT binding site subtypes. Finally, for each 5-HT receptor subtype identified, an attempt will be made to develop an in vitro biochemical assay in order to assess drug efficacy at the receptor. It is expected that at least 2 assays (adenylate cyclase and phosphatidylinositol turnover studies) will be used to develop these important correlations. This combination of molecular pharmacological and biochemical approaches should greatly facilitate the characterization of 5-HT receptor subtypes in the central nervous system. Increased knowledge of the pharmacological properties and biochemical effects of 5-HT receptor subtypes should clarify the role of 5-HT in both normal and abnormal human brain function.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS023560-04
Application #
3407207
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1990-09-21
Project End
1993-11-30
Budget Start
1990-09-21
Budget End
1991-11-30
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

Pierce, P A; Xie, G X; Levine, J D et al. (1996) 5-Hydroxytryptamine receptor subtype messenger RNAs in rat peripheral sensory and sympathetic ganglia: a polymerase chain reaction study. Neuroscience 70:553-9
Buchwalder, A; Welch, S K; Peroutka, S J (1996) Exclusion of 5-HT2A and 5-HT2C receptor genes as candidate genes for migraine. Headache 36:254-8
Guan, X M; Peroutka, S J; Kobilka, B K (1992) Identification of a single amino acid residue responsible for the binding of a class of beta-adrenergic receptor antagonists to 5-hydroxytryptamine1A receptors. Mol Pharmacol 41:695-8
Pierce, P A; Kim, J Y; Peroutka, S J (1992) Molecular structural basis of ligand selectivity for 5-HT2 versus 5-HT1C cortical receptors. Naunyn Schmiedebergs Arch Pharmacol 346:4-11
Peroutka, S J (1991) Serotonin receptor subtypes and neuropsychiatric diseases: focus on 5-HT1D and 5-HT3 receptor agents. Pharmacol Rev 43:579-86
Peroutka, S J; McCarthy, B G; Guan, X M (1991) 5-benzyloxytryptamine: a relatively selective 5-hydroxytryptamine 1D/1B agent. Life Sci 49:409-18
Liau, L M; Sleight, A J; Pitha, J et al. (1991) Characterization of a novel and potent 5-hydroxytryptamine1A receptor antagonist. Pharmacol Biochem Behav 38:555-9
Sleight, A J; Peroutka, S J (1991) Identification of 5-hydroxytryptamine1A receptor agents using a composite pharmacophore analysis and chemical database screening. Naunyn Schmiedebergs Arch Pharmacol 343:109-16
McKenna, D J; Guan, X M; Shulgin, A T (1991) 3,4-Methylenedioxyamphetamine (MDA) analogues exhibit differential effects on synaptosomal release of 3H-dopamine and 3H-5-hydroxytryptamine. Pharmacol Biochem Behav 38:505-12
Gonzalez-Heydrich, J; Peroutka, S J (1991) Postsynaptic localization of 5-HT1D receptor binding sites in human caudate. Exp Neurol 113:28-30

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