Abstract

The goal will be to identify and characterize serotonin (5-hydroxytryptaminne; 5-HT) receptor subtypes in the nervous system using a combination of molecular and electgrophysiological approaches. Three major techniques will be utilized. First, pharmacological characterization of 5-HT receptor subtypes will be performed using radioligand binding studies. An attempt will be made to define homogeneous populations of 5-HT receptor subtypes. Once identified, a specific pharmacologic """"""""profile"""""""" for each receptor subtype will be determined. Guanine nucleotide sensitivity will be used to predict the relative agonist versus antagonist properties of drugs. Second, 5-HT receptor subtypes will be anatomically localized by autoradiography. A general autoradiographic screen will be performed in order to locate brain regions containing relatively dense populations of 5-HT receptor subtypes. Relative densities of all known subtypes will be quantitated by autoradiographic analysis in two specific brain regions: the hippocampus and somatosensory cortex. Third, in these two specific areas, the effect of 5-HT and related agents on neuronal activity will be determined using neurophysiological techniques. Field potential analysis will be used to determine the relative potencies of serotonergic agents on neurotransmission. Intracellular studies will focus on drug effects in the dentate gyrus of the hippocampus. This combination of molecular and electrophysiological approaches should greatly facilitate the characterization of 5-HT receptor subtypes in the central nervous system. Increased knowledge of the pharmacologic properties, regional localization and neuronal effects of 5-HT receptor subtypes should clarify the role of 5-HT in both normal and abnormal brain function.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023560-02
Application #
3407212
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1986-12-01
Project End
1989-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
2
Fiscal Year
1988
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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