Serotonin in Alcoholism

This research concerns the study of serotonin (5-HT) synthesis, metabolism (turnover), and release. We hypothesize that neuronal 5-HT turnover and release is altered in alcoholic individuals, and that this plays a role in alcohol seeking behavior. We wish to determine the following: 1. Whether there are differences in 5-HT turnover and release in alcoholics compared to healthy research comparison participants, before and after Acute Tryptophan Depletion (ATD); 2. Whether putative differences in 5-HT turnover are governed primarily by genetic variation in the 5-HT transporter (5-HTT) in alcoholics; 3. Whether 5-HTT genetic variation correlates with \[(18) F\]-FCWAY/5-HT(1A), binding, and cerebrospinal fluid (CSF) 5-Hydroxyindoleacetic acid (5-HIAA) concentration, before and after ATD; and, 4. If regional cerebral blood flow (rCBF) differs at baseline and after ATD in alcoholics and healthy research comparison participants. To investigate the underlying biochemistry of 5-HT neurometabolism, we will use two experimental strategies, Acute Tryptophan (TRP) Depletion (ATD) and positron emission tomography (PET) imaging, to investigate 5-HT neurochemistry. We will deplete plasma TRP, using ATD, while simultaneously collecting CSF 5-HIAA and performing intermittent plasma sampling via indwelling catheters. TRP is the amino acid (AA) precursor needed for 5-HT synthesis. 5-HIAA is the principal metabolite of 5-HT. It is a neurochemical marker of neuronal 5-HT metabolism. PET will allow indirect measurements of synaptic 5-HT concentration by measuring binding of \[(18)F\]-FCWAY, a 5-HT (1A)-receptor antagonist. rCBF will be measured with \[(15)O\]-water imaging. Studies will be performed before and after ATD. Individuals will be genotyped for the 5-HT transporter (5-HTT). Plasma TRP and Large Neutral Amino Acids (LNAAs), and CSF TRP and 5-HIAA concentrations will be measured using High Performance Liquid Chromatography (HPLC).