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:

• 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);
• Whether putative differences in 5-HT turnover are governed primarily by genetic variation in the 5-HT transporter (5-HTT) in alcoholics;
• 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,
• 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).

Inclusion criteria

Patients who have met standard DSM-IV R criteria for alcohol dependence and limited number psychiatric conditions that characterize patients with mood disorders that are difficult to separate from their alcohol use.

Age and sex matched healthy research comparison participants. The healthy research comparison participants need to be free of medical, neurological, and psychiatric illness. They should be medication free at the time of study. They should not meet criteria for alcohol or substance abuse, and cannot have a history of such use placing them in questionable diagnostic categories.

The age range of study participants is from 18 to 65 years.

Subjects from a diverse racial, ethnic, and gender backgrounds will be included in the study. This is because alcohol dependence manifests itself differently in different racial and gender groups.

Exclusion criteria

Significant medical problems, e.g., active GI bleed, cancer, active hepatitis B infection or other medical diseases associated with liver pathology other than hepatitis C or alcoholism (e.g. Hemochromatosis).

Other psychiatric illnesses represent diagnostic categories not eligible for this study. Examples of these include Major Depressive Disorder, Bipolar Disorder, acute or chronic psychotic illness (e.g. Schizophrenia), and Substance Induced Mood Disorders (i.e. secondary to illicit drug dependence; e.g. heroin, cocaine, crack, PCP, and other illicit substances that affect brain function).

Intravenous drug use within the past three months.

Drug or medication use, strongly associated with liver dysfunction, CNS effects, or impaired GI absorption (e.g. high doses of acetaminophen, neuroleptic medications, and narcotic medications).

History of significant GI surgery (e.g. Roux en Y procedure, partial gastrectomy), which would interfere with normal GI absorption of dietary constituents.

Coagulation defects or lack of dual circulation.

Severe iron deficiency anemia, marked low hematocrit or hemoglobin.

Pregnancy: a positive pregnancy test will preclude further participation in this protocol.

Inability to give a clinical history or informed consent.

Positive human immunodeficiency virus (HIV) diagnosis: patients with positive HIV status/AIDS will be excluded form the study.

Individuals may be excluded from entering the study at the discretion of the Principal Investigator, Dr. Williams, based on his clinical judgment.

Participants who have had an adverse reaction that mimics any of the anticipated adverse events in response to a pharmacological challenge study or to a prescribed medication.

Cranial mass.