Impaired serotonin (5-HT) function has been implicated as a possible factor in the biological vulnerability for alcoholism, but most studies of the 5-HT system have been performed in animals or, if performed in humans, they involved only indirect measurements to assess the 5-HT system in the brain. The status of the 5-HT neurons in the brain of living alcohol dependent individuals remains unknown. To investigate the 5-HT system of the brain, quantitative PET studies of the brain 5-HT transporter (5-HTT; an established marker of serotonin neuron integrity) are proposed using [11C]McN5652 as radioligand for four groups of human subjects: family history negative (FHN) controls, family history positive (FHP) controls, FHN recovering alcoholics, and FHP recovering alcoholics. The hypothesis to be tested is that radioligand binding to the 5-HT transporter is significantly reduced as a function of both alcoholism and family history of alcoholism. Serotonin function will also be measured by quantification of plasma prolactin and cortisol increase in response to fluoxetine. The genetic aspect of 5-HT impairment will be investigated by measuring the frequency of specific polymorphisms of the 5-HTT gene. The hypothesis is that FHP alcoholics and FHP controls will have a higher frequency of the s-variant allele, the allele which has been associated with reduced 5-HTT expression/function in in vitro studies. The frequency of the s- variant allele is predicted to be higher in subjects with reduced 5-HTT densities (as determined by PET) and with reduced hormonal responses to fluoxetine. The results of this project will lead to better understanding of the role of serotonin in the biological vulnerability for alcoholism and may lead to improved approaches to prevent and treat alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA011653-01A1
Application #
2747613
Study Section
Special Emphasis Panel (ZRG4-HPD (03))
Program Officer
Witt, Ellen
Project Start
1999-01-01
Project End
2003-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Wang, Z Jane; Szabo, Zsolt; Lei, Peng et al. (2008) A Factor-Image Framework to Quantification of Brain Receptor Dynamic PET Studies. IEEE Trans Signal Process 53:3473-3487
McCann, Una D; Szabo, Zsolt; Vranesic, Melin et al. (2007) Quantitative positron emission tomography studies of the serotonin transporter in humans previously treated with the appetite suppressants fenfluramine or dexfenfluramine. Mol Imaging Biol 9:151-7
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McCann, Una D; Szabo, Zsolt; Seckin, Esen et al. (2005) Quantitative PET studies of the serotonin transporter in MDMA users and controls using [11C]McN5652 and [11C]DASB. Neuropsychopharmacology 30:1741-50
Szabo, Zsolt; Owonikoko, Taofeek; Peyrot, Mark et al. (2004) Positron emission tomography imaging of the serotonin transporter in subjects with a history of alcoholism. Biol Psychiatry 55:766-71
Szabo, Zsolt; McCann, Una D; Wilson, Alan A et al. (2002) Comparison of (+)-(11)C-McN5652 and (11)C-DASB as serotonin transporter radioligands under various experimental conditions. J Nucl Med 43:678-92
Varga, Jozsef; Szabo, Zsolt (2002) Modified regression model for the Logan plot. J Cereb Blood Flow Metab 22:240-4
Hilton, J; Yokoi, F; Dannals, R F et al. (2000) Column-switching HPLC for the analysis of plasma in PET imaging studies. Nucl Med Biol 27:627-30
Szabo, Z; Scheffel, U; Mathews, W B et al. (1999) Kinetic analysis of [11C]McN5652: a serotonin transporter radioligand. J Cereb Blood Flow Metab 19:967-81

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