Date of Award

9-29-2010

Document Type

Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Joan Kaufman

Second Advisor

John Krystal

Third Advisor

James Leckman, Bruce Rounsaville

Abstract

GABA RECEPTOR GENOTYPE AND BRAIN REWARD CIRCUITRY IN CHILDREN. Joseph Boonsiri, Michelle Hampson and Joan Kaufman. Child Study Center and Department of Psychiatry, Yale University School of Medicine, New Haven, CT. Early alcohol use in adolescence has been associated with psychiatric illness, illicit drug use and suicide. Multiple studies have demonstrated that alcohol use disorders are highly heritable, and there is growing evidence that GABA-A receptor genes interact with alcohol and are involved in the process of alcohol dependence, with the C-allele (single nucleotide polymorphism rs279858) of the GABRA2 gene associated with increased risk for alcohol dependence. Alcoholics also demonstrate alterations in the brain circuitry involved in calculations of risk and perception of reward. In this study we examine the effect of GABRA2 genotype on reward circuitry via functional Magnetic Resonance Imaging (fMRI). We examined (1) resting state functional connectivity maps, in which correlations between brain regions are measured at rest, and (2) brain activation during a gambling paradigm. A total of 9 children participated in the study. Approximately half were the high-risk CC genotype and half were TT. In the resting state connectivity analysis, the CC group demonstrated increased connectivity of the nucleus accumbens to the orbitofrontal cortex and anterior cingulate cortex (p<0.01, both correlations). This finding was consistent with our hypothesis and with the results of a prior study examining functional connectivity in individuals addicted to heroin. During the gambling task, the CC group also demonstrated higher activation of the anterior cingulate cortex and orbitofrontal cortex than the TT group while making calculations of risk and reward, as well as higher activation in the nucleus accumbens, amygdala, and orbitofrontal cortex during loss events (all comparisons, p<0.05). Clinical measures of impulsivity were negatively correlated with right (r=-0.91, p<.05) and left (r=-0.85, p<0.05) anterior cingulate cortex activity during the selection phase, and negatively correlated with right (r=-0.91, p < .05) and left (r=-0.86, p < .05) amygdala activity during the feedback phase of the gambling task. Our study was limited in its ability to form conclusions due to a very small sample size, but the pilot data demonstrated group differences between GABRA2 genotypes. Our study suggests that variation in GABRA2 genotype is associated with individual differences in resting state functional connectivity and patterns of activation of brain regions involved in reward circuitry. Further research in children prior to exposure to alcohol with larger sample sizes and longitudinal follow-up is warranted to determine if the observed findings are replicated and predictive of progression to alcoholism.

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