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Possible Protective Factors

Nora D. Volkow, MD; Gene-Jack Wang, MD; Henri Begleiter, MD, PhD; Bernice Porjesz, PhD; Joanna S. Fowler, PhD; Frank Telang, MD; Christopher Wong, MS; Yeming Ma, PhD; Jean Logan, PhD; Rita Goldstein, PhD; David Alexoff, BSE; Peter K. Thanos, PhD

Arch Gen Psychiatry. 2006;63:999-1008.

Context  Predisposition to alcoholism is likely an interaction between genetic and environmental factors that confer vulnerability and protection. Alcoholic subjects have low levels of dopamine D₂ receptors in striatum, and increasing D₂ receptor levels in laboratory animals reduces alcohol consumption.

Objectives  To test whether high levels of D₂ receptors may be protective against alcoholism and whether this is mediated by their modulation of activity in orbitofrontal cortex and cingulate gyrus (regions involved in salience attribution, emotional reactivity, and inhibitory control).

Design  Research (nonalcoholic subjects with a family history of alcoholism) and comparison (nonalcoholic subjects with a negative family history) sample.

Setting  Outpatient setting.

Participants  Fifteen nonalcoholic subjects who had an alcoholic father and at least 2 other first- or second-degree relatives who were alcoholics (family-positive group) and 16 nonalcoholic controls with no family history of alcoholism (family-negative group).

Main Outcome Measures  Results of positron emission tomography with raclopride C 11 to assess D₂ receptors and with fludeoxyglucose F 18 to assess brain glucose metabolism (marker of brain function). Personality measures were obtained with the Multidimensional Personality Questionnaire.

Results  Availability of D₂ receptors was significantly higher in caudate and ventral striatum in family-positive than family-negative subjects. In family-positive but not family-negative subjects, striatal D₂ receptors were associated with metabolism in anterior cingulate (Brodmann area 24/25) and orbitofrontal (Brodmann area 11) and prefrontal (Brodmann area 9/10) cortices, and with personality scores of positive emotionality.

Conclusions  The higher-than-normal D₂ receptor availability in nonalcoholic members of alcoholic families supports the hypothesis that high levels of D₂ receptors may protect against alcoholism. The significant associations between D₂ receptors and metabolism in frontal regions involved with emotional reactivity and executive control suggest that high levels of D₂ receptors could protect against alcoholism by regulating circuits involved in inhibiting behavioral responses and in controlling emotions.

Author Affiliations: National Institute on Drug Abuse (Dr Volkow) and National Institute on Alcohol Abuse and Alcoholism (Drs Volkow, Telang, Ma, and Thanos), Bethesda, Md; Medical Department (Drs Wang and Goldstein and Messrs Wong and Alexoff) and Chemistry Department (Drs Fowler and Logan), Brookhaven National Laboratory, Upton, NY; and Department of Psychiatry, State University of New York Downstate, Brooklyn (Drs Begleiter and Porjesz).

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