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Original Article
March 7, 2011

Gene × Disease Interaction on Orbitofrontal Gray Matter in Cocaine Addiction

Author Affiliations

Author Affiliations: Medical Department, Brookhaven National Laboratory, Upton, New York (Drs Alia-Klein, Woicik, Maloney, Shumay, R. Wang, Biegon, G.-J. Wang, Fowler, and Goldstein; Mr Parvaz; and Ms Konova); Departments of Biomedical Engineering (Mr Parvaz) and Psychology (Ms Konova), Stony Brook University, Stony Brook, New York; Mount Sinai School of Medicine, New York, New York (Drs G.-J. Wang and Fowler); National Institute on Alcohol and Alcoholism, Bethesda, Maryland (Drs Telang and Tomasi); and National Institute on Drug Abuse, Bethesda, Maryland (Dr Volkow).

Arch Gen Psychiatry. 2011;68(3):283-294. doi:10.1001/archgenpsychiatry.2011.10
Abstract

Context  Long-term cocaine use has been associated with structural deficits in brain regions having dopamine-receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability.

Objective  To examine variations in gray matter volume (GMV) as a function of lifetime drug use and the genotype of the monoamine oxidase A gene, MAOA, in men with cocaine use disorders (CUD) and healthy male controls.

Design  Cross-sectional comparison.

Setting  Clinical Research Center at Brookhaven National Laboratory.

Patients  Forty individuals with CUD and 42 controls who underwent magnetic resonance imaging to assess GMV and were genotyped for the MAOA polymorphism (categorized as high- and low-repeat alleles).

Main Outcome Measures  The impact of cocaine addiction on GMV, tested by (1) comparing the CUD group with controls, (2) testing diagnosis × MAOA interactions, and (3) correlating GMV with lifetime cocaine, alcohol, and cigarette smoking, and testing their unique contribution to GMV beyond other factors.

Results  (1) Individuals with CUD had reductions in GMV in the orbitofrontal, dorsolateral prefrontal, and temporal cortex and the hippocampus compared with controls. (2) The orbitofrontal cortex reductions were uniquely driven by CUD with low- MAOA genotype and by lifetime cocaine use. (3) The GMV in the dorsolateral prefrontal cortex and hippocampus was driven by lifetime alcohol use beyond the genotype and other pertinent variables.

Conclusions  Long-term cocaine users with the low-repeat MAOA allele have enhanced sensitivity to gray matter loss, specifically in the orbitofrontal cortex, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain. In addition, long-term alcohol use is a major contributor to gray matter loss in the dorsolateral prefrontal cortex and hippocampus, and is likely to further impair executive function and learning in cocaine addiction.

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