Gene x disease interaction on orbitofrontal gray matter in cocaine addiction

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.

Figure 1

Gray matter volume reductions as a function of cocaine addiction (CUDN=82). Each brain region is presented with a graph using the VOI to show that the main effects of addiction are contributed by both genotype groups (except for the OFC). The y-axis units display the percent GMV in the cluster around the peak coordinates listed in Table 2. Error bars represent standard error of the mean. The respective GMV maps in each of the graphs show the clusters of significance between the diagnostic groups (p<.05, FDR corrected, 100 voxels minimum). The parahippocampus is not shown since its values were identical to the hippocampus VOI as they came from the same cluster.

Figure 2

Gene-by-disease interaction in the orbitofrontal cortex. The GMV measures in CUD-Lred) and CUD-H<CON-H (blue) are overlaid on the SPM5 canonical template. The respective interaction graphs show regional GMV differences between the groups where CUD-L have the least GM than CUD-H and both CON groups. Error bars represent standard error of the mean. The y-axis units display the percent GMV cluster around the peak coordinates in Table 2 (p<.05, FDR corrected, 100 voxels minimum).

Figure 3

Lifetime effects of drug use on GMV. The central image shows correlation of GMV with lifetime use of each drug (cocaine=red, alcohol=yellow, smoking=green) overlaid on the SPM5 canonical template. The respective scatterplots are also overlaid with the correlations of GMV (y-axis) and lifetime years of cocaine in the CUD group (red) and lifetime years of alcohol (yellow) and smoking (green) in all subjects (the open circles are controls), with the respective slope (p<.001, uncorrected, 100 voxels minimum).