Gene-gene interaction associated with neural reward sensitivity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 19; pp. 8125 - 8130
• Main Authors: Yacubian, Juliana, Sommer, Tobias, Schroeder, Katrin, Gläscher, Jan, Kalisch, Raffael, Leuenberger, Boris, Braus, Dieter F, Büchel, Christian
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08-05-2007; National Acad Sciences
• Subjects: Adolescent; Adult; Basal ganglia; Behavioral neuroscience; Biological Sciences; Brain; Catechol O-Methyltransferase - genetics; Corpus Striatum - physiology; Dopamine Plasma Membrane Transport Proteins - genetics; Enzymes; Expected values; Genes; Genetic diversity; Genetic variation; Genotype; Genotype & phenotype; Genotypes; Humans; Magnetic Resonance Imaging; Male; Medical genetics; Middle Aged; Neurotransmitters; Polymerase chain reaction; Prefrontal cortex; Prefrontal Cortex - physiology; Reward; Volunteerism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0702029104

Reward processing depends on dopaminergic neurotransmission and is modulated by factors affecting dopamine (DA) reuptake and degradation. We used fMRI and a guessing task sensitive to reward-related activation in the prefrontal cortex and ventral striatum to study how individual variation in genes contributing to DA reuptake [DA transporter (DAT)] and degradation [catechol-o-methyltransferase (COMT)] influences reward processing. Prefrontal activity, evoked by anticipation of reward irrespective of reward probability and magnitude, was COMT genotype-dependent. Volunteers homozygous for the Met allele, associated with lower enzyme activity and presumably greater DA availability, showed larger responses compared with volunteers homozygous for the Val allele. A similar COMT effect was observed in the ventral striatum. As reported previously, the ventral striatum was also found to code gain-related expected value, i.e., the product of reward magnitude and gain probability. Individual differences in ventral striatal sensitivity for value were in part explained by an epistatic gene-gene interaction between COMT and DAT. Although most genotype combinations exhibited the expected activity increase with more likely and larger rewards, two genotype combinations (COMT Met/Met DAT 10R and COMT Val/Val 9R) were associated with blunted ventral striatal responses. In view of a consistent relationship between reduced reward sensitivity and addiction, our findings point to a potential genetic basis for vulnerability to addiction.