Article

Gene-gene interaction associated with neural reward sensitivity

NeuroImage Nord, Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2007; 104(19):8125-30. DOI: 10.1073/pnas.0702029104
Source: PubMed

ABSTRACT

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.

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    • "Developmental Review (2014), http://dx.doi.org/10.1016/j.dr.2014.05.003 models assume that the number of initial ''hits'' determines outcome, multiplicative models account for the dynamic nature of functional brain development by assuming that a few initial factors interact and amplify (or decrease) each other's effects during development. Multiplicative effects of gene–gene interaction on brain function (Yacubian et al., 2007) and behavior (Lakatos et al., 2003), have been described. One should be reminded, nonetheless, that the multivariate models we described above are based on the premise that there is a unitary autism phenotype, varying only in severity. "
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    • "Further studies have shown epistatic (i.e. gene-gene) interactions between COMT and DAT during cognitive tasks [Bertolino et al., 2008; Caldu et al., 2007; Prata et al., 2009b; Yacubian et al., 2007]. G72 regulates glutamatergic transmission, by activating D-amino acid oxidase (DAAO), which modulates the metabolism of D-amino acids like D-serine, a coagonist for the NMDA glutamate receptor [Boks et al., 2007]. "
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    • "One study showed increased activation of the dorsolateral PFC and ventral striatum (areas implicated in the anticipation of reward) and in the orbitofrontal cortex at the time of reward delivery in Met/Met homozygotes (Dreher et al., 2009 ) compared to the Val allele participants. A Similar pattern of results was previously observed in another study of reward processing (Yacubian et al., 2007). One study showed an opposite allelic effect (Camara et al., 2010), in the medial PFC (anterior cingulate) and ventral striatum, but using a slightly different paradigm involving unexpected rewards. "
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