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


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.


Available from: Jan Philipp Gläscher
  • Source
    • "Developmental Review (2014), 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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A fast growing field, the study of infants at risk because of having an older sibling with autism (i.e. infant sibs) aims to identify the earliest signs of this disorder, which would allow for earlier diag-nosis and intervention. More importantly, we argue, these studies offer the opportunity to validate existing neuro-developmental models of autism against experimental evidence. Although autism is mainly seen as a disorder of social interaction and communica-tion, emerging early markers do not exclusively reflect impairments of the ''social brain''. Evidence for atypical development of sensory and attentional systems highlight the need to move away from localized deficits to models suggesting brain-wide involvement in autism pathology. We discuss the implications infant sibs findings have for future work into the biology of autism and the development of interventions. Ó 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license ( licenses/by/3.0/).
    Developmental Review 06/2014; DOI:10.1016/j.dr.2014.05.003 · 3.23 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
    Human Brain Mapping 09/2013; 34(9). DOI:10.1002/hbm.22061 · 5.97 Impact Factor
  • Source
    • "The hypothesis that COMT might impact on striatal function under certain circumstances (see Discussion) is attractive, given strong evidence linking Val158Met with striatal activation during reward processing (e.g. [29], reviewed in [30]), for which striatal dopamine is key [31], [32]. It is also consistent with interactive effects of tolcapone and Val158Met genotype on the performance of a reward task [20], similar to the relationship described above for working memory. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The catechol-O-methyltransferase (COMT) enzyme metabolises catecholamines. COMT inhibitors are licensed for the adjunctive treatment of Parkinson's disease and are attractive therapeutic candidates for other neuropsychiatric conditions. COMT regulates dopamine levels in the prefrontal cortex (PFC) but plays a lesser role in the striatum. However, its significance in other brain regions is largely unknown, despite its links with a broad range of behavioural phenotypes hinting at more widespread effects. Here, we investigated the effect of acute systemic administration of the brain-penetrant COMT inhibitor tolcapone on tissue levels of dopamine, noradrenaline, and the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). We examined PFC, striatum, hippocampus and cerebellum in the rat. We studied both males and females, given sexual dimorphisms in several aspects of COMT's function. Compared with vehicle, tolcapone significantly increased dopamine levels in the ventral hippocampus, but did not affect dopamine in other regions, nor noradrenaline in any region investigated. Tolcapone increased DOPAC and/or decreased HVA in all brain regions studied. Notably, several of the changes in DOPAC and HVA, particularly those in PFC, were more prominent in females than males. These data demonstrate that COMT alters ventral hippocampal dopamine levels, as well as regulating dopamine metabolism in all brain regions studied. They demonstrate that COMT is of significance beyond the PFC, consistent with its links with a broad range of behavioural phenotypes. Furthermore, they suggest that the impact of tolcapone may be greater in females than males, a finding which may be of clinical significance in terms of the efficacy and dosing of COMT inhibitors.
    PLoS ONE 04/2013; 8(4):e61839. DOI:10.1371/journal.pone.0061839 · 3.23 Impact Factor
Show more