Abstract
The dynorphin/κ-opioid receptor (KOP-R) system has been shown to play a role in different types of behavior regulation, including reward-related behavior and drug craving. It has been shown that alleles with 3 or 4 repeats (HH genotype) of the variable nucleotide tandem repeat (68-bp VNTR) functional polymorphism of the prodynorphin (PDYN) gene are associated with higher levels of dynorphin peptides than alleles with 1 or 2 repeats (LL genotype). We used fMRI on N = 71 prescreened healthy participants to investigate the effect of this polymorphism on cerebral activation in the limbic-corticostriatal loop during reward anticipation. Individuals with the HH genotype showed higher activation than those with the LL genotype in the medial orbitofrontal cortex (mOFC) when anticipating a possible monetary reward. In addition, the HH genotype showed stronger functional coupling (as assessed by effective connectivity analyses) of mOFC with VMPFC, subgenual anterior cingulate cortex, and ventral striatum during reward anticipation. This hints at a larger sensitivity for upcoming rewards in individuals with the HH genotype, resulting in a higher motivation to attain these rewards. These findings provide first evidence in humans that the PDYN polymorphism modulates neural processes associated with the anticipation of rewards, which ultimately may help to explain differences between genotypes with respect to addiction and drug abuse.
Highlights
A growing number of genetic neuroimaging studies suggest that functional polymorphisms in genes regulating the dopamine system play a crucial role in mediating reward-related behavior [1,2,3,4]
In the human brain the PDYN gene is predominately expressed in the medial prefrontal cortex, the amygdala, the dentate gyrus and the striatum [12,13]
While several functions have been associated with the striatum, the medial orbitofrontal cortex and the amygdala, it is widely accepted that they play a dominant role in processes related to reward anticipation and consumption, in the control of mood, and motivation, as well as in stimulus-response learning [14,15,16,17,18,19]
Summary
A growing number of genetic neuroimaging studies suggest that functional polymorphisms in genes regulating the dopamine system play a crucial role in mediating reward-related behavior [1,2,3,4]. While several functions have been associated with the striatum, the medial orbitofrontal cortex (mOFC) and the amygdala, it is widely accepted that they play a dominant role in processes related to reward anticipation and consumption, in the control of mood, and motivation, as well as in stimulus-response learning [14,15,16,17,18,19] In line with these functions, there is evidence that increases in PDYN neurotransmission may contribute to the pathogenesis of depression, anxietylike behavior, dysphoria, and drug addiction [20,21,22,23]
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