Neural correlates of inhibitory control and functional genetic variation in the dopamine D4 receptor gene

The dopamine D4 receptor gene (DRD4) has been implicated in psychiatric disorders in which deficits of self-regulation are a prominent feature (e.g., attention-deficit hyperactivity disorder and substance use disorders) and in dopamine D4 receptor insensitivity within prefrontal regions of the brain. Our hypothesis was that carriers of 7-repeats in the Variable Number of Tandem Repeats (VNTR) of DRD4 (7R+) would recruit prefrontal brain regions involved in successful inhibitory control to a lesser degree than non-carriers (7R-) and demonstrate less inhibitory control as confirmed by observation of locally reduced blood oxygenation level dependent (BOLD) % signal change and lower accuracy while performing "No-Go" trials of a Go/No-Go task.

Participants (age=18, n=62, 33 females) were recruited from the general population of the St. Louis, Missouri region. Participants provided a blood or saliva sample for genotyping, completed drug and alcohol-related questionnaires and IQ testing, and performed a Go/No-Go task inside of a 3T fMRI scanner.

Go/No-Go task performance did not significantly differ between 7R+ and 7R- groups. Contrast of brain activity during correct "No-Go" trials with a non-target letter baseline revealed significant BOLD activation in a network of brain regions previously implicated in inhibitory control including bilateral dorsolateral prefrontal, inferior frontal, middle frontal, medial prefrontal, subcortical, parietal/temporal, and occipital/cerebellar brain regions. Mean BOLD % signal change during "No-Go" trials was significantly modulated by DRD4 genotype, with 7R+ showing a lower hemodynamic response than 7R- in right anterior prefrontal cortex/inferior frontal gyrus, left premotor cortex, and right occipital/cerebellar areas. Follow-up analyses suggested that 7-repeat status accounted for approximately 5-6% of the variance in the BOLD response during "No-Go" trials.

The DRD4 7-repeat allele may alter dopaminergic function in brain regions involved in inhibitory control. When individuals must inhibit a prepotent motor response, presence of this allele may account for 5-6% of the variance in BOLD signal in brain regions critically associated with inhibitory control, but its influence may be associated with a greater effect on brain than on behavior in 18-year-olds from the general population.