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

Background: 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. Methods: 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. Results: 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. Discussion: 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.