Polymorphisms in dopaminergic genes predict proactive processes of response inhibition.

The ability to inhibit a prepared emotional or motor action is difficult but critical to everyday functioning. It is well-established that response inhibition relies on the dopaminergic system in the basal ganglia. However, response inhibition is often measured imprecisely due to a process which slows our responses and increases subsequent inhibition success known as proactive inhibition. As the role of the dopamine system in proactive inhibition is unclear, we investigated the contribution of dopaminergic genes to proactive inhibition. We operationalised proactive inhibition as slower responses after failures to inhibit a response in a Go/No-Go paradigm and investigated its relationship to rs686/A at DRD1 (associated with increased gene expression) and rs1800497/T at DRD2 (associated with reduced D2 receptor availability). Even though our sample (N = 264) was relatively young (18-40 years), we found that proactive inhibition improves the ability to withhold erroneous responses in older participants (p = 0.002) and those with lower fluid intelligence scores (p < 0.001), indicating that proactive inhibition is likely a naturally occurring compensatory mechanism. Critically, we found that a polygenic risk score consisting of the number of rs686 A and rs1800497 T alleles predicts higher engagement of proactive inhibition (p = 0.040), even after controlling for age (p = 0.011). Furthermore, age seemed to magnify these genetic effects (p < 0.001). This suggests that the extent to which proactive inhibition is engaged depends on increased dopamine D1 and decreased D2 neurotransmission. These results provide important considerations for future work investigating disorders of the dopaminergic system.