Polymorphisms in dopaminergic genes predict proactive inhibition in a Go/No Go task

Efficient avoidance of actions that have been rendered inappropriate or maladaptive by altered environmental demands is a critical neurocognitive mechanism. Disturbed response inhibition is seen in many neurodegenerative... [ view full abstract ]

Efficient avoidance of actions that have been rendered inappropriate or maladaptive by altered environmental demands is a critical neurocognitive mechanism. Disturbed response inhibition is seen in many neurodegenerative pathologies, and is a putative early indicator endophenotype for some psychiatric disorders. One of the processes that contribute to response inhibition is the deliberate slowing of reaction time following an error, or where cessation of a prepotent response might become necessary. This process is referred to as proactive inhibition. The Go/No-Go paradigm (e.g., the Sustained Attention to Response Task) allows us to distinguish proactive inhibition (slowing of response speed following an error to improve the likelihood of successful inhibition on future no-go trials) from reactive inhibition (withholding a prepotent response on no-go trials). We isolated Post-Error Slowing (PES), an error-correction mechanism that approximates proactive inhibition, to reconcile the inconsistencies in the literature as to whether proactive inhibition relies on the indirect basal ganglia pathway and DRD2 receptors, or the hyperdirect pathway and DRD1 receptors. We investigated whether PES is better predicted by SNPs associated with enhanced dopamine D1 vs D2 neurotransmission (rs686/A at DRD1 is associated with increased expression of the DRD1 gene, and rs1800497/C at DRD2/ANKK1 is associated with increased D2 receptor density) in 260 healthy individuals. We report a main effect of rs686 and polygenic interaction derived from an unweighted genetic risk score (rs686 and rs1800497) that each indicate a genetic predisposition toward higher dopamine D1 neurotransmission increases proactive inhibition. This suggests that PES requires activation of the hyperdirect pathway.