Polymorphisms in dopaminergic genes predict proactive processes of response inhibition

Abstract

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.

Measurement of the response inhibition network in a brief battery of tasks: Introducing an assessment of reactive and proactive inhibition processes.

“…Therefore, designing and validating simpler tasks that minimise these confounds is critical. Indeed, older adults in the Bloemendaal et al study showed a trend towards increased (rather than decreased) proactive slowing in a simple 2-cue condition relative to young adults, a result that mirrors our own finding that older adults show increased PES (Beu, Burns, & Baetu, 2019). So, as it stands, proactive inhibition is likely task-dependent, and may indeed vary in validity across tasks, and perhaps even rely on separate neurochemical equilibrium (e.g., Beu et al, 2019;Rincón-Pérez et al, 2019).…”

“…To date, there is no adequate formal account of proactive inhibition. However, given the role of proactive inhibition as a strategy to compensate for what may be physiological constraints in achieving optimal reactive inhibition (e.g., Beu, Burns, & Baetu, 2019), it seems likely that it could take two forms in an experimental environment. The first could be considered a predictive form, characterised as attenuating a response pattern under conditions where there is a real or perceived increase in the likelihood of a need to inhibit a response, as in the task modification used by Bloemendaal and colleagues (Bloemendaal et al, 2016).…”

“…Each of these accounts are supported by some experimental data which are reviewed elsewhere, although the predictive form has not been conceptualised as a form of proactive inhibition (e.g., Aron, 2011, Aron et al, 2007Dutilh et al, 2012;Niewenhuis, Ridderinkhof, Blom, Band, & Kok., 2001;Ridderinkhof, Ullsperger, Crone, & Nieuwenhuis, 2004). Critically, though, predictive proactive inhibition seems to adhere to common reinforcement learning principles (i.e., learning by trial and error the likelihood of different events and adapting behaviour accordingly), whereas, on the other hand, PES has been the subject of competing explanations for some time (Beu, Burns, & Baetu, 2019;Dutilh et al, 2012b).…”

Acute tolerance to alcohol-induced impairment in cognitive performance.

“…Evidence of acute tolerance to impairment in response inhibition was not found in this study, because performance in both the alcohol and placebo group was similar at all time points for all SART measures. Although the observed variance in post−error slowing in the SART appeared high, it was not dissimilar to that found in previous studies (Beu, Burns, & Baetu, 2019). Because the SART did not show any effect of alcohol, there was not sufficient impairment to show recovery as evidence of acute tolerance.…”

Ropinirole, a dopamine agonist with high D3 affinity, reduces proactive inhibition: a double-blind, placebo-controlled study in healthy adults

“…Although the aforementioned studies have informed the role of dopamine in reactive inhibition, the literature concerning dopamine and proactive inhibition remains scarce. D 1 and D 2 gene polymorphisms have been shown to predict engagement of proactive inhibition (measured as post-error slowing in a go/no-go task), such that increased D 1 and decreased D 2 receptor expression are associated with increased proactive inhibition [38]. Given that ropinirole has a relatively high affinity for D 3 receptors, our work extends the mediators of proactive inhibition to include D 3 receptors, as well.…”