Abstract
BackgroundDopamine therapy in Parkinson disease (PD) can have differential effects on inhibitory action control, or the ability to inhibit reflexive or impulsive actions. Dopamine agonist (DAAg) medications, which preferentially target D2 and D3 receptors, can either improve or worsen control of impulsive actions in patients with PD. We have reported that the direction of this effect depends on baseline levels of performance on inhibitory control tasks. This observation suggests that there may exist certain biologic determinants that contribute to these patient‐specific differences. We hypothesized that one important factor might be functional polymorphisms in D2‐like receptor genes.AimThe goal of this study was to determine whether the direction of DAAg effects on inhibitory control depends on functional polymorphisms in the DRD2 and DRD3 genes.MethodsTwenty‐eight patients with PD were genotyped for known functional polymorphisms in DRD2 (rs6277 and rs1800497) and DRD3 (rs6280) receptors. These patients then completed the Simon conflict task both on and off DAAg therapy in a counterbalanced manner.ResultsWe found that patients with the rs1800497 Taq1A (A1) polymorphism (A1/A1 or A1/A2: 11 subjects) showed improved proficiency to suppress impulsive actions when on DAAg; conversely, patients with the A2/A2 allele (14 patients) became less proficient at suppressing incorrect response information on DAAg therapy (Group × Medication, F(1, 23) = 5.65, p < 0.05). Polymorphisms in rs6277 and rs6280 were not associated with a differential medication response.ConclusionThese results suggest that certain DRD polymorphisms may determine the direction of DAAg effects on critical cognitive control processes impaired in PD. Our findings have implications for understanding pharmacogenomics interactions on a larger scale and the role these may play in the wide variability of treatment effects seen in the PD population.
Highlights
Dopaminergic medications remain the mainstay treatment for Parkinson disease (PD) motor symptoms, but a growing body of research reveals both beneficial and detrimental effects of dopaminergic medications on specific cognitive processes in PD
Our results show that the Taq1A polymorphism in the DRD2 gene appears to modulate the Dopamine agonist (DAAg) therapeutic response on inhibitory motor control
Patients with the Taq1A polymorphism showed poorer inhibitory control of action impulses off DAAg medications and dramatic improvement on DAAg, while patients with the A2/A2 allele were much more proficient at inhibitory control off DAAg, but experienced a reduction in inhibitory control proficiency on DAAg therapy
Summary
Dopaminergic medications remain the mainstay treatment for Parkinson disease (PD) motor symptoms, but a growing body of research reveals both beneficial and detrimental effects of dopaminergic medications on specific cognitive processes in PD. Patients with PD who show impaired performance in an off medication state, presumably due to greater DA depletion, typically benefit from the addition of dopaminergic medications, whereas individuals who show near-normal performance in an off state often show decline in performance when dopaminergic medications are added (Cools, Barker, Sahakian, & Robbins, 2001; Wylie, Claassen et al, 2012) This inverted U-shaped DA performance curve is suggestive of differential dopaminergic pathology in cognitive circuits across patients (Cools & D’Esposito, 2011). We have reported that the direction of this effect depends on baseline levels of performance on inhibitory control tasks This observation suggests that there may exist certain biologic determinants that contribute to these patient-specific differences. Our findings have implications for understanding pharmacogenomics interactions on a larger scale and the role these may play in the wide variability of treatment effects seen in the PD population
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