Pramipexole Increases Go Timeouts but Not No-go Errors in Healthy Volunteers

Abstract

Parkinson’s disease (PD) is characterized by motor symptoms, such as resting tremor, bradykinesia and rigidity, but also features non-motor complications. PD patients taking dopaminergic therapy, such as levodopa but especially dopamine agonists (DAs), evidence an increase in impulse control disorders (ICDs), suggesting a link between dopaminergic therapy and impulsive pursuit of pleasurable activities. However, impulsivity is a multifaceted construct. Motor impulsivity refers to the inability to overcome automatic responses or cancel pre-potent responses. Previous research has suggested that PD patients, on dopaminergic medications, have decreased motor impulsivity. Whether effects on impulsivity are main effects of dopaminergic therapies or are specific to PD is unclear. Using a Go No-go task, we investigated the effect of a single dose of the DA pramipexole on motor impulsivity in healthy participants. The Go No-go task consisted of Go trials, for which keystroke responses were made as quickly as possible, and lesser frequency No-go trials, on which motor responses were to be inhibited. We hypothesized that pramipexole would decrease motor impulsivity. This would manifest as: (a) fewer No-go errors (i.e., fewer responses on trials in which a response ought to have been inhibited); and (b) more timed-out Go trials (i.e., more trials on which the deadline elapsed before a decision to make a keystroke occurred). Healthy volunteers were treated with either 0.5 mg of pramipexole or a standard placebo (randomly determined). During the 2-h wait period, they completed demographic, cognitive, physiological and affective measures. The pramipexole group had significantly more Go timeouts (p < 0.05) compared to the placebo group though they did not differ in percent of No-go errors. In contrast to its effect on pursuit of pleasurable activities, pramipexole did not increase motor impulsivity. In fact, in line with findings in PD and addiction, dopaminergic therapy might increase motor impulse control. In these patient groups, by enhancing function of the dorsal striatum (DS) of the basal ganglia in contrast to its effect on impulsive pursuit of pleasurable activities. These findings have implications for use and effects of pramipexole in PD as well as in other conditions (e.g., restless leg, dystonia, depression, addiction-related problems).

Dopaminergic Therapy Increases Go Timeouts in the Go/No-Go Task in Patients with Parkinson’s Disease

“…Our objective was to explicitly investigate, in back-to-back tests within PD patients, the effect of dopaminergic therapy on motor impulse control using an accepted measure of this process (i.e., Go/No-go; Rubia et al, 2001 ; Hamidovic et al, 2008 ; Antonelli et al, 2014 ). Here, in PD patients, we entirely replicated the pattern that we observed in healthy young controls (Yang et al, 2016 ). Specifically, we previously showed that dopaminergic therapy increases the Go Timeout rate in healthy young controls.…”

“…Specifically, we previously showed that dopaminergic therapy increases the Go Timeout rate in healthy young controls. We previously interpreted this pattern of results, as we have here, as evidence that dopaminergic therapy increases control over motor responses and decreases the tendency to make more impulsive responses (Yang et al, 2016 ).…”

“…In a previous study, we showed that healthy young controls using the same Go/No-go task that was implemented in the current study, evidenced greater Go Timeouts when they were taking the DA pramipexole relative to placebo, revealing more considered and less impulsive responding in the DA condition (Yang et al, 2016 ). This finding occurred despite the fact that there were no differences in response times (RTs) between ON and OFF medication states, making our findings consistent with differences in motor impulsivity, not motor ability (Yang et al, 2016 ). These results further corroborate findings from a study by Hiebert et al ( 2014a ).…”

“…In recent years, there has been tremendous interest in the autonomic and cognitive symptoms of PD (Poletti and Bonuccelli, 2013 ; Goldman and Postuma, 2014 ; Yang et al, 2016 ; Palmeri et al, 2017 ). Cognitive dysfunction in particular can cause devastating impairments to quality of life (Voon et al, 2009 ; Weintraub et al, 2015 ; Aarsland et al, 2017 ).…”

Striatum-Mediated Deficits in Stimulus-Response Learning and Decision-Making in OCD

“…DS encompasses the majority of the caudate nucleus and putamen. The DS has been implicated in decision-making (14), cognitive flexibility (15), and inhibition of habitual responses (16). In contrast, the VS is comprised of the nucleus accumbens and ventral regions of the caudate nucleus and putamen (10).…”