Multi-facetted impulsivity following nigral degeneration and dopamine replacement therapy

Abstract

Impulse control disorders (ICDs) are debilitating side effects of dopamine replacement therapy (DRT) in Parkinson’s disease (PD) that severely affect the quality of life of patients. While DRT, the pattern and extent of neurodegeneration, and prodromic factors of vulnerability (e.g. impulsivity) have all been hypothesized to play a role in the development of ICDs, their respective, and potentially interacting, contributions remain to be established. High impulsive (HI), Intermediate (Int) or low impulsive (LI) rats were identified based on their performance in both a differential reinforcement of low rate of responding (DRL) and a fixed consecutive number (FCN) schedules, that operationalize two independent facets of impulsivity, waiting and action inhibition (motor impulsivity). We investigated whether high impulsivity trait influenced the progressive development of a parkinsonian state induced by viral-mediated overexpression of α-synuclein, and whether impulsivity trait and nigrostriatal neurodegeneration independently or jointly influenced the effects of DRT on impulse control. α-synuclein-induced nigrostriatal neurodegeneration increased both waiting and motor impulsivity. The D2/D3 dopamine receptor agonist pramipexole exacerbated motor impulsivity more than waiting. However, the pramipexole-induced increase in waiting impulsivity observed in both sham and lesioned rats, was more pronounced in HI lesioned rats, which displayed a restricted α-synuclein-induced dopaminergic neurodegeneration. Thus, a PD-like nigrostriatal lesion increases both motor and waiting impulsivity, but its interaction with a pre-existing impulsivity trait, which, at the cellular level, confers resilience to dopaminergic neurodegeneration, worsens the detrimental effects of D2/D3 dopamine receptor agonists on inhibitory control.

Impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease: an update

“…In rats, alpha-synuclein induced nigrostriatal neurodegeneration increased waiting impulsivity and impulsive action. Pramipexole increased waiting impulsivity and impulsive action both in sham and lesioned rats but its effect on waiting impulsivity in lesioned rats was enhanced in animals with pre-existing impulsivity traits 105 . However, in contrast to impairments in decisional impulsivity in humans, studies either did not detect impairments 93 or showed improvement 106 in motor response inhibition in PD+ICD subjects tested using the stop signal task.…”

Neuropsychiatric Disorders in Parkinson’s Disease: What Do We Know About the Role of Dopaminergic and Non-dopaminergic Systems?

“…By contrast, pramipexole was not associated with changes in compulsivity. Similarly, α-synuclein-induced nigrostriatal neurodegeneration increases impulsivity by itself, subsequent chronic pramipexole administration exacerbating it (Engeln et al, 2016). Impulsive behavior does not develop in 6-OHDA-lesioned rodents (Baunez and Robbins, 1999;Carvalho et al, 2017).…”

Evidence for a Long-Lasting Compulsive Alcohol Seeking Phenotype in Rats

“…Compulsive, intermediate and non-compulsive (NC) animals were identified using a two-step K-mean cluster analysis of the number of completed seeking-taking cycles during the last 3 days of the seeking-taking punishment schedule (footshock intensity 0.45 mA; three data points per rat were considered). Cluster analysis has been shown to be a convenient and commonly used method for identifying objectively homogenous groups of objects within a data set (Tye et al, 2010;Murray et al, 2015;Engeln et al, 2016). Thus, the hypothesis-driven k-means clustering with maximization of distance between groups defined a priori as 3 was performed on a unique dimension (compulsivity) but in a three-dimensional space (repeated measures).…”

“…By contrast, a subpopulation of rats maintained their seeking response despite punishment, thereby displaying compulsive alcohol seeking behavior (Figure 2a and b). A cluster analysis (Tye et al, 2010;Murray et al, 2015;Engeln et al, 2016) performed on the completed seeking-taking cycles during the last 3 sessions of punishment (Supplementary Figure S3) confirmed the existence of three subgroups of rats: 34% of the population displayed compulsive alcohol seeking (compulsive, C, rats, n = 21), whereas, unexpectedly, a 30% sub-population greatly suppressed their seeking responses (NC rats, n = 18); 36% of the population (intermediate, I, rats, n = 22) between C and NC rats partially suppressed seeking when intermittently punished (compulsivity: F 2,55 = 84.55, po0.001, η 2 = 0.75 and time × compulsivity: F 18,495 = 16.75, po0.001, η 2 = 0.38). These data demonstrate that the propensity to drink alcohol is clearly not sufficient to predict the transition to compulsive alcohol seeking behavior (see SOM).…”