Pramipexole-induced increased probabilistic discounting: comparison between a rodent model of Parkinson's disease and controls.

The dopamine agonist pramipexole (PPX) can increase impulsiveness, and PPX therapy for neurological diseases (Parkinson's disease (PD) and restless leg syndrome) is associated with impulse control disorders (ICDs) in subpopulations of treated patients. A commonly reported ICD is pathological gambling of which risk taking is a prominent feature. Probability discounting is a measurable aspect of risk taking. We recently developed a probability discounting paradigm wherein intracranial self-stimulation (ICSS) serves as the positive reinforcer. Here we used this paradigm to determine the effects of PPX on discounting. We included assessments of a rodent model of PD, wherein 6-OHDA was injected into the dorsolateral striatum of both hemispheres, which produced persistent PD-like deficits in posture adjustment. Rats were trained to perform ICSS-mediated probability discounting, in which PD-like and control groups exhibited similar profiles. Rats were treated twice daily for 2 weeks with 2 mg/kg (±)PPX (ie, 1 mg/kg of the active form), a dose that improved lesion-induced motor deficits. In both groups, (±)PPX increased discounting; preference for the large reinforcer was enhanced 30-45% at the most uncertain probabilities. Tolerance did not develop with repeated treatments. Increased discounting subsided within 2 weeks of (±)PPX cessation, and re-exposure to (±)PPX reinstated heightened discounting. Such findings emulate the clinical scenario; therefore, ICSS for discounting assessments in rats exhibited high face validity. This model should prove useful in medication development where assessment of the propensity of a putative therapy to induce risk-taking behaviors is of interest.