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Evaluation of a novel treatment for dopamine agonist-induced impulse control disorders for Parkinson's patients

University of British Columbia

Selective dopamine D⅔ receptor agonists, such as ropinirole (ROP), effectively treat the motor symptoms of Parkinson’s Disease (PD), and unlike L-dopa, do not cause problematic dyskinesias after prolonged use. Thus, D⅔ agonists can be an attractive alternative to L-dopa for the long-term management of PD. However, D⅔ agonists induce impulse control and gambling disorders in a substantial minority of patients, raising concern over the use of these agents. Adjunctive medications that could be safely administered with D₂/₃ agonists and prevent the development of such psychiatric side-effects would therefore be highly desirable. GPR52 is a Gs-coupled g-protein coupled receptor (GPR) enriched in D2 receptor expressing neurons of the striatum. Activation of GPR52 has been demonstrated to attenuate behaviours associated with increased striatal dopamine release without altering basal function. We have previously shown that ROP increases preference for uncertain outcomes on a rodent test of gambling-like decision making known as the rodent betting task (rBT). This task measures preference for certain versus uncertain rewarding outcomes of equal expected value. Although most rats maintain a constant preference for the uncertain outcome regardless of the amount at stake, some rats increase their preference for guaranteed rewards as the wager-size increases, despite the relative expected value of the two options remaining constant. The choice strategy of these wager-sensitive rats may be considered mathematically non-normative, and such irrational decision-making patterns have been linked to the manifestation and severity of problem gambling. The degree of wager sensitivity has been associated with the density of D⅔ receptors in the dorsal striatum. I therefore hypothesized that GPR52 agonists may attenuate the ability of ROP to promote choice of uncertain outcomes in wager-sensitive rats on the rBT. I tested this hypothesis by administering GPR52 agonists BD442618 and S111224 in two cohorts of healthy male rats that were also implanted with osmotic pumps, delivering either ROP or saline. The rats performed the rBT for 28 days after osmotic pump implantation. A reduction in ROP’s ability to increase preference for uncertainty on the rBT would suggest that GPR52 agonists may be a potential treatment for iatrogenic impulse control and gambling disorders.

Text

2019-08-14

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71289

Psychology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/