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Neurobiological and behavioural effects of chronic administration of the D₂/₃ agonist ropinirole in relation to iatrogenic gambling disorder

University of British Columbia

Neurobiological changes in Parkinson’s Disease (PD) involve dramatic loss of dopamine neurons in the substantia nigra (SNc) and terminals in the dorsal striatum. L-DOPA, first line treatment for PD, can produce debilitating side-effects like dyskinesia over time. Preferential dopamine D2/3 agonists like ropinirole, are used to treat PD, but these newer drugs can lead to impulse control disorders (ICDs) and gambling disorder in a significant minority of patients. The mechanism mitigating dopamine replacement therapy (DRT)-induced ICDs, or whether premorbid behavioural tendencies are a risk factor are unknown. We show that chronic ropinirole increases preference for uncertainty on the rodent Betting task (rBT), regardless of animals’ baseline preference for the safe or uncertain option. Comparatively, ropinirole had subtle effects on choice of a cued version of the rat Gambling task (rGT), while increasing impulsivity, suggesting different neural mechanisms in performance of these tasks. GSK3ß has been involved in disorders of impulsivity suggesting a potential intracellular mechanism for DRT-ICDs. However, chronic administration of SB 216763, a GSK3ß inhibitor, did not attenuate gambling-like behaviours following ropinirole, but also did not reliably decrease GSK3ß levels, such that we were unable to unequivocally determine its role in ropinirole-induced preference for uncertainty. The “overdose” hypothesis, in which DRTs would replenish dopamine stores in the deteriorated dorsal striatum and improve movement, but overwhelm the mostly spared mesolimbic reward system, was suggested to explain DRT-ICDs in PD. However, newer studies suggest a potential involvement for the nigrostriatal, rather than mesolimbic, pathway in gambling disorders. We therefore manipulated the nigrostriatal pathway using designer receptors exclusively activated by designer drugs (DREADDs). Activation of dopamine neurons in the SNc increased preference for uncertainty on the rBT in wager-sensitive rats, partially mimicking the effect of ropinirole, while inhibition of these neurons had no effect on the increase in preference for uncertainty caused by ropinirole. These studies suggest a potential role for activation of the nigrostriatal pathway in DRT-ICDs. They also suggest that ICDs result from DRT alone, rather than from an interaction between medication and basal risk preference, or change in dopamine function caused by the diseases for which they are prescribed.

Text

2017-10-19

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/63360

Psychology

University of British Columbia

UBCV

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