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Chronic administration of the dopamine D2/3 agonist ropinirole invigorates performance of a rodent slot machine task, potentially indicative of less distractible or compulsive-like gambling behaviour

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Abstract

Rationale

Whilst dopamine agonist therapies can successfully manage the symptoms of diseases such as Parkinson’s disease (PD), fibromyalgia and restless leg syndrome, they can also cause impulse control and addiction disorders such as gambling disorder (GD). These compulsive behaviours seriously undermine the utility of such treatments.

Objectives

The objective of the study was to model this phenomenon using a rodent slot machine task (rSMT) in order to investigate the neurobiological basis underlying such behavioural changes.

Methods

Male Long Evans rats were trained to perform the rSMT. The D2-like agonist ropinirole, or saline, was then delivered continuously for 28 days via osmotic mini-pump. The effects of ropinirole on baseline rSMT performance, as well as extinction and reinstatement sessions, were determined during this time. Brain samples from key frontostriatal regions implicated in GD and PD were then harvested immediately or after a 4-week washout period during which behaviour returned to pre-drug baseline.

Results

Ropinirole invigorated task performance, in that drug treatment resulted in a robust and sustained increase in the number of trials completed. Ex vivo analyses revealed that chronic ropinirole treatment led to a pattern of changes indicative of upregulation within the β-arrestin-AKT-GSK3β intracellular cascade, recently theorised to dominate D2-mediated signalling under hyperdopaminergic conditions, in the dorsal striatum, rather than the canonical PKA-dependent signalling pathway associated with D2 receptor activation.

Conclusions

Such findings provide novel insight into the role of dopamine signalling in mediating compulsive-like gambling behaviour and may inform more directed pharmacotherapies for the treatment of both idiopathic and iatrogenic GD.

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Acknowledgments

This work was supported by an operating grant awarded to CAW from the Canadian Institutes of Health Research (CIHR). CAW also received salary support through the Michael Smith Foundation for Health Research and CIHR New Investigator Award program. PJC is funded through a graduate student award from Parkinson’s Society Canada. CAW has previously consulted for Shire on an unrelated matter.

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Authors and Affiliations

  1. Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

    Paul J. Cocker, M Tremblay, S Kaur & Catharine A. Winstanley

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  1. Paul J. Cocker
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  2. M Tremblay
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  3. S Kaur
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  4. Catharine A. Winstanley
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Corresponding authors

Correspondence to Paul J. Cocker or Catharine A. Winstanley.

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The testing and housing of all animals was in accordance with the Canadian Council of Animal Care, and all experimental protocols were approved by the Animal Care Committee of the University of British Columbia.

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The authors declare that they have no conflict of interest.

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Cocker, P.J., Tremblay, M., Kaur, S. et al. Chronic administration of the dopamine D2/3 agonist ropinirole invigorates performance of a rodent slot machine task, potentially indicative of less distractible or compulsive-like gambling behaviour. Psychopharmacology 234, 137–153 (2017). https://doi.org/10.1007/s00213-016-4447-y

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