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

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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