Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

This project aims to investigate the involvement of specific dopamine receptors on models of gambling behaviour, both in normal rats and in a rodent model of Parkinson's disease (PD). The more traditional drug treatment for PD, L-DOPA, has been shown over time to produce debilitating side-effects like dyskinesia. Selective dopamine D2/3 receptor agonists such as ropinirole are therefore increasingly used to treat the motor symptoms of PD. However, these drugs can lead to serious impulse control disorders (ICD), including pathological gambling (PG), in some patients. Pilot data indicate that ropinirole increases gambling behaviour in healthy rats. I propose to determine the effect of chronic ropinirole on different behavioural tasks modeling gambling in healthy rat. I will also investigate its effects in the dorsostriatal 6-hydroxydopamine (6-OHDA) lesion model of Parkinson's disease. Dopamine D4 receptors have been implicated in a variety of disorders including ICDs. It has been shown that the D4 antagonist L-745,870 improved aspects of gambling behaviours in rats, and also reduced the deleterious effects caused by a D2 agonist. This drug could therefore also reverse the impairments in decision-making caused by D2/3 receptor agonists. I therefore also intend to explore whether chronic administration of L-745,870 affects gambling behaviour when administered in isolation, and whether it can reverse the detrimental effects of chronic ropinirole in healthy or 6-OHDA lesioned rats. I intend to characterise any changes in dopamine receptor expression and related intracellular signalling pathways that accompany any behavioural changes using molecular techniques. Discovering the mechanisms by which dopamine agonist induce cognitive deficits in PD patients, as well as the potential reduction of these effects by co-administration of a D4 antagonist would have an important impact on the treatment of PD, as well as lead to new targets for drug development.