Impulsive behavior induced by Dopamine D3 receptor agonist treatment in Parkinson’s disease is mediated by β‐arrestin

Parkinson's Disease (PD) is a movement disorder characterized by progressive degeneration and loss of mid-brain dopaminergic neurons. Pramipexole (PRX), a Dopamine D3 receptor (D3R) agonist, has emerged as a potent therapeutic to treat motor deficits, but chronic therapy leads to impulse control disorders (ICDs) in PD patients. ICDs comprise a group of complex behavioral disorders characterized by failure to resist an impulse or temptation to perform an act that is harmful to the individual or to others. While the etiology of ICDs is not well understood, several clinical and animal studies have demonstrated that D3R agonist activity directly correlates with the development ICDs. D3Rs are highly expressed in the mesolimbic pathways and mediate motor and reward processes in the brain. D3R agonists can signal through multiple signaling pathways and predominantly through the activation of G-proteins, β-arrestin, or both. We hypothesize that activation of β-arrestin signaling pathway by D3R agonists such as PRX can induce ICDs in PD. To test this hypothesis, PD rats were trained to criteria in a 5-choice serial reaction time task (5CSRTT) and their baseline levels of impulsive responses (measured as premature responses), correct responses and omissions were recorded. Animals were then treated with vehicle or PRX or our G-protein biased D3R agonist SK609 for 3 weeks (1x/day; i.p) and their responses in the 5CSRTT were measured at the end of week-3. Results from the study demonstrated that PRX significantly increased omission, premature responses (PMR) compared to vehicle or SK609 treatment. SK609 reduced PMR and increased the correct responses and reduced omissions when compared to both PRX and vehicle treatment. The increase in PMR by PRX treatment correlated with an increase in anxiety as measured by time spent in the closed arms of the elevated plus maze. Current studies are aimed at understanding the molecular mechanisms of β-arrestin mediated signaling that promote ICDs. PRX treatment was further found to enhance β-arrestin expression whereas SK609 didn't in PD rats. Our study will augment the understanding of biased D3R signaling and its role in modulating ICDs in PD. This study's outcome will be directly translatable to optimizing therapy for PD without the risk of developing ICDs seen with existing therapies.