Role of D3 receptors in drug-induced impulsivity in a rat model of Parkinson's di

Rush University Medical Center, Chicago IL

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Abstract

DESCRIPTION (provided by applicant): This NRSA application is for support of my graduate training, including a translational research project focused on impulse control disorders (ICDs) in Parkinson's disease (PD). Pramipexole (PPX) is a dopamine (DA) D3 receptor (D3R)-preferring agonist used to treat motor dysfunctions in PD. A significant subset of treated patients (e.g., 13.6%1) develop ICDs, i.e., behavioral addictions like pathological gambling, hypersexuality, compulsive shopping and binge eating. Our lab has established a novel probability discounting task in rats that measures risk-taking by using intracranial self-stimulation (ICSS) as the positive reinforcer. Using this model, I plan to ascertain the role of the D3R in PPX-induced discounting. Thereafter, I plan to determine if the D3R-mediated effects involve intracellular mechanisms that are known to regulate learning as well as drug/behavioral addictions, i.e., trafficking of the glutamatergic receptor AMPA. Accordingly, my overall hypotheses are that D3R activation by PPX leads to increased risk-taking, which may be more pronounced in PD-like rats due to dysregulated dopamine systems, and that the neurobiology of this effect involves D3R-mediated increases in surface expression of AMPA receptors (Rs) in brain regions that govern impulsivity. I propose three Specific Aims to test these hypotheses. Rats with 6-hydroxydopamine-induced lesions of the dorsolateral striatum and controls will be tested. The Napier lab has already demonstrated that these PD-like rats acquire and perform ICSS-mediated probability discounting. In Aim 1, I will evaluate the effects of PPX at a low dose suprathreshold to improving motor deficits in the forelimb step task in the probability discounting task. It is my prediction that PPX will enhance risk-taking in PD-like rats, but not in control rat due to increased vulnerability of the PD brain state. In Aim 2, I will co-administer selective D3R antagonists with PPX, and predict that development and expression of PPX-induced risk-taking will be blocked. In Aim 3, I will evaluate D3R-mediated cell signaling that governs synaptic plasticity. I propose that D3R activation enhances AMPAR trafficking to the cell surface through an Akt/GSK-3b signaling pathway. I will assess the effects of PPX treatment on surface expression of AMPARs, as well as levels of activated Akt and GSK-3b signaling using a modified Western blot protocol ongoing in the Napier lab. I predict an increase in the efficacy of this signaling pathway in PD-like rats. In summary, this training opportunity will allow me to use a novel preclinical model of ICDs to pioneer the signal transduction pathways that are associated with PPX- induced risk-taking behaviors. Therefore, my extensive training not only will include highly sophisticated techniques, but experimental design for a wide range of applications. This exciting research, along with my training program, will provide me all the necessary skill sets for a future career in medications development for neuropathologies, especially those where diseases of motor function co-occur with dysregulation of mental health.