This grant builds upon the research from a prior grant: A Rodent Model of Pathological Gambling Associated with Medicated Parkinsonian Patients
Promising Outcomes of Original Grant:
In keeping with our original hypothesis, we determined the following: 1) Being in a parkinsonian state (i.e., following 6-OHDA-induced lesions) alters impulsivity profiles in rats. 2) Chronic treatments with pramipexole, which is associated with impulsive control disorders in PD patients, augments risk-taking behaviors in parkinsonian rats. Though not proposed in the original application, the pre-clinical model proved to be sufficiently stable as to allow an A-B-A design, and we verified that risk-taking returned to normal after terminating pramipexole treatments, and was reinstated upon reinitiating treatment. Another additional study verified that pramipexole can evoke reward-motivated behaviors (demonstrated by condition place preference studies) in PD-like rats.
Objectives for Supplemental Investigation:
The supplemental funds are requested to verify that the enhancement in risk-taking behaviors obtained with pramipexole are also seen in another D3-preferring dopamine agonists reported to increase impulse control disorders in PD, i.e., ropinerole. These disorders have been sometimes associated with the indirect agonist, L-DOPA, so we plan to also assess L-DOPA in our pre-clinical model of risk-taking. We hypothesize that the direct acting agonist, ropinerole will emulate pramipexole, whereas L-DOPA, which acts to presynaptically enhance DA release, will be less effective. These studies will help determine the cause of impulse control disorders in PD patients undergoing DA replacement therapy. If these predicted outcomes are obtained, future work may include using D3-preferring antagonists to block the agonist-induced effects and evaluating a D2-preferring agonist as a negative control. Such studies would strongly implicate that activation of D3 receptors subtypes underlies impulse control disorders in PD.
Importance of This Research for the Development of a New PD Therapy:
Demonstrating which pharamcologics used in DA replacement therapy for PD can enhance risk-taking behavior in rats greatly advances our understanding of the means by which impulse control disorders can occur in the human condition. This informs us as to what alterations need to be incorporated into current PD therapy to avoid this devastating side effect.
Progress Report
We developed a novel approach to measure impulsivity/risk-taking behavior in a rodent model of Parkinson’s disease (PD). This approach allowed us to investigate the ability of pramipexole (Mirapex®) to alter risk-taking in PD-like and control rats. The results from this study demonstrated that pramipexole enhances risky behaviors that discontinuing pramipexole treatment leads to a decrease in risk-taking, and re-exposure to pramipexole reinstated risk-taking. These findings are consistent with clinical observations that report some PD patients show pramipexole-induced enhancements in gambling behavior that often are reversed with dose reduction or drug discontinuation. We are currently testing the effects of other drugs, such as ropinirole (Requip®) to alter risk-taking in PD-like and controls rats.
Pramipexole increased risk-taking in both PD-like and control rats groups. This suggests that the PD-like condition is not a requisite for these effects of pramipexole. The findings also support clinical observations that the pramipexole can induce risk-taking in non-PD pathologies, like restless leg syndrome patients and patients with fibromyalgia.
Finally, we revealed that pramipexole itself has rewarding properties; such effect is enhanced in PD-like rats. Thus, if pramipexole can affect the reward regions of the brain, it may explain why pramipexole can drive reward-related behaviors, such as gambling.
Presentations & Publications
Report (and include copies of) any presentations, abstracts, findings, or papers (submitted for publication, in press, or published) that resulted from the work made possible by this award.
Abstracts and Poster Presentations (see appendix for copies)
Rokosik SL, Riddle, JL, and Napier TC. Pramipexole is rewarding and induces risk-taking behavior in rats. Behavior, Biology and Chemistry Conference, San Antonio TX, (2010).
Rokosik SL, Riddle JL, and Napier TC. Pramipexole-induced risky behavior in a pre-clinical model of Parkinson's disease. Movement Disorder Society Conference, Buenos Aires, Argentina (2010).
Napier TC, Riddle JL, Rokosik SL. Pramipexole induces a conditioned place preference in parkinsonian-like rats. Movement Disorder Society Conference, Buenos Aires, Argentina (2010).
Riddle JL, Rokosik SL, and Napier TC. Pramipexole induces a conditioned place preference in parkinsonian-like and control rats. Program No. 813.21, 2010. Neuroscience Meeting Planner, San Diego, CA: Society for Neuroscience Meeting, 2010. Online.
Rokosik SL, Riddle JL, and Napier TC. Pramipexole increases risk-taking in parkinsonian-like rats and sham controls without effecting ability to discriminate between the magnitude of reinforcers. Program No. 814.1, 2010. Neuroscience Meeting Planner, San Diego, CA: Society for Neuroscience Meeting, 2010. Online.
Papers submitted for publication (see appendix for copies)
Rokosik, S.L. and T.C. Napier. Pramipexole-induced risk-taking in a rodent model of Parkinson’s disease. Under review.
Rokosik, S.L. and T.C. Napier. Intracranial self-stimulation as a positive reinforcer to study impulsivity in a probability discounting paradigm. Under review.