Objective/Rationale:
The increase in impulsive and risky behaviors, like gambling, hyper-sexuality, and compulsive shopping are emotionally and financially devastating, and impose a significant burden on the patients and their families. The character and mechanisms that underlie this syndrome need to be better understood to allow for the development of better dopamine (DA)-based therapies that do not invoke this treatment- related side effect.
Project Description:
In Parkinson’s disease, it has become increasingly clear that a significant percentage of patients treated with DA agonists display a DA dysregulation syndrome that includes enhanced impulsivity and compulsivity (e.g., pathological gambling). This impulsivity disorder is has an enormous impact on the patients and their families. Critically needed is an animal model of this co-morbidity that will allow evaluations of the behavioral phenotype and associated neuroplasticity. This model will aid in developing treatments that avoid this syndrome. The proposed project will develop this pre-clinical model.
Core to the assessment will be 1) comparisons between clinically used DA-based pharmacotherapies (pramipexol) as monotherapy or in combination with LDOPA, on the degree of the impact on impulsivity, and 2) DA agonist comparisons between normal and nigrostriatal lesioned rats. To accomplish these objectives, 6-hydroxydopamine will be bilaterally injected into the dorsal lateral striatum of rats with doses that reduce striatal DA levels to approximately 80 percent of normal. To study reward motivated behavior, intracranial self-stimulation of the medial forebrain bundle will be used.
Common to both rats and humans are two core behavioral features of impulsivity. They are risk-taking and discounting. Risk-taking is the tendency to choose a large/uncertain reward over a smaller/certain reward. Discounting is the tendency to minimize the value of an object (i.e., people or money). Probability discounting procedures are already in use to study features of impulsivity in both humans and rats. All techniques used to test the hypotheses are well established in the lab of the P.I. and have previously been employed by our group in addiction research. We now plan to implement them to study the character and mechanism of the DA dysregulation syndrome which is a disabling treatment-related side effect suffered by numerous PD patients.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Parkinson’s disease is the second most common neurodegenerative disease. This work has the potential to greatly impact current treatment regimens, and thus the quality of life for PD patients and their care takers.
Anticipated Outcome:
We expect to establish a rodent model of pramipexole-induced impulsive behavior and to establish the brain regions responsible for this impulsive behavior.