Dopamine (DA) gonists, pramipexole (PPX;Mirapex(R)) and ropinirole (ROP;Requip(R)) are FDA-approved for the treatment of motor dysfunction in Parkinson's disease (PD) and restless leg syndrome. A significant subset of these patients treated with DA agonists develop impulse control disorders (ICDs) such as gambling disorders, compulsive sexual behavior, compulsive buying, and binge-eating. There is strong evidence that ICDs are associated with DA agonist therapy;lacking are preclinical models of ICDs to test this assumption. One common aspect of ICDs is the tendency to choose immediately available rewards over larger rewards that cannot be obtained until later (i.e., choosing a $5 reward immediately vs. $50 next week). This impulsive choice tendency can be measured in rodents using a delayed discounting task. In this task, reinforcers are typically in the form of food, however, due to the variability of rewards that drive ICDs (e.g., money, sex, shopping, as well as food) this option is not optimal. We pose a new approach which uses intracranial self- stimulation (ICSS) to directly target the neurocircuitry that is common to all rewards that drive ICDs. We contend this is a far improved means to model ICDs. Thus, the objective of the current grant application is to develop a rodent model of ICDs using a delayed discounting paradigm with ICSS as a positive reinforcer. Once developed, such a model will allow investigations into the neurobiology and pharmacology of ICDs. Accordingly, our central hypotheses are that (1) DA agonists used to treat PD and other neurological disorders will increase impulsive choice in PD-like and control rats, and (2) DA D3 receptors (D3Rs) underlie DA agonist-induced impulsivity. We propose two Specific Aims to test these hypotheses.
In Aim 1, we will implement ICSS-mediated delayed discounting to establish basal levels of impulsive choice in a well- established 6-OHDA-treated rat model of PD and non-PD control rats. We hypothesize that treatment with PPX and ROP will promote impulsive choice in both groups of rats.
In Aim 2, we will test the hypothesis that highly selective D3R antagonists will block development and expression of PPX- and ROP-induced impulsive choice in both PD-like and control rats. PPX and ROP activate all receptors in the D2R family;however both have slightly higher affinity for the D3R subtype, which is highly expressed in reward regions of the brain. Thus, we expect Aim 2 outcomes to verify that the D3R subtype is critical for ICDs. In sum, the work proposed in these two Specific Aims are expected to produce an innovative model of ICDs in PD-like and control rats, and to establish a role for D3Rs in this phenomenon. Such results are expected to set the stage for translational research to validate current theories regarding DA agonist-induced impulsivity and potentially lead to better treatments for symptoms in PD and non-PD disorders, while reducing the burden of untoward effects such as ICDs. Moreover, we predict this model will provide a completely new means to rapidly screen compounds under development as therapeutics for CNS disorders for potential of the compound to induced ICDs.
The proposed research is relevant to public health because it will develop a new paradigm that will assess the neurobiological underpinnings of impulse control disorders and determine why some treatments used for Parkinson's disease, and other neuropathologies, result in these disorders. Understanding the neurobiology of impulse control disorders should lead to better treatments that are devoid of these devastating side effects. Thus, the proposed research is relevant to the part of NIH's mission that pertains to the pursuit of fundamental knowledge about the nature of impulse control disorders.
|Tedford, Stephanie E; Persons, Amanda L; Napier, T Celeste (2015) Dopaminergic lesions of the dorsolateral striatum in rats increase delay discounting in an impulsive choice task. PLoS One 10:e0122063|
|Napier, T Celeste; Corvol, Jean-Christophe; Grace, Anthony A et al. (2015) Linking neuroscience with modern concepts of impulse control disorders in Parkinson's disease. Mov Disord 30:141-9|