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Samantha R. Cote
Pharmacology & Physiology Program
B.S. 2009, Sacred Heart University
Thesis Advisor: Eldo V. Kuzhikandathil, Ph.D.
Department of Pharmacology & Physiology
Tuesday, November 26, 2013
12:00 P.M., MSB Room H-609
The dopaminergic system and its G-protein coupled receptors are involved in regulation of various functions including voluntary movement, and have been implicated in many disorders including Parkinsonís disease (PD). The roles of the D1 and D2 dopamine receptors have been extensively studied in circuits responsible for locomotion, and have been shown to play a role in PD. However, the role of the D3 dopamine receptor (D3R) in locomotion and potential implications for PD is unknown. Although the D3R shares a high homology with D2, it possesses distinct signaling properties when repeatedly stimulated with agonist. The D3, but not the closely-related D2 receptor, undergoes tolerance in vitro, wherein repeated agonist stimulation produces a significant attenuation of response without receptor internalization. Here we show the D3R tolerance property occurs in vivo at both the signaling and behavioral levels. We show that tolerance-causing agonist PD128907 induces tolerance in the D3R-MAPK pathway in the striatum and an attenuation of D3R mediated hypolocomotion in drd3-EGFP mice. We have also further characterized newly discovered non-tolerance causing agonist ES609 at the D3R-MAPK pathway in vitro and show it is also a non-tolerance causing agonist in vivo. The mechanism(s) underlying D3R tolerance have not yet been established. Phosphorylation has been proposed as a potential mechanism of D3R tolerance. Here we show the D3 receptor is phosphorylated during PD128907-induced tolerance, but not with non-tolerance causing agonist ES609 using an in vitro kinase assay. The D3R has been implicated in the development of Levodopa-induced dyskinesia (LID) during PD. However, the role of the D3R tolerance property has not been studied in a PD-LID model. Here we show the D3R expression is elevated in the striatum of an MPTP/p rodent model of PD under chronic L-DOPA treatment. In this paradigm we also saw dysregulated D3R-MAPK function, which was attributed to D3 receptor tolerance. Lastly, we investigated if D3R overexpression in the striatum is sufficient to induce dyskinesia in the rat. We show that D3R overexpression in the rat dorsolateral striatum induces dyskinetic behaviors with L-DOPA and PD128907, and that these behaviors are attenuated when rats are treated with ES609. Taken together, the results of this thesis project show the D3R tolerance property occurs in vivo and has a potential role in pathophysiological mechanisms such as PD-LID.