Marek Schwendt, Ph.D.
Research Assistant Professor
Pilot Grant - The Role of Striatal RGS4 in the Cellular Mechanisms of Cocaine-seeking After Abstinence.
My research interests involve studying changes in dopamine- and glutamate-driven cellular signaling and gene expression within cortico-striatal circuitry in response to psychostimulant exposure. The research goal is to understand the character of molecular adaptations resulting from brief or chronic exposure to psychostimulants (amphetamine, methamphetamine, cocaine). Further, by selective manipulation of identified signaling pathways inhibit drug-induced plasticity and reverse drug-induced behaviors.
Of particular interest to me are factors regulating G-protein-coupled receptor signaling. Regulators of G-protein signaling (RGS) and activators of G-protein signaling (AGS) represent unique families of proteins capable of limiting signaling of dopamine and glutamate receptors thus regulating psychostimulant-induced cellular plasticity. For example, it has been shown that expression of RGS4 protein in rat prefrontal cortex and dorsal striatum is regulated by psychostimulants. Our finding that in vivo manipulation of RGS4 levels in the striatum interferes with amphetamine-induced behavioral activation and signaling supports the role of RGS4 in psychostimulant addiction.
A high risk of relapse to drug-taking even after long periods of abstinence represents one of the key challenges in successful treatment of drug addiction. Animal models have provided evidence that a propensity to relapse arises from persistent neuroadaptations in cortico-striatal glutamatergic circuitry. However, the character of these neuroadaptations is not well understood. Interestingly, re-exposure to a cocaine-associated environment following prolonged abstinence period not only triggers robust drug-seeking but also dynamically regulates RGS4 expression within cortico-striatal circuitry. Therefore, current projects in the laboratory are aimed at investigating the role of RGS4 protein in molecular mechanisms underlying relapse to drug-seeking. Towards this aim, the effects of in vivo RGS4 manipulation (using recombinant lentiviruses) on cue-induced drug-seeking and G-protein cellular signaling are being investigated. In parallel, additional studies will include characterization of candidate receptors regulated by RGS4 in vivo, with specific focus on mGluR5 and 7 glutamate receptors. Further, taking advantage of recently available RGS4-GFP BAC transgenic mice, future studies will address neuronal cell-types expressing RGS4 in the striatum and possibly explore cell-type specific regulation of RGS4 expression by cocaine. In general, progress in understanding the regulatory role of RGS4 (or other RGS proteins) in striatal signaling induced by drug-associated cues would represent progress in understanding neuroplasticity underlying drug relapse.