RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states
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Author(s)
Mitsi, Vasiliki
Terzi, Dimitra
Purushothaman, Immanuel
Manouras, Lefteris
Gaspari, Sevasti
Neve, Rachael L.
Stratinaki, Maria
Feng, Jian
Shen, Li
Zachariou, Venetia
Date Issued
September 2015
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Mitsi, Vasiliki, Dimitra Terzi, Immanuel Purushothaman, Lefteris Manouras, Sevasti Gaspari, Rachael L. Neve, Maria Stratinaki, Jian Feng, Li Shen, and Venetia Zachariou. “RGS9-2–controlled Adaptations in the Striatum Determine the Onset of Action and Efficacy of Antidepressants in Neuropathic Pain States.” Proc Natl Acad Sci USA 112, no. 36 (August 24, 2015): E5088–E5097.
Version
Final published version
Abstract
The striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) plays a key modulatory role in opioid, monoamine, and other G-protein–coupled receptor responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs). Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein α and βγ subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5, which are important for TCA responsiveness. Furthermore, information from RNA-sequencing analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
McGovern Institute for Brain Research at MIT
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DOI of Published Version
https://doi.org/10.1073/pnas.1504283112
