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RGS4 overexpression in the rat dorsal striatum modulates mGluR5- and amphetamine-mediated behavior and signaling

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Abstract

Rationale

Regulator of G-protein signaling 4 (RGS4) is a brain-enriched negative modulator of G-protein-coupled receptor signaling. Decreased availability of RGS4 in the frontal cortex and striatum has been described in animal models of schizophrenia and drug addiction. However, cellular and behavioral consequences of dysregulated RGS4-dependent receptor signaling in the brain remain poorly understood.

Objective

This study aims to investigate whether RGS4, through inhibiting the function of mGluR5 receptors in the dorsal striatum (dSTR), regulates cellular and behavioral responses to acute amphetamine.

Methods

After herpes simplex virus-RGS4 was infused into the dSTR, RGS4 overexpression as well as binding of recombinant RGS4 to mGluR5 was assessed. The effect of RGS4 overexpression on behavioral activity induced by the intrastriatal mGluR5 agonist, DHPG, or amphetamine was recorded. Activation of extracellular signal-regulated kinase (ERK) and Akt (protein kinase B) was measured in the dSTR tissue at the end of each behavioral experiment.

Results

RGS4 overexpressed in the dSTR coimmunoprecipitated with mGluR5 receptors and suppressed both behavioral activity and phospho-ERK levels induced by DHPG. RGS4 overexpression or the mGluR5 antagonist, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP), attenuated amphetamine-induced phospho-ERK (but not phospho-Akt) levels. RGS4 suppressed amphetamine-induced vertical activity and augmented horizontal activity over 90 min. Similarly, MTEP augmented amphetamine-induced horizontal activity, but did not affect vertical activity.

Conclusions

The present data demonstrate that RGS4 in the dSTR attenuates amphetamine-induced ERK signaling and decreases the behavioral efficacy of acute amphetamine likely by limiting mGluR5 function.

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Acknowledgments

The authors would like to thank Amena Smith, Adrian Gomez, and John Yang for their excellent technical assistance. This work was supported by the National Institutes of Health grants R01 DA03982 (JFM), R21 DA025846 (MS), and CO6 RR01 5155 from the Extramural Research Facilities Program of the National Center for Research Resources.

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  1. Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, BSB 403, MSC 510, Charleston, SC, 29425-5100, USA

    Marek Schwendt, Stacey A. Sigmon & Jacqueline F. McGinty

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Correspondence to Jacqueline F. McGinty.

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Schwendt, M., Sigmon, S.A. & McGinty, J.F. RGS4 overexpression in the rat dorsal striatum modulates mGluR5- and amphetamine-mediated behavior and signaling. Psychopharmacology 221, 621–635 (2012). https://doi.org/10.1007/s00213-011-2606-8

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