Regulator of G-protein signaling 4 interacts with metabotropic glutamate receptor subtype 5 in rat striatum: relevance to amphetamine behavioral sensitization.

Regulator of G-protein signaling (RGS) 4 negatively modulates signaling of several Galpha(q)-coupled receptors, including metabotropic glutamate receptor (mGluR) subtype 5 in neuronal and non-neuronal cell lines. In the brain, both RGS4 and mGluR5 receptors are enriched in the striatum, and their functions have been linked to psychostimulant-induced behavior and synaptic plasticity. However, it is not known whether RGS4 and mGluR5 interactions occur in rat striatum and whether chronic amphetamine (AMPH) treatment produces changes in RGS4 levels that are correlated with mGluR5 receptor activity. Using coimmunoprecipitation, the present study demonstrated that endogenous RGS4 binds mGluR5 receptors as well as key mGluR5-associated proteins, Galpha(q/11), and phospholipase C-beta1 (PLCbeta1) in preparations from rat striatum. In the next experiment, rats were treated with AMPH (5 mg/kg i.p. daily) for 5 days followed by 3 weeks of abstinence. At this time point, animals pretreated with AMPH displayed sensitized behavioral responses to AMPH challenge and decreased RGS4 protein in dorsal striatum and nucleus accumbens. Behavioral sensitization to AMPH was also accompanied by an increase in Galpha(q/11) and PLCbeta1 in dorsal striatum. In contrast, total levels of mGluR5 receptors in the striatum were not altered by any AMPH treatment. In conclusion, the present study demonstrates that RGS4 protein is an integral part of the mGluR5 protein complex in the striatum. This study further suggests that AMPH-induced changes in mGluR5-associated protein levels (RGS4, Galpha(q/11), and PLCbeta1) may be related to altered coupling of striatal mGluR5 receptors in animals sensitized to AMPH.