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

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 To investigate whether RGS4, through inhibiting function of mGluR5 receptors in the dorsal striatum (dSTR), regulates cellular and behavioral responses to acute amphetamine. Methods After HSV-RGS4 was infused into dSTR, RGS4 overexpression as well as binding of recombinant RGS4 to mGluR5 were assessed. The effect of RGS4 overexpression on behavioral activity induced by the intra-striatal 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 co-immunoprecipitated with mGluR5 receptors and suppressed both behavioral activity, as well as phospho-ERK levels induced by DHPG. RGS4 over-expression or the mGluR5 antagonist, 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.

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

“…For example, overexpression of RGS9 in the NAcc attenuates acute and chronic cocaine-induced locomotor activity, which parallels the reduced locomotor stimulation by D2 receptor, but not D1 receptor, agonists (Rahman et al, 2003). Furthermore, lentiviral RGS4 overexpression in the dorsal striatum suppresses acute AMPH-induced locomotor stimulation and weakens the AMPH-induced phosphor-ERK level, which may be mediated by glutamate receptor 5 (Schwendt et al, 2012). These data suggest that RGS proteins can modulate the effect of psychostimulants through specific interactions with certain receptors in a brain region-dependent manner.…”

Regulators of G-Protein-Signaling Proteins: Negative Modulators of G-Protein-Coupled Receptor Signaling

“…RGS4 was found in most cortical neuronal layers and at all stages of development. RGS4-GFP was present in gray matter and less so in white matter, implying that RGS4 is not expressed in glial cells (Schwendt et al, 2012). Expression of RGS4 and that of acetylcholinesterase overlapped implicating a physiological role for RGS4 in the regulation of mAch receptor signaling.…”

Rab Family Proteins Regulate the Endosomal Trafficking and Function of RGS4

“…For example, the observation that RGS4 function may be selectively regulated by Rab5 and Rab11 in a manner that is independent from the M1R-G q signaling complexes provides new insight into mechanisms whereby manipulating Rab activity may allow for differential control of GPCR pathways. Although we focused our attention on the regulation of the M1 muscarinic receptor by RGS4, we expect that these same paradigms will be relevant to the regulation of other GPCRs with which it is known to interact (6,9,47,53,(91)(92)(93)(94). These data may also help us to uncover additional pathophysiological mechanisms that contribute to altered disease susceptibility in the face of decreased RGS4 function (5-7, 10, 46, 93, 95).…”