Regulator of G-Protein Signaling 4 (RGS4) Controls Morphine Reward by Glutamate Receptor Activation in the Nucleus Accumbens of the Mouse Brain
Juhwan Kim1,2,8, Sueun Lee1, Sohi Kang1, Tae-Il Jeon5, Man-Jong Kang5, Tae-Hoon Lee6,8,
Yong Sik Kim7, Key-Sun Kim2,4, Heh-In Im2,3,4,*, and Changjong Moon1,*
1Department of Veterinary Anatomy, College of Veterinary Medicine and BK21 Plus Project Team, Chonnam National University, Gwangju 61186, Korea, 2Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea, 3Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea, 4Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea, 5Department of Animal Science, College of Agriculture and Life Science, Chonnam National University, Gwangju 61186, Korea, 6Department of Oral Biochemistry, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 61186, Korea, 7Department of Pharmacology, Seoul National University College of Medicine, Seoul 08826, Korea, 8Department of Molecular Medicine (BK21plus), Chonnam National University Graduate School, Gwangju 61186, Korea
*Correspondence: moonc@chonnam.ac.kr (CM); him@kist.re.kr (HII)
Received January 9, 2018; Revised February 2, 2018; Accepted March 8, 2018.; Published online May 10, 2018.
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ABSTRACT
Crosstalk between G-protein signaling and glutamatergic transmission within the brain reward circuits is critical for long-term emotional effects (depression and anxiety), cravings, and negative withdrawal symptoms associated with opioid addiction. A previous study showed that Regulator of G-protein signaling 4 (RGS4) may be implicated in opiate action in the nucleus accumbens (NAc). However, the mechanism of the NAc-specific RGS4 actions that induce the behavioral responses to opiates remains largely unknown. The present study used a short hairpin RNA (shRNA)-mediated knock-down of RGS4 in the NAc of the mouse brain to investigate the relationship between the activation of ionotropic glutamate receptors and RGS4 in the NAc during morphine reward. Additionally, the shRNA-mediated RGS4 knock-down was implemented in NAc/striatal primary-cultured neurons to investigate the role that striatal neurons have in the morphine- induced activation of ionotropic glutamate receptors. The results of this study show that the NAc-specific knockdown of RGS4 significantly increased the behaviors associated with morphine and did so by phosphorylation of the GluR1 (Ser831) and NR2A (Tyr1325) glutamate receptors in the NAc. Furthermore, the knock-down of RGS4 enhanced the phosphorylation of the GluR1 and NR2A glutamate receptors in the primary NAc/striatal neurons during spontaneous morphine withdrawal. These findings show a novel molecular mechanism of RGS4 in glutamatergic transmission that underlies the negative symptoms associated with morphine administration.
Keywords: addiction, glutamatergic transmission, morphine,
nucleus accumbensm, regulator of G-protein signaling 4


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30 April 2018 Volume 41,
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