title: Regulator of G-Protein Signaling 7 Regulates Reward Behavior by Controlling Opioid Signaling in the Striatum.
abstract: Morphine mediates its euphoric and analgesic effects by acting on the μ-opioid receptor (MOR). MOR belongs to the family of G-protein coupled receptors whose signaling efficiency is controlled by the regulator of G-protein signaling (RGS) proteins. Our understanding of the molecular diversity of RGS proteins that control MOR signaling, their circuit specific actions, and underlying cellular mechanisms is very limited.
  
  
  
  We used genetic approaches to ablate regulator of G-protein signaling 7 (RGS7) both globally and in specific neuronal populations. We used conditioned place preference and self-administration paradigms to examine reward-related behavior and a battery of tests to assess analgesia, tolerance, and physical dependence to morphine. Electrophysiology approaches were applied to investigate the impact of RGS7 on morphine-induced alterations in neuronal excitability and plasticity of glutamatergic synapses. At least three animals were used for each assessment.
  
  
  
  Elimination of RGS7 enhanced reward, increased analgesia, delayed tolerance, and heightened withdrawal in response to morphine administration. RGS7 in striatal neurons was selectively responsible for determining the sensitivity of rewarding and reinforcing behaviors to morphine without affecting analgesia, tolerance, and withdrawal. In contrast, deletion of RGS7 in dopaminergic neurons did not influence morphine reward. RGS7 exerted its effects by controlling morphine-induced changes in excitability of medium spiny neurons in nucleus accumbens and gating the compositional plasticity of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptors.
  
  
  
  This study identifies RGS7 as a novel regulator of MOR signaling by dissecting its circuit specific actions and pinpointing its role in regulating morphine reward by controlling the activity of nucleus accumbens neurons.
authors.affiliation: Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Laurie P
authors.initials: LP
authors.lastname: Sutton
authors.affiliation: Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Olga
authors.initials: O
authors.lastname: Ostrovskaya
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Maria
authors.initials: M
authors.lastname: Dao
authors.affiliation: Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Xie
authors.affiliation: Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Cesare
authors.initials: C
authors.lastname: Orlandi
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Roy
authors.initials: R
authors.lastname: Smith
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Sunmee
authors.initials: S
authors.lastname: Wee
authors.affiliation: Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida. Electronic address: kirill@scripps.edu.
authors.forename: Kirill A
authors.initials: KA
authors.lastname: Martemyanov
mesh_terms: D000818:Animals; D003213:Conditioning, Psychological; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000502:physiology; D004361:Drug Tolerance / Q000502:physiology; D005260:Female; D018698:Glutamic Acid / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000502:physiology; D009714:Nucleus Accumbens / Q000502:physiology; D010147:Pain Measurement / Q000187:drug effects; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012201:Reward; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
chemical_list: D020710:RGS Proteins; C485692:Rgs6 protein, mouse; C492038:Rgs7 protein, mouse; D018698:Glutamic Acid; D009020:Morphine
keywords: Addiction; G Protein coupled receptors (GPCRs); Opioids; Regulators of G-protein signaling (RGS); Reward circuit; Striatum