Archival Report| Volume 80, ISSUE 3, P235-245, August 01, 2016

Download started.


Regulator of G-Protein Signaling 7 Regulates Reward Behavior by Controlling Opioid Signaling in the Striatum



      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.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Koob G.F.
        Addiction is a reward deficit and stress surfeit disorder.
        Front Psychiatry. 2013; 4: 72
        • Chang H.T.
        • Kitai S.T.
        Projection neurons of the nucleus accumbens: An intracellular labeling study.
        Brain Res. 1985; 347: 112-116
        • O’Donnell P.
        • Grace A.A.
        Synaptic interactions among excitatory afferents to nucleus accumbens neurons: Hippocampal gating of prefrontal cortical input.
        J Neurosci. 1995; 15: 3622-3639
        • Wolf M.E.
        • Sun X.
        • Mangiavacchi S.
        • Chao S.Z.
        Psychomotor stimulants and neuronal plasticity.
        Neuropharmacology. 2004; 47: 61-79
        • Le Merrer J.
        • Becker J.A.
        • Befort K.
        • Kieffer B.L.
        Reward processing by the opioid system in the brain.
        Physiol Rev. 2009; 89: 1379-1412
        • Wassum K.M.
        • Ostlund S.B.
        • Maidment N.T.
        • Balleine B.W.
        Distinct opioid circuits determine the palatability and the desirability of rewarding events.
        Proc Natl Acad Sci U S A. 2009; 106: 12512-12517
        • Matthes H.W.
        • Maldonado R.
        • Simonin F.
        • Valverde O.
        • Slowe S.
        • Kitchen I.
        • et al.
        Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene.
        Nature. 1996; 383: 819-823
        • Olmstead M.C.
        • Franklin K.B.
        The development of a conditioned place preference to morphine: Effects of microinjections into various CNS sites.
        Behav Neurosci. 1997; 111: 1324-1334
        • Jhou T.C.
        • Xu S.P.
        • Lee M.R.
        • Gallen C.L.
        • Ikemoto S.
        Mapping of reinforcing and analgesic effects of the mu opioid agonist endomorphin-1 in the ventral midbrain of the rat.
        Psychopharmacology (Berl). 2012; 224: 303-312
        • Johnson S.W.
        • North R.A.
        Opioids excite dopamine neurons by hyperpolarization of local interneurons.
        J Neurosci. 1992; 12: 483-488
        • Leone P.
        • Pocock D.
        • Wise R.A.
        Morphine-dopamine interaction: Ventral tegmental morphine increases nucleus accumbens dopamine release.
        Pharmacol Biochem Behav. 1991; 39: 469-472
        • Margolis E.B.
        • Hjelmstad G.O.
        • Fujita W.
        • Fields H.L.
        Direct bidirectional mu-Opioid control of midbrain dopamine neurons.
        J Neurosci. 2014; 34: 14707-14716
        • Gysling K.
        • Wang R.Y.
        Morphine-induced activation of A10 dopamine neurons in the rat.
        Brain Res. 1983; 277: 119-127
        • Hnasko T.S.
        • Sotak B.N.
        • Palmiter R.D.
        Morphine reward in dopamine-deficient mice.
        Nature. 2005; 438: 854-857
        • Mansour A.
        • Fox C.A.
        • Burke S.
        • Akil H.
        • Watson S.J.
        Immunohistochemical localization of the cloned mu opioid receptor in the rat CNS.
        J Chem Neuroanat. 1995; 8: 283-305
        • Cui Y.
        • Ostlund S.B.
        • James A.S.
        • Park C.S.
        • Ge W.
        • Roberts K.W.
        • et al.
        Targeted expression of mu-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward.
        Nat Neurosci. 2014; 17: 254-261
        • Hollinger S.
        • Hepler J.R.
        Cellular regulation of RGS proteins: Modulators and integrators of G protein signaling.
        Pharmacol Rev. 2002; 54: 527-559
        • Ross E.M.
        • Wilkie T.M.
        GTPase-activating proteins for heterotrimeric G proteins: Regulators of G protein signaling (RGS) and RGS-like proteins.
        Annu Rev Biochem. 2000; 69: 795-827
        • Traynor J.
        mu-Opioid receptors and regulators of G protein signaling (RGS) proteins: From a symposium on new concepts in mu-opioid pharmacology.
        Drug Alcohol Depend. 2012; 121: 173-180
        • Cao Y.
        • Pahlberg J.
        • Sarria I.
        • Kamasawa N.
        • Sampath A.P.
        • Martemyanov K.A.
        Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons.
        Proc Natl Acad Sci U S A. 2012; 109: 7905-7910
        • Dang M.T.
        • Yokoi F.
        • Yin H.H.
        • Lovinger D.M.
        • Wang Y.
        • Li Y.
        Disrupted motor learning and long-term synaptic plasticity in mice lacking NMDAR1 in the striatum.
        Proc Natl Acad Sci U S A. 2006; 103: 15254-15259
        • Zachariou V.
        • Georgescu D.
        • Sanchez N.
        • Rahman Z.
        • DiLeone R.
        • Berton O.
        • et al.
        Essential role for RGS9 in opiate action.
        Proc Natl Acad Sci U S A. 2003; 100: 13656-13661
        • Piazza P.V.
        • Deroche-Gamonent V.
        • Rouge-Pont F.
        • Le Moal M.
        Vertical shifts in self-administration dose-response functions predict a drug-vulnerable phenotype predisposed to addiction.
        J Neurosci. 2000; 20: 4226-4232
        • Kalivas P.W.
        • Lalumiere R.T.
        • Knackstedt L.
        • Shen H.
        Glutamate transmission in addiction.
        Neuropharmacology. 2009; 56: 169-173
        • Masuho I.
        • Xie K.
        • Martemyanov K.A.
        Macromolecular composition dictates receptor and G protein selectivity of regulator of G protein signaling (RGS) 7 and 9-2 protein complexes in living cells.
        J Biol Chem. 2013; 288: 25129-25142
        • Garzon J.
        • Lopez-Fando A.
        • Sanchez-Blazquez P.
        The R7 subfamily of RGS proteins assists tachyphylaxis and acute tolerance at mu-opioid receptors.
        Neuropsychopharmacology. 2003; 28: 1983-1990
        • Gold S.J.
        • Ni Y.G.
        • Dohlman H.G.
        • Nestler E.J.
        Regulators of G-protein signaling (RGS) proteins: Region-specific expression of nine subtypes in rat brain.
        J Neurosci. 1997; 17: 8024-8037
        • Gaspari S.
        • Papachatzaki M.M.
        • Koo J.W.
        • Carr F.B.
        • Tsimpanouli M.E.
        • Stergiou E.
        • et al.
        Nucleus accumbens-specific interventions in RGS9-2 activity modulate responses to morphine.
        Neuropsychopharmacology. 2014; 39: 1968-1977
        • Han M.H.
        • Renthal W.
        • Ring R.H.
        • Rahman Z.
        • Psifogeorgou K.
        • Howland D.
        • et al.
        Brain region specific actions of regulator of G protein signaling 4 oppose morphine reward and dependence but promote analgesia.
        Biol Psychiatry. 2010; 67: 761-769
        • Orlandi C.
        • Posokhova E.
        • Masuho I.
        • Ray T.A.
        • Hasan N.
        • Gregg R.G.
        • Martemyanov K.A.
        GPR158/179 regulate G protein signaling by controlling localization and activity of the RGS7 complexes.
        J Cell Biol. 2012; 197: 711-719
        • Psifogeorgou K.
        • Terzi D.
        • Papachatzaki M.M.
        • Varidaki A.
        • Ferguson D.
        • Gold S.J.
        • Zachariou V.
        A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia.
        J Neurosci. 2011; 31: 5617-5624
        • Barbano M.F.
        • Cador M.
        Opioids for hedonic experience and dopamine to get ready for it.
        Psychopharmacology (Berl). 2007; 191: 497-506
        • Ostrovskaya O.
        • Xie K.
        • Masuho I.
        • Fajardo-Serrano A.
        • Lujan R.
        • Wickman K.
        • Martemyanov K.A.
        RGS7/Gbeta5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling.
        Elife. 2014; 3: e02053
        • Robinson T.E.
        • Kolb B.
        Structural plasticity associated with exposure to drugs of abuse.
        Neuropharmacology. 2004; 47: 33-46
        • Russo S.J.
        • Dietz D.M.
        • Dumitriu D.
        • Morrison J.H.
        • Malenka R.C.
        • Nestler E.J.
        The addicted synapse: Mechanisms of synaptic and structural plasticity in nucleus accumbens.
        Trends Neurosci. 2010; 33: 267-276
        • Chartoff E.H.
        • Connery H.S.
        It’s MORe exciting than mu: Crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system.
        Front Pharmacol. 2014; 5: 116
        • Manzoni O.J.
        • Williams J.T.
        Presynaptic regulation of glutamate release in the ventral tegmental area during morphine withdrawal.
        J Neurosci. 1999; 19: 6629-6636
        • LaLumiere R.T.
        • Kalivas P.W.
        Glutamate release in the nucleus accumbens core is necessary for heroin seeking.
        J Neurosci. 2008; 28: 3170-3177
        • Garzon J.
        • Rodriguez-Munoz M.
        • Sanchez-Blazquez P.
        Direct association of Mu-opioid and NMDA glutamate receptors supports their cross-regulation: Molecular implications for opioid tolerance.
        Curr Drug Abuse Rev. 2012; 5: 199-226
        • Thomas M.J.
        • Kalivas P.W.
        • Shaham Y.
        Neuroplasticity in the mesolimbic dopamine system and cocaine addiction.
        Br J Pharmacol. 2008; 154: 327-342
        • Kauer J.A.
        • Malenka R.C.
        Synaptic plasticity and addiction.
        Nat Rev Neurosci. 2007; 8: 844-858
        • Grudt T.J.
        • Williams J.T.
        Opioid receptors and the regulation of ion conductances.
        Rev Neurosci. 1995; 6: 279-286
        • Heng L.J.
        • Yang J.
        • Liu Y.H.
        • Wang W.T.
        • Hu S.J.
        • Gao G.D.
        Repeated morphine exposure decreased the nucleus accumbens excitability during short-term withdrawal.
        Synapse. 2008; 62: 775-782
        • Wu X.
        • Shi M.
        • Wei C.
        • Yang M.
        • Liu Y.
        • Liu Z.
        • et al.
        Potentiation of synaptic strength and intrinsic excitability in the nucleus accumbens after 10 days of morphine withdrawal.
        J Neurosci Res. 2012; 90: 1270-1283
        • Wu X.
        • Shi M.
        • Ling H.
        • Wei C.
        • Liu Y.
        • Liu Z.
        • Ren W.
        Effects of morphine withdrawal on the membrane properties of medium spiny neurons in the nucleus accumbens shell.
        Brain Res Bull. 2013; 90: 92-99