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Cortical GluN2B deletion attenuates punished suppression of food reward-seeking

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Abstract

Rationale

Compulsive behavior, which is a hallmark of psychiatric disorders such as addiction and obsessive-compulsive disorder, engages corticostriatal circuits. Previous studies indicate a role for corticostriatal N-methyl-d-aspartate receptors (NMDARs) in mediating compulsive-like responding for drugs of abuse, but the specific receptor subunits controlling reward-seeking in the face of punishment remain unclear.

Objectives

The current study assessed the involvement of corticostriatal GluN2B-containing NMDARs in measures of persistent and punished food reward-seeking.

Methods

Mice with genetic deletion of GluN2B in one of three distinct neuronal populations, cortical principal neurons, forebrain interneurons, or striatal medium spiny neurons, were tested for (1) sustained food reward-seeking when reward was absent, (2) reward-seeking under a progressive ratio schedule of reinforcement, and (3) persistent reward-seeking after a footshock punishment.

Results

Mutant mice with genetic deletion of GluN2B in cortical principal neurons demonstrated attenuated suppression of reward-seeking during punishment. These mice performed normally on other behavioral measures, including an assay for pain sensitivity. Mutants with interneuronal or striatal GluN2B deletions were normal on all behavioral assays.

Conclusions

Current findings offer novel evidence that loss of GluN2B-containing NMDARs expressed on principal neurons in the cortex results in reduced punished food reward-seeking. These data support the involvement of GluN2B subunit in cortical circuits regulating cognitive flexibility in a variety of settings, with implications for understanding the basis of inflexible behavior in neuropsychiatric disorders including obsessive-compulsive disorders (OCD) and addictions.

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References

  • Badanich KA, Doremus‐Fitzwater TL, Mulholland PJ, Randall PK, Delpire E, Becker HC (2011) NR2B‐deficient mice are more sensitive to the locomotor stimulant and depressant effects of ethanol. Genes Brain Behav 10:805–816

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Balleine BW, Delgado MR, Hikosaka O (2007) The role of the dorsal striatum in reward and decision-making. J Neurosci 27:8161–8165

    Article  CAS  PubMed  Google Scholar 

  • Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, Quinlan EM, Nakazawa K (2010) Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 13:76–83

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Belin D, Berson N, Balado E, Piazza PV, Deroche-Gamonet V (2011) High-novelty-preference rats are predisposed to compulsive cocaine self-administration. Neuropsychopharmacology 36:569–579

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Breiter HC, Rauch SL, Kwong KK, Baker JR, Weisskoff RM, Kennedy DN, Kendrick AD, Davis TL, Jiang A, Cohen MS (1996) Functional magnetic resonance imaging of symptom provocation in obsessive-compulsive disorder. Arch Gen Psychiatry 53:595–606

    Article  CAS  PubMed  Google Scholar 

  • Brigman JL, Daut RA, Wright T, Gunduz-Cinar O, Graybeal C, Davis MI, Jiang Z, Saksida LM, Jinde S, Pease M (2013) GluN2B in corticostriatal circuits governs choice learning and choice shifting. Nat Neurosci 16:1101–1110

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brigman JL, Wright T, Talani G, Prasad-Mulcare S, Jinde S, Seabold GK, Mathur P, Davis MI, Bock R, Gustin RM (2010) Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J Neurosci 30:4590–4600

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Burgos-Robles A, Vidal-Gonzalez I, Santini E, Quirk GJ (2007)  Consolidation of fear extinction requires NMDA receptor-dependent bursting in the ventromedial prefrontal cortex. Neuron 53(6):871–880

  • Cannella N, Halbout B, Uhrig S, Evrard L, Corsi M, Corti C, Deroche-Gamonet V, Hansson AC, Spanagel R (2013) The mGluR2/3 agonist LY379268 induced anti-reinstatement effects in rats exhibiting addiction-like behavior. Neuropsychopharmacology 38:2048–2056

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen BT, Yau H-J, Hatch C, Kusumoto-Yoshida I, Cho SL, Hopf FW, Bonci A (2013) Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 496:359–362

    Article  CAS  PubMed  Google Scholar 

  • Clayton DA, Mesches MH, Alvarez E, Bickford PC, Browning MD (2002) A hippocampal NR2B deficit can mimic age-related changes in long-term potentiation and spatial learning in the Fischer 344 rat. J Neurosci 22:3628–3637

    CAS  PubMed  Google Scholar 

  • Cryan JF, Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4:775–790

    Article  CAS  PubMed  Google Scholar 

  • Cull-Candy S, Brickley S, Farrant M (2001) NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 11:327–335

    Article  CAS  PubMed  Google Scholar 

  • Dalley JW, Cardinal RN, Robbins TW (2004) Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 28:771–784

    Article  CAS  PubMed  Google Scholar 

  • Dalton GL, Ma LM, Phillips AG, Floresco SB (2011) Blockade of NMDA GluN2B receptors selectively impairs behavioral flexibility but not initial discrimination learning. Psychopharmacology 216:525–535

    Article  CAS  PubMed  Google Scholar 

  • Dalton GL, Wang YT, Floresco SB, Phillips AG (2008) Disruption of AMPA receptor endocytosis impairs the extinction, but not acquisition of learned fear. Neuropsychopharmacology 33:2416–2426

    Article  CAS  PubMed  Google Scholar 

  • Dalton GL, Wu DC, Wang YT, Floresco SB, Phillips AG (2012) NMDA GluN2A and GluN2B receptors play separate roles in the induction of LTP and LTD in the amygdala and in the acquisition and extinction of conditioned fear. Neuropharmacology 62:797–806

    Article  CAS  PubMed  Google Scholar 

  • Dang MT, Yokoi F, Yin HH, Lovinger DM, Wang Y, Li Y (2006) Disrupted motor learning and long-term synaptic plasticity in mice lacking NMDAR1 in the striatum. Proc Natl Acad Sci 103:15254–15259

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Davies DA, Greba Q, Howland JG (2013) GluN2B-containing NMDA receptors and AMPA receptors in medial prefrontal cortex are necessary for odor span in rats. Front Behav Neurosci 7

  • Deroche-Gamonet V, Belin D, Piazza PV (2004) Evidence for addiction-like behavior in the rat. Science 305:1014–1017

    Article  CAS  PubMed  Google Scholar 

  • Duffy S, Labrie V, Roder JC (2008) D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning. Neuropsychopharmacology 33:1004–1018

    Article  CAS  PubMed  Google Scholar 

  • Engelmann JM, Versace F, Robinson JD, Minnix JA, Lam CY, Cui Y, Brown VL, Cinciripini PM (2012) Neural substrates of smoking cue reactivity: a meta-analysis of fMRI studies. Neuroimage 60:252–262

    Article  PubMed Central  PubMed  Google Scholar 

  • Everitt BJ, Belin D, Economidou D, Pelloux Y, Dalley JW, Robbins TW (2008) Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction. Phil Trans R Soc B: Biol Sci 363:3125–3135

    Article  Google Scholar 

  • Feyder M, Wiedholz L, Sprengel R, Holmes A (2007) Impaired associative fear learning in mice with complete loss or haploinsufficiency of AMPA GluR1 receptors. Front Behav Neurosci 1:4

    Article  PubMed Central  PubMed  Google Scholar 

  • Griebel G, Holmes A (2013) 50 years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov 12:667–687

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hamilton DA, Brigman JL (2015) Behavioral flexibility in rats and mice: contributions of distinct frontocortical regions. Genes Brain Behav

  • Holmes A, Spanagel R, Krystal JH (2013) Glutamatergic targets for new alcohol medications. Psychopharmacology 229:539–554

    Article  CAS  PubMed  Google Scholar 

  • Howland JG, Cazakoff BN (2010) Effects of acute stress and GluN2B-containing NMDA receptor antagonism on object and object–place recognition memory. Neurobiol Learn Mem 93:261–267

    Article  CAS  PubMed  Google Scholar 

  • Jentsch JD, Taylor JR (1999) Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology 146:373–390

    Article  CAS  PubMed  Google Scholar 

  • Jonkman S, Pelloux Y, Everitt BJ (2012) Differential roles of the dorsolateral and midlateral striatum in punished cocaine seeking. J Neurosci 32:4645–4650

    Article  CAS  PubMed  Google Scholar 

  • Kiselycznyk C, Jury NJ, Halladay LR, Nakazawa K, Mishina M, Sprengel R, Grant SG, Svenningsson P, Holmes A (2015) NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism. Behav Brain Res 287:89–95

    Article  CAS  PubMed  Google Scholar 

  • Kiselycznyk C, Svenningsson P, Delpire E, Holmes A (2011) Genetic, pharmacological and lesion analyses reveal a selective role for corticohippocampal GLUN2B in a novel repeated swim stress paradigm. Neuroscience 193:259–268

    Article  CAS  PubMed  Google Scholar 

  • Lovinger DM, White G, Weight FF (1989) Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243:1721–1724

    Article  CAS  PubMed  Google Scholar 

  • Maltby N, Tolin DF, Worhunsky P, O'Keefe TM, Kiehl KA (2005) Dysfunctional action monitoring hyperactivates frontal–striatal circuits in obsessive–compulsive disorder: an event-related fMRI study. Neuroimage 24:495–503

    Article  PubMed  Google Scholar 

  • Mathur P, Graybeal C, Feyder M, Davis MI, Holmes A (2009) Fear memory impairing effects of systemic treatment with the NMDA NR2B subunit antagonist, Ro 25-6981, in mice: attenuation with ageing. Pharmacol Biochem Behav 91:453–460

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Milton AL, Merlo E, Ratano P, Gregory BL, Dumbreck JK, Everitt BJ (2013) Double dissociation of the requirement for GluN2B-and GluN2A-containing NMDA receptors in the destabilization and restabilization of a reconsolidating memory. J Neurosci 33:1109–1115

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nagy J (2004) The NR2B subtype of NMDA receptor: a potential target for the treatment of alcohol dependence. Curr Drug Targets CNS Neurol Disord 3:169–179

    Article  CAS  PubMed  Google Scholar 

  • Nieh EH, Matthews GA, Allsop SA, Presbrey KN, Leppla CA, Wichmann R, Neve R, Wildes CP, Tye KM (2015) Decoding neural circuits that control compulsive sucrose seeking. Cell 160:528–541

    Article  CAS  PubMed  Google Scholar 

  • Otis JM, Fitzgerald MK, Mueller D (2014) Infralimbic BDNF/TrkB enhancement of GluN2B currents facilitates extinction of a cocaine-conditioned place preference. J Neurosci 34:6057–6064

    Article  PubMed Central  PubMed  Google Scholar 

  • Pelloux Y, Murray JE, Everitt BJ (2013) Differential roles of the prefrontal cortical subregions and basolateral amygdala in compulsive cocaine seeking and relapse after voluntary abstinence in rats. Eur J Neurosci

  • Radwanska K, Kaczmarek L (2012) Characterization of an alcohol addiction‐prone phenotype in mice. Addict Biol 17:601–612

    Article  CAS  PubMed  Google Scholar 

  • Schoenbaum G, Shaham Y (2008) The role of orbitofrontal cortex in drug addiction: a review of preclinical studies. Biol Psychiatry 63:256–262

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Seif T, Chang S-J, Simms JA, Gibb SL, Dadgar J, Chen BT, Harvey BK, Ron D, Messing RO, Bonci A (2013) Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake. Nat Neurosci 16:1094–1100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Seif T, Simms JA, Lei K, Wegner S, Bonci A, Messing RO, Hopf FW (2015) D-serine and D-cycloserine reduce compulsive alcohol intake in rats. Neuropsychopharmacology

  • Shipton OA, Paulsen O (2014) GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity. Phil Trans R Soc London B: Biol Sci 369:20130163

    Article  Google Scholar 

  • Thompson SM, Josey M, Holmes A, Brigman JL (2015) Conditional loss of GluN2B in cortex and hippocampus impairs attentional set formation. Behav Neurosci 129:105

    Article  PubMed Central  PubMed  Google Scholar 

  • Tsien JZ, Chen DF, Gerber D, Tom C, Mercer EH, Anderson DJ, Mayford M, Kandel ER, Tonegawa S (1996) Subregion-and cell type–restricted gene knockout in mouse brain. Cell 87:1317–1326

    Article  CAS  PubMed  Google Scholar 

  • Vendruscolo LF, Barbier E, Schlosburg JE, Misra KK, Whitfield TW, Logrip ML, Rivier C, Repunte-Canonigo V, Zorrilla EP, Sanna PP (2012) Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats. J Neurosci 32:7563–7571

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vengeliene V, Bachteler D, Danysz W, Spanagel R (2005) The role of the NMDA receptor in alcohol relapse: a pharmacological mapping study using the alcohol deprivation effect. Neuropharmacology 48:822–829

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, Wang G-J, Ma Y, Fowler JS, Wong C, Ding Y-S, Hitzemann R, Swanson JM, Kalivas P (2005) Activation of orbital and medial prefrontal cortex by methylphenidate in cocaine-addicted subjects but not in controls: relevance to addiction. J Neurosci 25:3932–3939

    Article  CAS  PubMed  Google Scholar 

  • Vollstädt‐Klein S, Wichert S, Rabinstein J, Bühler M, Klein O, Ende G, Hermann D, Mann K (2010) Initial, habitual and compulsive alcohol use is characterized by a shift of cue processing from ventral to dorsal striatum. Addiction 105:1741–1749

    Article  PubMed  Google Scholar 

  • von Engelhardt J, Doganci B, Jensen V, Hvalby Ø, Göngrich C, Taylor A, Barkus C, Sanderson DJ, Rawlins JNP, Seeburg PH (2008) Contribution of hippocampal and extra-hippocampal NR2B-containing NMDA receptors to performance on spatial learning tasks. Neuron 60:846–860

    Article  Google Scholar 

  • Wang J, Carnicella S, Phamluong K, Jeanblanc J, Ronesi JA, Chaudhri N, Janak PH, Lovinger DM, Ron D (2007) Ethanol induces long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum: implications for alcohol drinking behavior. J Neurosci 27:3593–3602

    Article  CAS  PubMed  Google Scholar 

  • Wang M, Yang Y, Wang C-J, Gamo NJ, Jin LE, Mazer JA, Morrison JH, Wang X-J, Arnsten AF (2013) NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. Neuron 77:736–749

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Waters RP, Moorman DE, Young AB, Feltenstein MW, See RE (2014) Assessment of a proposed "three-criteria" cocaine addiction model for use in reinstatement studies with rats. Psychopharmacology (Berl) 231:3197–3205

    Article  CAS  Google Scholar 

  • Wong TP, Howland JG, Robillard JM, Ge Y, Yu W, Titterness AK, Brebner K, Liu L, Weinberg J, Christie BR (2007) Hippocampal long-term depression mediates acute stress-induced spatial memory retrieval impairment. Proc Natl Acad Sci 104:11471–11476

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Woodward JJ (2000) Ethanol and NMDA receptor signaling. Critical Reviews™ in Neurobiology 14

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Acknowledgments

We are grateful to Munisa Bachu, Shaun Flynn, and Adrina Kocharian for technical assistance and to Dr. Jonathan Brigman for the cartoons of the behavioral procedures. This research was supported by the NIAAA Intramural Research Program and NIMH grant K22MH099164.

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Authors and Affiliations

  1. Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA

    Anna K. Radke & Andrew Holmes

  2. Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA

    Kazu Nakazawa

  3. 5625 Fishers Lane Room 2N09, Rockville, MD, USA

    Anna K. Radke

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  1. Anna K. Radke
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  2. Kazu Nakazawa
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  3. Andrew Holmes
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Correspondence to Anna K. Radke.

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Radke, A.K., Nakazawa, K. & Holmes, A. Cortical GluN2B deletion attenuates punished suppression of food reward-seeking. Psychopharmacology 232, 3753–3761 (2015). https://doi.org/10.1007/s00213-015-4033-8

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  • DOI: https://doi.org/10.1007/s00213-015-4033-8

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