Psychopharmacology

, Volume 232, Issue 20, pp 3753–3761 | Cite as

Cortical GluN2B deletion attenuates punished suppression of food reward-seeking

Original Investigation

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.

Keywords

Addiction NMDA Prefrontal cortex Motivation Striatum Interneuron Alcohol Drug 

Notes

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.

References

  1. 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 10:805–816PubMedCentralCrossRefPubMedGoogle Scholar
  2. Balleine BW, Delgado MR, Hikosaka O (2007) The role of the dorsal striatum in reward and decision-making. J Neurosci 27:8161–8165CrossRefPubMedGoogle Scholar
  3. 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 13:76–83PubMedCentralCrossRefPubMedGoogle Scholar
  4. Belin D, Berson N, Balado E, Piazza PV, Deroche-Gamonet V (2011) High-novelty-preference rats are predisposed to compulsive cocaine self-administration. Neuropsychopharmacology 36:569–579PubMedCentralCrossRefPubMedGoogle Scholar
  5. 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 53:595–606CrossRefPubMedGoogle Scholar
  6. 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 16:1101–1110PubMedCentralCrossRefPubMedGoogle Scholar
  7. 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 30:4590–4600PubMedCentralCrossRefPubMedGoogle Scholar
  8. 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):871–880Google Scholar
  9. 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 38:2048–2056PubMedCentralCrossRefPubMedGoogle Scholar
  10. 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 496:359–362CrossRefPubMedGoogle Scholar
  11. 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 22:3628–3637PubMedGoogle Scholar
  12. Cryan JF, Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4:775–790CrossRefPubMedGoogle Scholar
  13. Cull-Candy S, Brickley S, Farrant M (2001) NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 11:327–335CrossRefPubMedGoogle Scholar
  14. Dalley JW, Cardinal RN, Robbins TW (2004) Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 28:771–784CrossRefPubMedGoogle Scholar
  15. Dalton GL, Ma LM, Phillips AG, Floresco SB (2011) Blockade of NMDA GluN2B receptors selectively impairs behavioral flexibility but not initial discrimination learning. Psychopharmacology 216:525–535CrossRefPubMedGoogle Scholar
  16. Dalton GL, Wang YT, Floresco SB, Phillips AG (2008) Disruption of AMPA receptor endocytosis impairs the extinction, but not acquisition of learned fear. Neuropsychopharmacology 33:2416–2426CrossRefPubMedGoogle Scholar
  17. 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 62:797–806CrossRefPubMedGoogle Scholar
  18. 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 103:15254–15259PubMedCentralCrossRefPubMedGoogle Scholar
  19. 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 7Google Scholar
  20. Deroche-Gamonet V, Belin D, Piazza PV (2004) Evidence for addiction-like behavior in the rat. Science 305:1014–1017CrossRefPubMedGoogle Scholar
  21. Duffy S, Labrie V, Roder JC (2008) D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning. Neuropsychopharmacology 33:1004–1018CrossRefPubMedGoogle Scholar
  22. 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 60:252–262PubMedCentralCrossRefPubMedGoogle Scholar
  23. 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 363:3125–3135CrossRefGoogle Scholar
  24. 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 1:4PubMedCentralCrossRefPubMedGoogle Scholar
  25. Griebel G, Holmes A (2013) 50 years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov 12:667–687PubMedCentralCrossRefPubMedGoogle Scholar
  26. Hamilton DA, Brigman JL (2015) Behavioral flexibility in rats and mice: contributions of distinct frontocortical regions. Genes Brain BehavGoogle Scholar
  27. Holmes A, Spanagel R, Krystal JH (2013) Glutamatergic targets for new alcohol medications. Psychopharmacology 229:539–554CrossRefPubMedGoogle Scholar
  28. 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 93:261–267CrossRefPubMedGoogle Scholar
  29. Jentsch JD, Taylor JR (1999) Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology 146:373–390CrossRefPubMedGoogle Scholar
  30. Jonkman S, Pelloux Y, Everitt BJ (2012) Differential roles of the dorsolateral and midlateral striatum in punished cocaine seeking. J Neurosci 32:4645–4650CrossRefPubMedGoogle Scholar
  31. 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 287:89–95CrossRefPubMedGoogle Scholar
  32. 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 193:259–268CrossRefPubMedGoogle Scholar
  33. Lovinger DM, White G, Weight FF (1989) Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243:1721–1724CrossRefPubMedGoogle Scholar
  34. 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 24:495–503CrossRefPubMedGoogle Scholar
  35. 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 91:453–460PubMedCentralCrossRefPubMedGoogle Scholar
  36. 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 33:1109–1115PubMedCentralCrossRefPubMedGoogle Scholar
  37. Nagy J (2004) The NR2B subtype of NMDA receptor: a potential target for the treatment of alcohol dependence. Curr Drug Targets CNS Neurol Disord 3:169–179CrossRefPubMedGoogle Scholar
  38. 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 160:528–541CrossRefPubMedGoogle Scholar
  39. Otis JM, Fitzgerald MK, Mueller D (2014) Infralimbic BDNF/TrkB enhancement of GluN2B currents facilitates extinction of a cocaine-conditioned place preference. J Neurosci 34:6057–6064PubMedCentralCrossRefPubMedGoogle Scholar
  40. 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 NeurosciGoogle Scholar
  41. Radwanska K, Kaczmarek L (2012) Characterization of an alcohol addiction‐prone phenotype in mice. Addict Biol 17:601–612CrossRefPubMedGoogle Scholar
  42. Schoenbaum G, Shaham Y (2008) The role of orbitofrontal cortex in drug addiction: a review of preclinical studies. Biol Psychiatry 63:256–262PubMedCentralCrossRefPubMedGoogle Scholar
  43. 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 16:1094–1100PubMedCentralCrossRefPubMedGoogle Scholar
  44. 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. NeuropsychopharmacologyGoogle Scholar
  45. Shipton OA, Paulsen O (2014) GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity. Phil Trans R Soc London B: Biol Sci 369:20130163CrossRefGoogle Scholar
  46. Thompson SM, Josey M, Holmes A, Brigman JL (2015) Conditional loss of GluN2B in cortex and hippocampus impairs attentional set formation. Behav Neurosci 129:105PubMedCentralCrossRefPubMedGoogle Scholar
  47. 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 87:1317–1326CrossRefPubMedGoogle Scholar
  48. 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 32:7563–7571PubMedCentralCrossRefPubMedGoogle Scholar
  49. 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 48:822–829CrossRefPubMedGoogle Scholar
  50. 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 25:3932–3939CrossRefPubMedGoogle Scholar
  51. 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 105:1741–1749CrossRefPubMedGoogle Scholar
  52. 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 60:846–860CrossRefGoogle Scholar
  53. 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 27:3593–3602CrossRefPubMedGoogle Scholar
  54. 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 77:736–749PubMedCentralCrossRefPubMedGoogle Scholar
  55. 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) 231:3197–3205CrossRefGoogle Scholar
  56. 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 104:11471–11476PubMedCentralCrossRefPubMedGoogle Scholar
  57. Woodward JJ (2000) Ethanol and NMDA receptor signaling. Critical Reviews™ in Neurobiology 14Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2015

Authors and Affiliations

  1. 1.Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and AlcoholismNIHBethesdaUSA
  2. 2.Department of Psychiatry and Behavioral NeurobiologyUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.RockvilleUSA

Personalised recommendations