Skip to main content

Advertisement

SpringerLink
Log in

Blockade of NMDA GluN2B receptors selectively impairs behavioral flexibility but not initial discrimination learning

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Behavioral flexibility is the ability to adjust behavior when environmental contingencies change and is compromised in disease states such as schizophrenia, attention deficit hyperactivity disorder, and following damage to the prefrontal cortex.

Methods

The present study investigated the contribution of N-methyl-d-aspartate GluN2B receptor subunits in the initial learning and in shifting between or within discrimination strategies (i.e., strategy set-shifting and reversal learning), using tasks conducted in operant chambers. Strategy set-shifting required rats initially to learn a visual-cue discrimination (day 1) and on day 2, shift to using an egocentric spatial response strategy to obtain reward. For reversal learning, rats were trained on a response discrimination on day 1 and then required to select the opposite lever on day 2.

Results

Blockade of GluN2B receptors with systemic administration of Ro25-6981 on day 1 did not impair initial acquisition of either a response or visual-cue discrimination nor did these treatments affect performance of strategy or reversal shifts on day 2. However, administration of Ro25-6981 prior to a set-shift or reversal on day 2 significantly impaired performance on both tasks, inducing a selective increase in perseverative errors, indicative of a disruption the ability to suppress a previously acquired prepotent response.

Conclusions

These data suggest that systemic blockade of GluN2B receptors Ro25-6981 does not appear to interfere with the initial acquisition of simple visual or response discriminations. However, these receptors do appear to play a central and selective role in the modification of previously acquired strategies or stimulus–reward associations, facilitating behavioral inhibition so that novel patterns of behavior may emerge.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Bannerman DM, Niewoehner B, Lyon L, Romberg C, Schmitt WB, Taylor A, Sanderson DJ, Cottam J, Sprengel R, Seeburg PH, Köhr G, Rawlins JN (2008) NMDA receptor subunit NR2A is required for rapidly acquired spatial working memory but not incremental spatial reference memory. J Neurosci 28:3623–3630

    Article  PubMed  CAS  Google Scholar 

  • Bissonette GB, Martins GJ, Franz TM, Harper ES, Schoenbaum G, Powell EM (2008) Double dissociation of the effects of medial and orbital prefrontal cortical lesions on attentional and affective shifts in mice. J Neurosci 28:11124–11130

    Article  PubMed  CAS  Google Scholar 

  • Block AE, Dhanji H, Thompson-Tardif SF, Floresco SB (2007) Thalamic-prefrontal cortical-ventral striatal circuitry mediates dissociable components of strategy set shifting. Cereb Cortex 17:1625–1636

    Article  PubMed  Google Scholar 

  • Boulougouris V, Dalley JW, Robbins TW (2007) Effects of orbitofrontal, infralimbic and prelimbic cortical lesions on serial spatial reversal learning in the rat. Behav Brain Res 179:219–228

    Article  PubMed  Google Scholar 

  • Brigman JL, Feyder M, Saksida LM, Bussey TJ, Mishina M, Holmes A (2008) Impaired discrimination learning in mice lacking the NMDA receptor NR2A subunit. Learn Mem 15:50–54

    Article  PubMed  Google Scholar 

  • Brigman JL, Wright T, Talani G, Prasad-Mulcare S, Jinde S, Seabold GK, Mathur P, Davis MI, Bock R, Gustin RM, Colbran RJ, Alvarez VA, Nakazawa K, Delpire E, Lovinger DM, Holmes A (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  CAS  Google Scholar 

  • Castañé A, Theobald DE, Robbins TW (2010) Selective lesions of the dorsomedial striatum impair serial spatial reversal learning in rats. Behav Brain Res 210:74–83

    Article  PubMed  Google Scholar 

  • Chenard BL, Menniti FS (1999) Antagonists selective for NMDA receptors containing the NR2B subunit. Curr Pharm Des 5:381–404

    PubMed  CAS  Google Scholar 

  • Chenard BL, Shalaby IA, Koe BK, Ronau RT, Butler TW, Prochniak MA, Schmidt AW, Fox CB (1991) Separation of alpha 1 adrenergic and N-methyl-D-aspartate antagonist activity in a series of ifenprodil compounds. J Med Chem 34:3085–3090

    Article  PubMed  CAS  Google Scholar 

  • Chudasama Y, Robbins TW (2003) Dissociable contributions of the orbitofrontal and infralimbic cortex to pavlovian autoshaping and discrimination reversal learning: further evidence for the functional heterogeneity of the rodent frontal cortex. J Neurosci 23:8771–8780

    PubMed  CAS  Google Scholar 

  • Clarke HF, Dalley JW, Crofts HS, Robbins TW, Roberts AC (2004) Cognitive inflexibility after prefrontal serotonin depletion. Science 304:878–880

    Article  PubMed  CAS  Google Scholar 

  • Clarke HF, Walker SC, Dalley JW, Robbins TW, Roberts AC (2007) Cognitive inflexibility after prefrontal serotonin depletion is behaviorally and neurochemically specific. Cereb Cortex 17:18–27

    Article  PubMed  CAS  Google Scholar 

  • Collingridge GL, Olsen RW, Peters J, Spedding M (2009) A nomenclature for ligand-gated ion channels. Neuropharmacology 56:2–5

    Article  PubMed  CAS  Google Scholar 

  • Crofts HS, Dalley JW, Collins P, Van Denderen JC, Everitt BJ, Robbins TW, Roberts AC (2001) Differential effects of 6-OHDA lesions of the frontal cortex and caudate nucleus on the ability to acquire an attentional set. Cereb Cortex 11:1015–1026

    Article  PubMed  CAS  Google Scholar 

  • Dalton, GL, Floresco SB, Phillips AG (2007) Blockade of NMDA NR2B receptors disrupts the extinction, but not acquisition, of auditory fear conditioning: dependence on context. Soc Neurosci Abst 91.21

  • 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  PubMed  CAS  Google Scholar 

  • Dix S, Gilmour G, Potts S, Smith JW, Tricklebank M (2010) A within-subject cognitive battery in the rat: differential effects of NMDA receptor antagonists. Psychopharmacology 212:227–242

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Eagle DM, Bari A, Robbins TW (2008) The neuropsychopharmacology of action inhibition: cross-species translation of the stop-signal and go/no-go tasks. Psychopharmacology 199:439–456

    Article  PubMed  CAS  Google Scholar 

  • Egerton A, Reid L, McKerchar CE, Morris BJ, Pratt JA (2005) Impairment in perceptual attentional set-shifting following PCP administration: a rodent model of set-shifting deficits in schizophrenia. Psychopharmacology (Berl) 179:77–84

    Article  CAS  Google Scholar 

  • Fischer G, Mutel V, Trube G, Malherbe P, Kew JN, Mohacsi E, Heitz MP, Kemp JA (1997) Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro. J Pharmacol Exp Ther 283:1285–1292

    PubMed  CAS  Google Scholar 

  • Floresco SB, Jentsch JD (2011) Pharmacological enhancement of memory and executive functioning in laboratory animals. Neuropsychopharmacology 36:227–250

    Article  PubMed  CAS  Google Scholar 

  • Floresco SB, Magyar O, Ghods-Sharifi S, Vexelman C, Tse MT (2006a) Multiple dopamine receptor subtypes in the medial prefrontal cortex of the rat regulate set-shifting. Neuropsychopharmacology 31:297–309

    Article  PubMed  CAS  Google Scholar 

  • Floresco SB, Ghods-Sharifi S, Vexelman C, Magyar O (2006b) Dissociable roles for the nucleus accumbens core and shell in regulating set shifting. J Neurosci 26:2449–2457

    Article  PubMed  CAS  Google Scholar 

  • Floresco SB, Block AE, Tse MT (2008) Inactivation of the medial prefrontal cortex of the rat impairs strategy set-shifting, but not reversal learning, using a novel, automated procedure. Behav Brain Res 190:85–96

    Article  PubMed  Google Scholar 

  • Floresco SB, Zhang Y, Enomoto T (2009) Neural circuits subserving behavioral flexibility and their relevance to schizophrenia. Behav Brain Res 204:396–409

    Article  PubMed  Google Scholar 

  • Fox CJ, Russell KI, Wang YT, Christie BR (2006) Contribution of NR2A and NR2B NMDA subunits to bidirectional synaptic plasticity in the hippocampus in vivo. Hippocampus 16:907–915

    Article  PubMed  CAS  Google Scholar 

  • Ge Y, Dong Z, Bagot RC, Howland JG, Phillips AG, Wong TP, Wang YT (2010) Hippocampal long-term depression is required for the consolidation of spatial memory. Proc Natl Acad Sci USA 107(38):16697–16702

    Article  PubMed  CAS  Google Scholar 

  • Ghods-Sharifi S, Haluk DM, Floresco SB (2008) Differential effects of inactivation of the orbitofrontal cortex on strategy set-shifting and reversal learning. Neurobiol Learn Mem 89:567–573

    Article  PubMed  Google Scholar 

  • Goldberg TE, Weinberger DR, Berman KF, Pliskin NH, Podd MH (1987) Further evidence for dementia of the prefrontal type in schizophrenia? A controlled study of teaching the Wisconsin Card Sorting Test. Arch Gen Psychiatry 44:1008–1014

    PubMed  CAS  Google Scholar 

  • Goosens KA, Maren S (2004) NMDA receptors are essential for the acquisition, but not expression, of conditional fear and associative spike firing in the lateral amygdala. Eur J Neurosci 20:537–548

    Article  PubMed  Google Scholar 

  • Gould TJ, McCarthy MM, Keith RA (2002) MK-801 disrupts acquisition of contextual fear conditioning but enhances memory consolidation of cued fear conditioning. Behav Pharmacol 13:287–294

    Article  PubMed  CAS  Google Scholar 

  • Haluk DM, Floresco SB (2009) Ventral striatal dopamine modulation of different forms of behavioral flexibility. Neuropsychopharmacology 34:2041–2052

    Article  PubMed  CAS  Google Scholar 

  • Higgins GA, Ballard TM, Huwyler J, Kemp JA, Gill R (2003) Evaluation of the NR2B-selective NMDA receptor antagonist Ro 63–1908 on rodent behaviour: evidence for an involvement of NR2B NMDA receptors in response inhibition. Neuropharmacology 44:324–341

    Article  PubMed  CAS  Google Scholar 

  • Idris NF, Repeto P, Neill JC, Large CH (2005) Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and D-amphetamine in the rat. Psychopharmacology (Berl) 179:336–348

    Article  CAS  Google Scholar 

  • Jin DH, Jung YW, Ko BH, Moon IS (1997) Immunoblot analyses on the differential distribution of NR2A and NR2B subunits in the adult rat brain. Mol Cells 7:749–754

    PubMed  CAS  Google Scholar 

  • Jones B, Mishkin M (1972) Limbic lesions and the problem of stimulus-reinforcement associations. Exp Neurol 36:362–377

    Article  PubMed  CAS  Google Scholar 

  • Kehagia AA, Murray GK, Robbins TW (2010) Learning and cognitive flexibility: frontostriatal function and monoaminergic modulation. Curr Opin Neurobiol 20:199–204

    Article  PubMed  CAS  Google Scholar 

  • Laurie DJ, Bartke I, Schoepfer R, Naujoks K, Seeburg PH (1997) Regional, developmental and interspecies expression of the four NMDAR2 subunits, examined using monoclonal antibodies. Brain Res Mol Brain Res 51:23–32

    Article  PubMed  CAS  Google Scholar 

  • Lombardi WJ, Andreason PJ, Sirocco KY, Rio DE, Gross RE, Umhau JC, Hommer DW (1999) Wisconsin Card Sorting Test performance following head injury: dorsolateral fronto-striatal circuit activity predicts perseveration. J Clin Exp Neuropsychol 21:2–16

    Article  PubMed  CAS  Google Scholar 

  • Lynch DR, Shim SS, Seifert KM, Kurapathi S, Mutel V, Gallagher MJ, Guttmann RP (2001) Pharmacological characterization of interactions of RO 25-6981 with the NR2B (epsilon2) subunit. Eur J Pharmacol 416:185–195

    Article  PubMed  CAS  Google Scholar 

  • McAlonan K, Brown VJ (2003) Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat. Behav Brain Res 146:97–103

    Article  PubMed  Google Scholar 

  • Mesulam M-M (2002) The human frontal lobes: transcending the default mode through contingent encoding. In: Stuss DT, Knight RT (eds) Principles of frontal lobe function. Oxford University Press, Oxford, pp 8–30

    Chapter  Google Scholar 

  • Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH (1994) Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12(3):529–540

    Article  PubMed  CAS  Google Scholar 

  • Morris RG (1989) Synaptic plasticity and learning: selective impairment of learning rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5. J Neurosci 9:3040–3057

    PubMed  CAS  Google Scholar 

  • Morris RG, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319:774–776

    Article  PubMed  CAS  Google Scholar 

  • Murray TK, Ridley RM, Snape MF, Cross AJ (1995) The effect of dizocilpine (MK-801) on spatial and visual discrimination tasks in the rat. Behav Pharmacol 6:540–549

    PubMed  CAS  Google Scholar 

  • Mutel V, Buchy D, Klingelschmidt A, Messer J, Bleuel Z, Kemp JA, Richards JG (1998) In vitro binding properties in rat brain of [3H]Ro 25-6981, a potent and selective antagonist of NMDA receptors containing NR2B subunits. J Neurochem 70:2147–2155

    Article  PubMed  CAS  Google Scholar 

  • O'Neill M, Brown VJ (2007) The effect of striatal dopamine depletion and the adenosine A2A antagonist KW-6002 on reversal learning in rats. Neurobiol Learn Mem 88:75–81

    Article  PubMed  Google Scholar 

  • Palencia CA, Ragozzino ME (2005) The contribution of NMDA receptors in the dorsolateral striatum to egocentric response learning. Behav Neurosci 119:953–960

    Article  PubMed  Google Scholar 

  • Pantelis C, Barber FZ, Barnes TR, Nelson HE, Owen AM, Robbins TW (1999) Comparison of set-shifting ability in patients with chronic schizophrenia and frontal lobe damage. Schizophr Res 37:251–270

    Article  PubMed  CAS  Google Scholar 

  • Pinard E, Alanine A, Bourson A, Büttelmann B, Gill R, Heitz M, Jaeschke G, Mutel V, Trube G, Wyler R (2001) Discovery of (R)-1-[2-hydroxy-3-(4-hydroxy-phenyl)-propyl]-4-(4-methyl-benzyl)-piperidin-4-ol: a novel NR1/2B subtype selective NMDA receptor antagonist. Bioorg Med Chem Lett 11:2173–2176

    Article  PubMed  CAS  Google Scholar 

  • Ragozzino ME (2002) The effects of dopamine D(1) receptor blockade in the prelimbic-infralimbic areas on behavioral flexibility. Learn Mem 9:18–28

    Article  PubMed  Google Scholar 

  • Ragozzino ME, Detrick S, Kesner RP (1999) Involvement of the prelimbic-infralimbic areas of the rodent prefrontal cortex in behavioral flexibility for place and response learning. J Neurosci 19:4585–4594

    PubMed  CAS  Google Scholar 

  • Riekkinen M, Stefanski R, Kuitunen J, Riekkinen P Jr (1996) Effects of combined block of alpha 1-adrenoceptors and NMDA receptors on spatial and passive avoidance behavior in rats. Eur J Pharmacol 300(1–2):9–16

    Article  PubMed  CAS  Google Scholar 

  • Rigby M, Le Bourdellès B, Heavens RP, Kelly S, Smith D, Butler A, Hammans R, Hills R, Xuereb JH, Hill RG, Whiting PJ, Sirinathsinghji DJ (1996) The messenger RNAs for the N-methyl-D-aspartate receptor subunits show region-specific expression of different subunit composition in the human brain. Neuroscience 73:429–447

    Article  PubMed  CAS  Google Scholar 

  • Rubia K, Smith AB, Brammer MJ, Taylor E (2007a) Temporal lobe dysfunction in medication-naive boys with attention-deficit/hyperactivity disorder during attention allocation and its relation to response variability. Biol Psychiatry 62:999–1006

    Article  PubMed  Google Scholar 

  • Rubia K, Smith AB, Brammer M, Taylor E (2007b) Performance of children with attention deficit hyperactivity disorder (ADHD) on a test battery for impulsiveness. Child Neuropsychol 30:659–695

    Google Scholar 

  • Stefani MR, Moghaddam B (2005) Systemic and prefrontal cortical NMDA receptor blockade differentially affect discrimination learning and set-shift ability in rats. Behav Neurosci 119:420–428

    Article  PubMed  CAS  Google Scholar 

  • Stefani MR, Moghaddam B (2010) Activation of type 5 metabotropic glutamate receptors attenuates deficits in cognitive flexibility induced by NMDA receptor blockade. Eur J Pharmacol 639:26–32

    Article  PubMed  CAS  Google Scholar 

  • van der Meulen JA, Bilbija L, Joosten RN, de Bruin JP, Feenstra MG (2003) The NMDA-receptor antagonist MK-801 selectively disrupts reversal learning in rats. NeuroReport 14:2225–2228

    Article  PubMed  Google Scholar 

  • von Engelhardt J, Doganci B, Jensen V, Hvalby Ø, Göngrich C, Taylor A, Barkus C, Sanderson DJ, Rawlins JN, Seeburg PH, Bannerman DM, Monyer H (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 YH, Bosy TZ, Yasuda RP, Grayson DR, Vicini S, Pizzorusso T, Wolfe BB (1995) Characterization of NMDA receptor subunit-specific antibodies: distribution of NR2A and NR2B receptor subunits in rat brain and ontogenic profile in the cerebellum. J Neurochem 65:176–183

    Article  PubMed  CAS  Google Scholar 

  • Watanabe M, Inoue Y, Sakimura K, Mishina M (1993) Distinct distributions of five N-methyl-D-aspartate receptor channel subunit mRNAs in the forebrain. J Comp Neurol 338:377–390

    Article  PubMed  CAS  Google Scholar 

  • Wenzel A, Fritschy JM, Mohler H, Benke D (1997) NMDA receptor heterogeneity during postnatal development of the rat brain: differential expression of the NR2A, NR2B, and NR2C subunit proteins. J Neurochem 68:469–478

    Article  PubMed  CAS  Google Scholar 

  • Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF (2005) Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review. Biol Psychiatry 57:1336–1346

    Article  PubMed  Google Scholar 

  • Wong TP, Howland JG, Robillard JM, Ge Y, Yu W, Titterness AK, Brebner K, Liu L, Weinberg J, Christie BR, Phillips AG, Wang YT (2007) Hippocampal long-term depression mediates acute stress-induced spatial memory retrieval impairment. Proc Natl Acad Sci USA 104(27):11471–11476

    Article  PubMed  CAS  Google Scholar 

  • Ylinen A, Pitkänen M, Sirviö J, Hartikainen T, Sivenius J, Koivisto E, Riekkinen PJ Sr (1995) The effects of NMDA receptor antagonists at anticonvulsive doses on the performance of rats in the water maze task. Eur J Pharmacol 274:159–165

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada to AGP and SBF. SBF is a Michael Smith Foundation for Health Research Senior Scholar.

Author information

Authors and Affiliations

  1. Department of Psychology and Brain Research Centre, University of British Columbia, 2136 West Mall, Vancouver, BC, V6T 1Z4, Canada

    Gemma L. Dalton & Stan B. Floresco

  2. Department of Psychiatry and Brain Research Centre, University of British Columbia, 2136 West Mall, Vancouver, BC, V6T 1Z4, Canada

    Gemma L. Dalton, Liya M. Ma & Anthony G. Phillips

Authors
  1. Gemma L. Dalton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liya M. Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anthony G. Phillips
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stan B. Floresco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stan B. Floresco.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dalton, G.L., Ma, L.M., Phillips, A.G. et al. Blockade of NMDA GluN2B receptors selectively impairs behavioral flexibility but not initial discrimination learning. Psychopharmacology 216, 525–535 (2011). https://doi.org/10.1007/s00213-011-2246-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2246-z

Keywords

Search

Navigation