Skip to main content

Advertisement

SpringerLink
Log in

The uncompetitive NMDA receptor antagonists ketamine and memantine preferentially increase the choice for a small, immediate reward in low-impulsive rats

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

Abstract

Rationale

Impulsive behavior is categorically differentiated between impulsive action, the inability to withhold from acting out a response, and impulsive choice, the greater preference for an immediate and smaller reward over a delayed but more advantageous reward. While the effects of N-methyl-d-aspartic acid (NMDA) receptor antagonists on impulsive action have been extensively characterized, there are very few and conflicting reports on the effects of this class of drugs on impulsive choice.

Objectives

Using a modified adjusting delay task, we investigated the effects of uncompetitive and competitive blockade of NMDA receptors on impulsive choice.

Methods

Male Wistar rats were trained in a modified adjusting delay task, which involved repeated choice between a low reinforcing solution delivered immediately and a highly reinforcing solution delivered after a variable delay. Rats were then administered either the NMDA receptor uncompetitive antagonists ketamine or memantine, or the competitive antagonists D-AP-5 or CGS 19755.

Results

Ketamine treatment dose-dependently increased impulsive choice, and this effect was selective for low-impulsive but not high-impulsive rats. Similarly, memantine treatment dose-dependently increased impulsive choice with a preferential effect for low-impulsive rats. While D-AP-5 treatment did not affect impulsive choice, CGS 19755 increased impulsivity, however, at the same doses at which it caused a marked response inhibition.

Conclusions

NMDA receptor uncompetitive, but not competitive, antagonists significantly increased impulsive choice, preferentially in low-impulsive rats. These findings demonstrate that the effects of NMDA receptor blockade on impulsive choice are not generalizable and depend on the specific mechanism of action of the antagonist used.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Adams J, Crosbie J, Wigg K, Ickowicz A, Pathare T, Roberts W, Malone M, Schachar R, Tannock R, Kennedy JL, Barr CL (2004) Glutamate receptor, ionotropic, N-methyl d-aspartate 2A (GRIN2A) gene as a positional candidate for attention-deficit/hyperactivity disorder in the 16p13 region. Mol Psychiatr 9:494–499

    Article  CAS  Google Scholar 

  • Amitai N, Markou A (2010) Disruption of performance in the five-choice serial reaction time task induced by administration of N-methyl-d-aspartate receptor antagonists: relevance to cognitive dysfunction in schizophrenia. Biol Psychiatry 68:5–16

    Article  PubMed  CAS  Google Scholar 

  • Ardayfio PA, Benvenga MJ, Chaney SF, Love PL, Catlow J, Swanson SP, Marek GJ (2008) The 5-hydroxytryptamine2A receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol (M100907) attenuates impulsivity after both drug-induced disruption (dizocilpine) and enhancement (antidepressant drugs) of differential-reinforcement-of-low-rate 72-s behavior in the rat. J Pharmacol Exp Ther 327:891–897

    Article  PubMed  CAS  Google Scholar 

  • Baviera M, Invernizzi RW, Carli M (2008) Haloperidol and clozapine have dissociable effects in a model of attentional performance deficits induced by blockade of NMDA receptors in the mPFC. Psychopharmacology (Berl) 196:269–280

    Article  CAS  Google Scholar 

  • Bennett DA, Bernard PS, Amrick CL, Wilson DE, Liebman JM, Hutchison AJ (1989) Behavioral pharmacological profile of CGS 19755, a competitive antagonist at N-methyl-d-aspartate receptors. J Pharmacol Exp Ther 250:454–460

    PubMed  CAS  Google Scholar 

  • Benveniste M, Mayer ML (1991) Structure-activity analysis of binding kinetics for NMDA receptor competitive antagonists: the influence of conformational restriction. Br J Pharmacol 104:207–221

    Article  PubMed  CAS  Google Scholar 

  • Berz S, Battig K, Welzl H (1992) Effects of CGS 19755 and dizocilpine (MK 801) on delayed time discrimination performance. Behav Brain Res 51:185–192

    Article  PubMed  CAS  Google Scholar 

  • Bespalov A, Zvartau E (1997) NMDA receptor antagonists prevent conditioned activation of intracranial self-stimulation in rats. Eur J Pharmacol 326:109–112

    Article  PubMed  CAS  Google Scholar 

  • Blanpied TA, Boeckman FA, Aizenman E, Johnson JW (1997) Trapping channel block of NMDA-activated responses by amantadine and memantine. J Neurophysiol 77:309–323

    PubMed  CAS  Google Scholar 

  • Blasio A, Narayan AR, Kaminski BJ, Steardo L, Sabino V, Cottone P (2011) A modified adjusting delay task to assess impulsive choice between isocaloric reinforcers in non-deprived male rats: effects of 5-HT(2A/C) and 5-HT (1A) receptor agonists. Psychopharmacology (Berl) 219:377–386

    Article  Google Scholar 

  • Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D (1997) Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry 154:805–811

    PubMed  CAS  Google Scholar 

  • Carli M, Baviera M, Invernizzi RW, Balducci C (2006) Dissociable contribution of 5-HT1A and 5-HT2A receptors in the medial prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rats. Neuropsychopharmacology 31:757–767

    Article  PubMed  CAS  Google Scholar 

  • Carlsson ML (2001) On the role of prefrontal cortex glutamate for the antithetical phenomenology of obsessive compulsive disorder and attention deficit hyperactivity disorder. Progr Neuro Psychopharmacol Biol Psychiatr 25:5–26

    Article  CAS  Google Scholar 

  • Chamberlain SR, Sahakian BJ (2007) The neuropsychiatry of impulsivity. Curr Opin Psychiatr 20:255–261

    Google Scholar 

  • Cottone P, Sabino V, Nagy TR, Coscina DV, Zorrilla EP (2007a) Feeding microstructure in diet-induced obesity susceptible versus resistant rats: central effects of urocortin 2. J Physiol 583:487–504

    Article  PubMed  CAS  Google Scholar 

  • Cottone P, Sabino V, Steardo L, Zorrilla EP (2007b) FG 7142 specifically reduces meal size and the rate and regularity of sustained feeding in female rats: evidence that benzodiazepine inverse agonists reduce food palatability. Neuropsychopharmacology 32:1069–1081

    Article  PubMed  CAS  Google Scholar 

  • Cottone P, Sabino V, Roberto M, Bajo M, Pockros L, Frihauf JB, Fekete EM, Steardo L, Rice KC, Grigoriadis DE, Conti B, Koob GF, Zorrilla EP (2009) CRF system recruitment mediates dark side of compulsive eating. Proc Natl Acad Sci U S A 106:20016–20020

    PubMed  CAS  Google Scholar 

  • Ebert B, Mikkelsen S, Thorkildsen C, Borgbjerg FM (1997) Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol 333:99–104

    Article  PubMed  CAS  Google Scholar 

  • Evenden JL (1999) Varieties of impulsivity. Psychopharmacology (Berl) 146:348–361

    Article  CAS  Google Scholar 

  • Fletcher PJ, Rizos Z, Noble K, Higgins GA (2011) Impulsive action induced by amphetamine, cocaine and MK801 is reduced by 5-HT(2C) receptor stimulation and 5-HT(2A) receptor blockade. Neuropharmacology 61:468–477

    Article  PubMed  CAS  Google Scholar 

  • Floresco SB, Tse MT, Ghods-Sharifi S (2008) Dopaminergic and glutamatergic regulation of effort- and delay-based decision making. Neuropsychopharmacology 33:1966–1979

    Article  PubMed  CAS  Google Scholar 

  • Foltin RW, Danysz W, Bisaga A (2008) A novel procedure for assessing the effects of drugs on satiation in baboons: effects of memantine and dexfenfluramine. Psychopharmacology (Berl) 199:583–592

    Article  CAS  Google Scholar 

  • Grottick AJ, Higgins GA (2000) Effect of subtype selective nicotinic compounds on attention as assessed by the five-choice serial reaction time task. Behav Brain Res 117:197–208

    Article  PubMed  CAS  Google Scholar 

  • Heale V, Harley C (1990) MK-801 and AP5 impair acquisition, but not retention, of the Morris milk maze. Pharmacol Biochem Behav 36:145–149

    Article  PubMed  CAS  Google Scholar 

  • Heresco-Levy U, Javitt DC (1998) The role of N-methyl-d-aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes. European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology 8:141–152

    Article  CAS  Google Scholar 

  • Higgins GA, Enderlin M, Haman M, Fletcher PJ (2003) The 5-HT2A receptor antagonist M100,907 attenuates motor and 'impulsive-type' behaviours produced by NMDA receptor antagonism. Psychopharmacology (Berl) 170:309–319

    Article  CAS  Google Scholar 

  • Iemolo A, Valenza M, Tozier L, Knapp CM, Kornetsky C, Steardo L, Sabino V, Cottone P (2012) Withdrawal from chronic, intermittent access to a highly palatable food induces depressive-like behavior in compulsive eating rats. Behav Pharmacol 23(5-6):593-602

    Google Scholar 

  • Johnson JW, Kotermanski SE (2006) Mechanism of action of memantine. Curr Opin Pharmacol 6:61–67

    Article  PubMed  CAS  Google Scholar 

  • Koek W, Woods JH, Ornstein P (1987) A simple and rapid method for assessing similarities among directly observable behavioral effects of drugs: PCP-like effects of 2-amino-5-phosphonovalerate in rats. Psychopharmacology (Berl) 91:297–304

    Article  CAS  Google Scholar 

  • Leung LS, Shen B (1999) N-methyl-d-aspartate receptor antagonists are less effective in blocking long-term potentiation at apical than basal dendrites in hippocampal CA1 of awake rats. Hippocampus 9:617–630

    Article  PubMed  CAS  Google Scholar 

  • Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A (1997) Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17:141–150

    Article  PubMed  CAS  Google Scholar 

  • Mar AC, Robbins TW (2007) Delay discounting and impulsive choice in the rat. Current protocols in neuroscience/editorial board, Jacqueline N Crawley [et al.] Chapter 8: Unit 8 22

  • Mirjana C, Baviera M, Invernizzi RW, Balducci C (2004) The serotonin 5-HT2A receptors antagonist M100907 prevents impairment in attentional performance by NMDA receptor blockade in the rat prefrontal cortex. Neuropsychopharmacology 29:1637–1647

    Article  PubMed  CAS  Google Scholar 

  • Moeller FG, Barratt ES, Dougherty DM, Schmitz JM, Swann AC (2001) Psychiatric aspects of impulsivity. Am J Psychiatry 158:1783–1793

    Article  PubMed  CAS  Google Scholar 

  • Monaghan DT, Irvine MW, Costa BM, Fang G, Jane DE (2012) Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators. Neurochemistry international

  • Murphy ER, Dalley JW, Robbins TW (2005) Local glutamate receptor antagonism in the rat prefrontal cortex disrupts response inhibition in a visuospatial attentional task. Psychopharmacology (Berl) 179:99–107

    Article  CAS  Google Scholar 

  • Murphy ER, Fernando AB, Urcelay GP, Robinson ES, Mar AC, Theobald DE, Dalley JW, Robbins TW (2012) Impulsive behaviour induced by both NMDA receptor antagonism and GABAA receptor activation in rat ventromedial prefrontal cortex. Psychopharmacology (Berl) 219:401–410

    Article  CAS  Google Scholar 

  • Nemeth CL, Paine TA, Rittiner JE, Beguin C, Carroll FI, Roth BL, Cohen BM, Carlezon WA Jr (2010) Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats. Psychopharmacology (Berl) 210:263–274

    Article  CAS  Google Scholar 

  • Oberlin BG, Bristow RE, Heighton ME, Grahame NJ (2010) Pharmacologic dissociation between impulsivity and alcohol drinking in high alcohol preferring mice. Alcohol Clin Exp Res 34:1363–1375

    PubMed  CAS  Google Scholar 

  • Ogden KK, Traynelis SF (2011) New advances in NMDA receptor pharmacology. Trends Pharmacol Sci 32:726–733

    Article  PubMed  CAS  Google Scholar 

  • Oliver YP, Ripley TL, Stephens DN (2009) Ethanol effects on impulsivity in two mouse strains: similarities to diazepam and ketamine. Psychopharmacology (Berl) 204:679–692

    Article  CAS  Google Scholar 

  • Paine TA, Carlezon WA Jr (2009) Effects of antipsychotic drugs on MK-801-induced attentional and motivational deficits in rats. Neuropharmacology 56:788–797

    Article  PubMed  CAS  Google Scholar 

  • Paoli F, Spignoli G, Pepeu G (1990) Oxiracetam and d-pyroglutamic acid antagonize a disruption of passive avoidance behaviour induced by the N-methyl-d-aspartate receptor antagonist 2-amino-5-phosphonovalerate. Psychopharmacology (Berl) 100:130–131

    Article  CAS  Google Scholar 

  • Parsons CG, Danysz W, Quack G (1999) Memantine is a clinically well tolerated N-methyl-d-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacology 38:735–767

    Article  PubMed  CAS  Google Scholar 

  • Pattij T, Vanderschuren LJ (2008) The neuropharmacology of impulsive behaviour. Trends Pharmacol Sci 29:192–199

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic, Orlando

    Google Scholar 

  • Perry JL, Larson EB, German JP, Madden GJ, Carroll ME (2005) Impulsivity (delay discounting) as a predictor of acquisition of IV cocaine self-administration in female rats. Psychopharmacology (Berl) 178:193–201

    Article  CAS  Google Scholar 

  • Perry JL, Joseph JE, Jiang Y, Zimmerman RS, Kelly TH, Darna M, Huettl P, Dwoskin LP, Bardo MT (2011) Prefrontal cortex and drug abuse vulnerability: translation to prevention and treatment interventions. Brain Res Rev 65:124–149

    Article  PubMed  Google Scholar 

  • Potenza MN (2007) To do or not to do? The complexities of addiction, motivation, self-control, and impulsivity. Am J Psychiatry 164:4–6

    Article  PubMed  Google Scholar 

  • Pozzi L, Baviera M, Sacchetti G, Calcagno E, Balducci C, Invernizzi RW, Carli M (2011) Attention deficit induced by blockade of N-methyl d-aspartate receptors in the prefrontal cortex is associated with enhanced glutamate release and cAMP response element binding protein phosphorylation: role of metabotropic glutamate receptors 2/3. Neuroscience 176:336–348

    Article  PubMed  CAS  Google Scholar 

  • Quarta D, Naylor CG, Morris HV, Patel S, Genn RF, Stolerman IP (2007) Different effects of ionotropic and metabotropic glutamate receptor antagonists on attention and the attentional properties of nicotine. Neuropharmacology 53:421–430

    Article  PubMed  CAS  Google Scholar 

  • Robbins TW, Murphy ER (2006) Behavioural pharmacology: 40+ years of progress, with a focus on glutamate receptors and cognition. Trends Pharmacol Sci 27:141–148

    Article  PubMed  CAS  Google Scholar 

  • Roberto M, Cruz MT, Gilpin NW, Sabino V, Schweitzer P, Bajo M, Cottone P, Madamba SG, Stouffer DG, Zorrilla EP, Koob GF, Siggins GR, Parsons LH (2010) Corticotropin releasing factor-induced amygdala gamma-aminobutyric Acid release plays a key role in alcohol dependence. Biol Psychiatry 67:831–839

    Article  PubMed  CAS  Google Scholar 

  • Sabino V, Cottone P, Koob GF, Steardo L, Lee MJ, Rice KC, Zorrilla EP (2006) Dissociation between opioid and CRF1 antagonist sensitive drinking in Sardinian alcohol-preferring rats. Psychopharmacology (Berl) 189:175–186

    Article  CAS  Google Scholar 

  • Sabino V, Cottone P, Steardo L, Schmidhammer H, Zorrilla EP (2007) 14-Methoxymetopon, a highly potent mu opioid agonist, biphasically affects ethanol intake in Sardinian alcohol-preferring rats. Psychopharmacology (Berl) 192:537–546

    Article  CAS  Google Scholar 

  • Sabino V, Cottone P, Zhao Y, Iyer MR, Steardo L Jr, Steardo L, Rice KC, Conti B, Koob GF, Zorrilla EP (2009) The sigma-receptor antagonist BD-1063 decreases ethanol intake and reinforcement in animal models of excessive drinking. Neuropsychopharmacology 34:1482–1493

    Article  PubMed  CAS  Google Scholar 

  • Sabino V, Cottone P, Blasio A, Iyer MR, Steardo L, Rice KC, Conti B, Koob GF, Zorrilla EP (2011) Activation of sigma-receptors induces binge-like drinking in Sardinian alcohol-preferring rats. Neuropsychopharmacology 36:1207–1218

    Article  PubMed  CAS  Google Scholar 

  • Smith JW, Gastambide F, Gilmour G, Dix S, Foss J, Lloyd K, Malik N, Tricklebank M (2011) A comparison of the effects of ketamine and phencyclidine with other antagonists of the NMDA receptor in rodent assays of attention and working memory. Psychopharmacology (Berl) 217:255–269

    Article  CAS  Google Scholar 

  • Sobolevsky AI, Koshelev SG, Khodorov BI (1998) Interaction of memantine and amantadine with agonist-unbound NMDA-receptor channels in acutely isolated rat hippocampal neurons. J Physiol 512(Pt 1):47–60

    Article  PubMed  CAS  Google Scholar 

  • Springer DA, Baker KC (2007) Effect of ketamine anesthesia on daily food intake in Macaca mulatta and Cercopithecus aethiops. Am J Primatol 69:1080–1092

    Article  PubMed  CAS  Google Scholar 

  • Takashima A, Maeda Y, Itoh S (1990) Effect of caerulein on decreased latency of passive avoidance response in rats treated with NMDA receptor antagonists. Peptides 11:1263–1267

    Article  PubMed  CAS  Google Scholar 

  • Terry AV Jr, Buccafusco JJ, Schade RF, Vandenhuerk L, Callahan PM, Beck WD, Hutchings EJ, Chapman JM, Li P, Bartlett MG (2012) The nicotine metabolite, cotinine, attenuates glutamate (NMDA) antagonist-related effects on the performance of the five choice serial reaction time task (5C-SRTT) in rats. Biochem Pharmacol 83:941–951

    Article  PubMed  CAS  Google Scholar 

  • Thomson DM, McVie A, Morris BJ, Pratt JA (2011) Dissociation of acute and chronic intermittent phencyclidine-induced performance deficits in the 5-choice serial reaction time task: influence of clozapine. Psychopharmacology (Berl) 213:681–695

    Article  CAS  Google Scholar 

  • Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62:405–496

    Article  PubMed  CAS  Google Scholar 

  • Turic D, Langley K, Mills S, Stephens M, Lawson D, Govan C, Williams N, Van Den Bree M, Craddock N, Kent L, Owen M, O'Donovan M, Thapar A (2004) Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD. Mol Psychiatr 9:169–173

    Article  CAS  Google Scholar 

  • Valenstein ES, Cox VC, Kakolewski JW (1967) Polydipsia elicited by the synergistic action of a saccharin and glucose solution. Science 157:552–554

    Article  PubMed  CAS  Google Scholar 

  • Winstanley CA, Eagle DM, Robbins TW (2006) Behavioral models of impulsivity in relation to ADHD: translation between clinical and preclinical studies. Clin Psychol Rev 26:379–395

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Tamara Zeric, Fanny Jiang, Shawn Hsu, and Stephen St. Cyr for technical assistance, as well as Angelo Blasio for helpful discussions. We thank the NIMH's Chemical Synthesis and Drug Supply Program for providing D-AP-5 and CGS 19755.

Acknowledgments of funding

This publication was made possible by grant numbers DA023680, DA030425, MH091945, MH093650A1 and AA016731 from the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute on Alcohol Abuse and Alcoholism (NIAAA), by the Peter Paul Career Development Professorship (P.C.), and by Boston University's Undergraduate Research Opportunities Program (UROP) (A.R.N., J.K.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The authors declare no conflict of interest. The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Laboratory of Addictive Disorders, Boston University School of Medicine, 72 E Concord St., R-618, Boston, MA, 02118, USA

    Pietro Cottone, Attilio Iemolo, Aditi R. Narayan, Jina Kwak, Duncan Momaney & Valentina Sabino

  2. Department of Psychiatry, Laboratory of Addictive Disorders, Boston University School of Medicine, 72 E Concord St., R-618, Boston, MA, 02118, USA

    Pietro Cottone, Attilio Iemolo, Aditi R. Narayan, Jina Kwak, Duncan Momaney & Valentina Sabino

Authors
  1. Pietro Cottone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Attilio Iemolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aditi R. Narayan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jina Kwak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Duncan Momaney
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Valentina Sabino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Pietro Cottone or Valentina Sabino.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cottone, P., Iemolo, A., Narayan, A.R. et al. The uncompetitive NMDA receptor antagonists ketamine and memantine preferentially increase the choice for a small, immediate reward in low-impulsive rats. Psychopharmacology 226, 127–138 (2013). https://doi.org/10.1007/s00213-012-2898-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-012-2898-3

Keywords

Search

Navigation