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An examination of NMDA receptor contribution to conditioned responding evoked by the conditional stimulus effects of nicotine

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Abstract

Rationale

Research using a drug discriminated goal-tracking (DGT) task showed that the N-methyl-d-aspartate (NMDA) channel blocker MK-801 (dizocilpine) reduced the nicotine-evoked conditioned response (CR).

Objectives

Given the unknown mechanism of the effect, Experiment 1 replicated the MK-801 results and included tests with NMDA receptor ligands. Experiments 2a and 2b tested whether MK-801 pretreatment blocked DGT via a state-dependency effect.

Methods

In Experiment 1, adult male Sprague–Dawley rats received intermittent access to liquid sucrose following nicotine (0.4 mg base/kg); no sucrose was delivered on intermixed saline sessions. Conditioning was indicated by increased anticipatory dipper entries (goal-tracking) on nicotine compared to saline sessions. Antagonism and/or substitution tests were conducted with MK-801, phencyclidine, CGP 39551, d-CPPene (SDZ EAA 494), Ro 25,6981, L-701,324, ACPC, and NMDA. In Experiment 2a, rats received nicotine and sucrose on every session—no intermixed saline sessions without sucrose. Tests combined MK-801 or the non-competitive nicotinic acetylcholine receptor antagonist, mecamylamine with either nicotine or saline. Experiment 2b had sucrose delivered on saline sessions and no sucrose on intermixed nicotine sessions followed by MK-801 antagonism tests of the saline CS.

Results

MK-801 and phencyclidine dose-dependently attenuated the CR in Experiment 1. Ro-25,6981 enhanced the CR, but did not substitute for nicotine. Other ligands showed inconsistent effects. In Experiment 2a, MK-801 pretreatment reduced goal-tracking when given before nicotine and saline test sessions; mecamylamine pretreatment had no effect. In Experiment 2b, MK-801 dose-dependently attenuated the saline-evoked CR.

Conclusions

Combined, the results suggest that MK-801 blocks discriminated goal-tracking by virtue of state-changing properties.

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References

  • Besheer J, Palmatier MI, Metschke DM, Bevins RA (2004) Nicotine as a signal for the presence or absence of sucrose reward: a Pavlovian drug appetitive conditioning preparation in rats. Psychopharmacology 172:108–117

    Article  CAS  PubMed  Google Scholar 

  • Bevins RA (2009) Altering the motivational function of nicotine through conditioning processes. In: Bevins RA, Caggiula AR (eds) The motivational impact of nicotine and its role in tobacco use: the 55th Nebraska symposium on motivation. Springer, New York, pp 111–129

    Google Scholar 

  • Bevins RA, Palmatier MI (2004) Extending the role of associative learning processes in nicotine addiction. Behav Cog Neurosci Rev 3:143–158

    Article  Google Scholar 

  • Bevins RA, Besheer J, Pickett KS (2001) Nicotine-conditioned locomotor activity in rats: dopaminergic and GABAergic influences on conditioned expression. Pharmacol Biochem Behav 68:135–145

    Article  CAS  PubMed  Google Scholar 

  • Bevins RA, Penrod RD, Reichel CM (2007) Nicotine does not produce state-dependent effects on learning in a Pavlovian appetitive goal-tracking task with rats. Behav Brain Res 177:134–141

    Article  CAS  PubMed  Google Scholar 

  • Blaise M-C, Sowdhamini R, Pradhan N (2005) Comparative analysis of different competitive antagonists interaction with NR2A and NR2B subunits of N-methyl-d-aspartate (NMDA) ionotropic glutamate receptor. J Mol Model 11:489–502

    Article  CAS  PubMed  Google Scholar 

  • Bristow LJ, Landon L, Saywell KL, Tricklebank MD (1995) The glycine/NMDA receptor antagonist, L-701, 324 reverses isolation-induced deficits in prepulse inhibition in the rat. Psychopharmacology 188:230–232

    Article  Google Scholar 

  • Chance WT, Murfin D, Krynock GM, Rosecrans JA (1977) A description of the nicotine stimulus and tests of its generalization to amphetamine. Psychopharmacology 55:19–26

    Article  CAS  PubMed  Google Scholar 

  • Chaperon F, Müller W, Auberson YP, Tricklebank MD, Neijt HC (2003) Substitution for PCP, disruption of prepulse inhibition and hyperactivity induced by N-methyl-d-aspartate receptor antagonists: preferential involvement of the NR2B rather than the NR2A subunit. Behav Pharmacol 14:477–487

    CAS  PubMed  Google Scholar 

  • Clements JD, Westbrook GL (1991) Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-d-aspartate receptor. Neuron 7:605–613

    Article  CAS  PubMed  Google Scholar 

  • Davies J, Evans RH, Herrling PL, Jones AW, Olverman HJ, Pook P, Watkins JC (1986) CPP, a new potent and selective NMDA antagonist. Depression of central neuron responses, affinity for [3H]D-AP5 binding sites on brain membranes and anticonvulsant activity. Brain Res 382:169–173

    Article  CAS  PubMed  Google Scholar 

  • Desai R, Barber DJ, Terry P (2003) Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats. Psychopharmacology 167:335–343

    CAS  PubMed  Google Scholar 

  • Doty P, Dykstra LA, Picker MJ (1994) Discriminative stimulus effects of phencyclidine: pharmacologically specific interactions with Δ9- and Δ8-tetrahydrocannabinol. Drug Alcohol Depend 35:151–158

    Article  CAS  PubMed  Google Scholar 

  • Fagg GE, Olpe H-R, Pozza MF, Baud J, Steinmann M, Schmutz M, Portet C, Baumann P, Thedinga K, Bittiger H, Allgeier H, Heckendorn R, Angst C, Brundish D, Dingwall JG (1990) CGP 37849 and CGP 39551: novel and potent competitive N-methyl-d-aspartate receptor antagonists with oral activity. Prog Clin Biol Res 361:421–427

    CAS  PubMed  Google Scholar 

  • Farwell BJ, Ayres JJB (1997) Stimulus-reinforcer and response-reinforcer relations in the control of conditioned appetitive headpoking (“goal-tracking”) in rats. Learn Motiv 10:295–312

    Article  Google Scholar 

  • Fischer G, Mutel V, Trube G, Malherbe P, Kew JNC, 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

    CAS  PubMed  Google Scholar 

  • Glick SD, Maisonneuve IM, Kitchen BA (2002) Modulation of nicotine self-administration in rats by combination therapy with agents blocking α3β4 nicotinic receptors. Eur J Pharmacol 448:185–191

    Article  CAS  PubMed  Google Scholar 

  • Grech DM, Willetts J, Balster RL (1993) Pharmacological specificity of N-methyl-d-aspartate discrimination in rats. Neuropharmacology 32:349–354

    Article  CAS  PubMed  Google Scholar 

  • Halliwell RF, Peters JA, Lambert JJ (1989) The mechanism of action and pharmacological specificity of the anticonvulsant NMDA antagonist MK-801: a voltage clamp study on neuronal cells in culture. Br J Pharmacol 96:480–494

    CAS  PubMed  Google Scholar 

  • Hundt W, Danysz W, Hölter SM, Spanagel R (1998) Ethanol and N-methyl-d-aspartate receptor complex interactions: a detailed drug discrimination study in the rat. Psychopharmacology 135:44–51

    Article  CAS  PubMed  Google Scholar 

  • Jackson A, Koek W, Colpaert FC (1992) NMDA antagonists make learning and recall state-dependent. Behav Pharmacol 3:415–421

    Article  CAS  PubMed  Google Scholar 

  • Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–531

    Article  CAS  PubMed  Google Scholar 

  • Kemp JA, Leeson PD (1993) The glycine site of the NMDA receptor—5 years on. Trends Pharmacol Sci 14:20–25

    Article  CAS  PubMed  Google Scholar 

  • Kim DJB, Brioni JD (1995) Modulation of the discriminative stimulus properties of (−)-nicotine by diazepam and ethanol. Drug Dev Res 34:47–54

    Article  CAS  Google Scholar 

  • Konitsiotis S, Tsironis C, Kiortsis DN, Evangelou A (2006) Effects of N-methyl-d-aspartate receptor antagonism on neuroleptic-induced orofacial dyskinesias. Psychopharmacology 185:369–377

    Article  CAS  PubMed  Google Scholar 

  • Kosowski AR, Cebers G, Cebere A, Swanhagen AC, Liljequist S (2004) Nicotine-induced dopamine release in the nucleus accumbens is inhibited by the novel AMPA antagonist ZK200775 and the NMDA antagonist CGP39551. Psychopharmacology 175:114–123

    Article  CAS  PubMed  Google Scholar 

  • Li B, Chen N, Luo T, Otsu Y, Murphy TH, Raymond LA (2002) Differential regulation of synaptic and extra-synaptic NMDA receptors. Nat Neurosci 5:833–834

    Article  CAS  PubMed  Google Scholar 

  • Lowe DA, Emre M, Frey P, Kelly PH, Malanowski J, McAllister KH, Neijt HC, Rüdeberg C, Urwyler S, White TG, Herring PL (1994) The pharmacology of SDZ EAA 494, a competitive NMDA antagonist. Neurochem Int 25:583–600

    Article  CAS  PubMed  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 (ε2) subunit. Eur J Pharmacol 416:185–195

    Article  CAS  PubMed  Google Scholar 

  • Massey PV, Johnson BE, Moult PR, Auberson YP, Brown MW, Molnar E, Collingridge GL, Bashir ZI (2004) Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J Neurosci 24:7821–7828

    Article  CAS  PubMed  Google Scholar 

  • Murray JE, Bevins RA (2007a) Behavioral and neuropharmacological characterization of nicotine as a conditional stimulus. Eur J Pharmacol 561:91–104

    Article  CAS  PubMed  Google Scholar 

  • Murray JE, Bevins RA (2007b) The conditional stimulus effects of nicotine vary as a function of training dose. Behav Pharmacol 18:707–716

    Article  CAS  PubMed  Google Scholar 

  • Murray JE, Penrod RD, Bevins RA (2009a) Nicotine-evoked conditioned responding is dependent on concentration of sucrose unconditioned stimulus. Behav Process 81:136–139

    Article  Google Scholar 

  • Murray JE, Wells NR, Lyford GD, Bevins RA (2009b) Investigation of endocannabinoid modulation of conditioned responding evoked by a nicotine CS and the Pavlovian stimulus effects of CP 55, 940 in adult male rats. Psychopharmacology 205:655–665

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Nahum-Levy R, Fossom LH, Skolnick P, Benveniste M (1999) Putative partial agonist 1-aminocyclopropanecarboxylic acid acts concurrently as a glycine-site agonist and a glutamate-site antagonist at N-methyl-d-aspartate receptors. Mol Pharmacol 56:1207–1218

    CAS  PubMed  Google Scholar 

  • National Research Council (2003) Guidelines for the care and use of mammals in neuroscience and behavioral research. National Academy, Washington, DC

    Google Scholar 

  • Papp M, Gruca P, Willner P (2002) Selective blockade of drug-induced place preference conditioning by ACPC, a functional NMDA-receptor antagonist. Neuropsychopharmacology 27:727–743

    Article  CAS  PubMed  Google Scholar 

  • Pratt JA, Stolerman IP, Garcha HS, Giardini V, Feyerabend C (1983) Discriminative stimulus properties of nicotine: further evidence for mediation at a cholinergic receptor. Psychopharmacology 81:54–60

    Article  CAS  PubMed  Google Scholar 

  • Rosecrans JA, Villanueva HF (1991) Discriminative stimulus properties of nicotine: mechanisms of transduction. NIDA Res Monogr 116:101–116

    CAS  PubMed  Google Scholar 

  • Rowley M, Leeson PD, Stevenson GI, Moseley AM, Stansfield I, Sanderson I, Robinson L, Baker R, Kemp JA, Marshall GR, Foster AC, Grimwood S, Tricklebank MD, Saywell KL (1993) 3-Acyl-4-hydroxyquinolin-2(1H)-ones. Systemically active anticonvulsants acting by antagonism at the glycine site of the N-methyl-d-aspartate receptor complex. J Med Chem 36:3386–3396

    Article  CAS  PubMed  Google Scholar 

  • Schmidt WJ, Tzschentke TM, Kretschmer BD (1999) State-dependent blockade of haloperidol-induced sensitization of catalepsy by MK-801. Eur J Neurosci 11:3365–3368

    Article  CAS  PubMed  Google Scholar 

  • Sheinin A, Nahum-Levy R, Shavit S, Benveniste M (2002) Specificity of putative partial agonist, 1-aminocyclopropanecarboxylic acid, for rat N-methyl-d-aspartate subunits. Neurosci Lett 317:77–80

    Article  CAS  PubMed  Google Scholar 

  • Shoaib M, Benwell ME, Akbar MT, Stolerman IP, Balfour DJ (1994) Behavioural and neurochemical adaptations to nicotine in rats: influence of NMDA antagonists. Br J Pharmacol 111:1073–1080

    CAS  PubMed  Google Scholar 

  • Smith JW, Stolerman IP (2009) Recognising nicotine: the neurobiological basis of nicotine discrimination. Handb Exp Psych 192:295–333

    CAS  Google Scholar 

  • Solinas M, Panlilio LV, Justinova Z, Yasar S, Goldberg SR (2006) Using drug-discrimination techniques to study the abuse-related effects of psychoactive drugs in rats. Nature Protocol 1:1194–1206

    Article  CAS  Google Scholar 

  • Stocca G, Vicini S (1998) Increased contribution of NR2A subunit to synaptic NMDA receptors in developing rat cortical neurons. J Physiol 507:13–24

    Article  CAS  PubMed  Google Scholar 

  • Stolerman IP, Chandler CJ, Garcha HS, Newton JM (1997) Selective antaghonism of behavioural effects of nicotine by dihydro-β-erythroidine in rats. Psychopharmacology 129:390–397

    Article  CAS  PubMed  Google Scholar 

  • Struthers AM, Wilkinson JL, Dwoskin LP, Crooks PA, Bevins RA (2009) Mecamylamine, dihydro-β-erythroidine, and dextromethorphan block conditioned responding evoked by the conditional stimulus effects of nicotine. Pharmacol Biochem Behav 94:319–328

    Article  CAS  PubMed  Google Scholar 

  • Tzschentke TM, Schmidt WJ (2000) Blockade of behavioral sensitization by MK-801: fact or artifact? Psychopharmacology 151:142–151

    Article  CAS  PubMed  Google Scholar 

  • Wilkinson JL, Murray JE, Li C, Wiltgen SM, Penrod RD, Berg SA, Bevins RA (2006) Interoceptive Pavlovian conditioning with nicotine as the conditional stimulus varies as function of number of conditioning trials and unpaired sucrose. Behav Pharmacol 17:161–172

    Article  CAS  PubMed  Google Scholar 

  • Willetts J, Balster RL (1988) Phencyclidine-like discriminative stimulus properties of MK-801 in rats. Eur J Pharmacol 146:167–169

    Article  CAS  PubMed  Google Scholar 

  • Wise RA, Mendrek A, Carlezon WA Jr (1996) MK-801 (dizocilpine): synergist and conditioned stimulus in bromocriptine-induced psychomotor sensitization. Synapse 22:362–368

    Article  CAS  PubMed  Google Scholar 

  • Wolosker H (2007) NMDA receptor regulation by d-serine: new findings and perspectives. Mol Neurobiol 36:152–164

    Article  CAS  PubMed  Google Scholar 

  • Wong EHF, Kemp JA, Priestley T, Knight AR, Woodruff GN, Iversen LL (1986) The anticonvulsant MK-801 is a potent N-methyl-d-aspartate antagonist. Proc Natl Acad Sci USA 83:7104–7108

    Article  CAS  PubMed  Google Scholar 

  • Woodhall G, Evand DI, Cunningham MO, Jones RSG (2001) NR2B-containing NMDA autoreceptors at synapses on entorhinal cortical neurons. J Neurophysiol 86:1644–1651

    CAS  PubMed  Google Scholar 

  • Wooters TE, Bevins RA, Bardo MT (2009) Neuropharmacology of the interoceptive stimulus properties of nicotine. Curr Drug Abuse Rev 2:243–255

    Article  CAS  PubMed  Google Scholar 

  • Yang X-C, Reis DJ (1999) Agmatine selectively blocks the N-methyl-d-aspartate subclass of glutamate receptor channels in rat hippocampal neurons. J Pharmacol Exp Ther 288:544–549

    CAS  PubMed  Google Scholar 

  • Zakharova ES, Danysz W, Bespalov AY (2005) Drug discrimination analysis of NMDA receptor channel blockers as nicotinic receptor antagonists in rats. Psychopharmacology 179:128–135

    Article  CAS  PubMed  Google Scholar 

  • Zaniewska M, McCreary AC, Sezer G, Przegaliński E, Filip M (2008) Effects of agmatine on nicotine-evoked behavioral responses in rats. Pharmacol Rep 60:645–654

    CAS  PubMed  Google Scholar 

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Acknowledgments

We are grateful for the excellent laboratory assistance of George D. Lyford and Jacob M. Williams. We thank Gonzalo Urcelay for his insightful comments on an earlier version of the report and the National Institute on Drug Abuse Drug Supply Program for providing the phencyclidine. The research and R.A. Bevins were supported by United States Public Health Service grant DA018114. J.E. Murray was supported by NIDA F31 DA025399 and MRC 9536855 (to B.J. Everitt) during the preparation of this manuscript. None of these organizations had any role in the study design, the data collection, analysis, or interpretation, or in the writing of the manuscript or the decision to submit the paper for publication. All MED-PC programs used in the present article are available upon request to R.A. Bevins, rbevins1@unl.edu. Correspondence related to this article should be addressed to Jennifer E. Murray, Department of Experimental Psychology, Downing Street, Cambridge, UK, CB2 3EB, or e-mail jem98@cam.ac.uk.

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  1. Department of Psychology, University of Nebraska—Lincoln, Lincoln, NE, 68588-0308, USA

    Jennifer E. Murray, Andrew W. Walker, Robert J. Polewan & Rick A. Bevins

  2. Department of Experimental Psychology, University of Cambridge, Cambridge, CB2 3EB, UK

    Jennifer E. Murray

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  1. Jennifer E. Murray
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Correspondence to Jennifer E. Murray.

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Murray, J.E., Walker, A.W., Polewan, R.J. et al. An examination of NMDA receptor contribution to conditioned responding evoked by the conditional stimulus effects of nicotine. Psychopharmacology 213, 131–141 (2011). https://doi.org/10.1007/s00213-010-2022-5

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  • DOI: https://doi.org/10.1007/s00213-010-2022-5

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