Skip to main content
SpringerLink
Log in

AMPA antagonists differ from NMDA antagonists in their effects on operant DRL and delayed matching to position tasks

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

Abstract

The effects of NBQX (1.56–7.5 mg/kg, IP), a competitive antagonist at the AMPA type of glutamate receptor, were studied in two operant behavioural paradigms, differential reinforcement of low response rates (DRL), and delayed matching to position (DMTP), which have been shown to be sensitive to the antagonists of the NMDA type of glutamate receptor. Additionally, the non-competitive AMPA antagonist, GYKI 52466 (7.5–15 mg/kg, IP), was studied in the DRL procedure. As a positive control, the non-competitive NMDA antagonist, MK 801 (0.0125–0.1 mg/kg, IP) was studied in both procedures. During performance of the DRL schedule, MK 801 increased response rates in a dose dependent manner, and decreased the number of reinforcers obtained. The increase in response rates could be attributed to both a shift in the median inter-response time (IRT) to shorter intervals, and to a marked, dose dependent increase in the occurrence of bursts of responses (responses occurring within 3 s of a previous response). In contrast, NBQX and GYKI 52466 both decreased response rates in a dose dependent fashion, and did not shift the distribution of the IRTs, or increase the occurrence of burst responding. In the DMTP procedure, accuracy of matching decreased with increasing delay (up to 30 s, between presentation of sample and opportunity to respond). NBQX disrupted responding at a dose of 7.5 mg/kg, but lower doses were ineffective in influencing accuracy of performance of the discrimination. In contrast, MK 801 (0.1 and 0.2 mg/kg) reduced accuracy of matching at all delays, while tending to increase the speed of responding. These data demonstrate differences in the effects of AMPA and NMDA antagonists on performance of well trained operant behaviour.

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

Similar content being viewed by others

References

  • Baddeley AD (1981) The concept of working memory: a review of its current state and probable future development. Cognition 10:17–23

    Google Scholar 

  • Balster RL, Baird JB (1979) Effects of phencyclidine,d-amphetamine and pentobarbital on spaced responding in mice. Pharmacol Biochem Behav 11:617–623

    Google Scholar 

  • Balster RL, Wessinger WD (1983) Central nervous depressant effects of phencyclidine. In: Kamenka J-M, Domino EF, Geneste P (eds) Phencyclidine and related arylcyclohexylamines: present and future applications. NPP Books, Ann Arbor, Michigan, pp 231–309

    Google Scholar 

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

    Google Scholar 

  • Boast CA, Pastor G, Gerhardt SC, Hall NR, Liebman JM (1988) Behavioral tolerance and sensitization to CGS 19755, a competitive antagonist atN-methyl-d-aspartate receptors. J Pharmacol Exp Ther 247:556–561

    Google Scholar 

  • Carter AJ (1992) Glycine antagonists: regulation of the NMDA receptor complex by the strychnine insensitive glycine site. Drugs Future 17:595–613

    Google Scholar 

  • Carter C, Benavides J, Legendre P, Vincent JD, Noel F, Thuret F, Lloyd KG, Arbilla S, Zivkovic B, MacKenzie ET, Scatton B, Langer SZ (1988) Ifenprodil and SL 82.0715 as cerebral antiischemic agents. II. Evidence forN-methyl-d-aspartate receptor antagonist properties. J Pharmacol Exp Ther 247:1222–1232

    Google Scholar 

  • Cervo L, Samanin R (1995) Effects of dopaminergic and glutamatergic receptor antagonists on the acquisition and expression of cocaine conditioning place preference. Brain Res 673:242–250

    Google Scholar 

  • Cole BJ, Hillmann M (1994) Effects of benzodiazepine receptor ligands on the performance of an operant delayed matching to position task in rats: opposite effects of FG 7142 and lorazepam. Psychopharmacology 115:350–357

    Google Scholar 

  • Cole BJ, Klewer M, Jones GH, Stephens DN (1993) Contrasting effects of the competitive NMDA antagonist CPP and the noncompetitive NMDA antagonist MK 801 on performance of an operant delayed matching to position task in rats. Psychopharmacology 111:465–471

    Google Scholar 

  • Cotman CW, Monaghan DT, Ottersen OP, Storm-Matthisen J (1987) Anatomical organisation of excitatory amino acid receptors and their pathways. Trends Neurosci 10:273–280

    Google Scholar 

  • Curtis DR, Phillis JW, Watkins JC (1959) Chemical excitation of spinal neurones. Nature 183:610–612

    Google Scholar 

  • Davies J, Francis AA, Jones AW, Watkins JC (1981) 2-Amino-5-phosphonovalerate (2-APV), a potent and selective antagonist of amino-acid induced and synaptic excitation. Neurosci Lett 21:77–81

    Google Scholar 

  • Danysz W, Wroblewski JT (1989) Amnesic properties of glutamate receptor antagonists. Neurosci Res Commun 479:9–18

    Google Scholar 

  • Danysz W, Wroblewski JT, Costa E (1988) Learning impairment in rats byN-methyl-d-aspartate receptor antagonists. Neuropharmacology 27:653–656

    Google Scholar 

  • Danysz W, Zajaczkowski W, Parsons CG (1995) Modulation of learning processes by ionotropic glutamate receptor ligands. Behav Pharmacol 6:455–474

    Google Scholar 

  • Durmuller N, Craggs M, Meldrum BS (1994) The effect of the non-NMDA receptor antagonists GYKI 52466 and NBQX, and the competitive NMDA receptor antagonistd-CPPene on the development of amygdala kindling, and on amygdala kindled seizures. Epilepsy Res 17:167–174

    Google Scholar 

  • Flood JF, Baker ML, Davis JL (1990) Modulation of memory processing by glutamic acid receptor agonists and antagonists Brain Res 521:197–202

    Google Scholar 

  • Gray JA (1981) The neuropsychology of anxiety. Oxford University Press, Oxford

    Google Scholar 

  • Hudzik TJ, Slifer BL (1992) Interaction of sigma and PCP-like drugs on operant behaviors in the rat. Psychopharmacology 108:115–122

    Google Scholar 

  • Izquierdo I (1994) Pharmacological evidence for an involvement of long term potentiation in memory. FASEB J 8:1139–1145

    Google Scholar 

  • Jerulinsky D, Ferreira MBC, Walz R, Dasilva RC, Bianchin M, Ruschel AC, Zanatta MS, Medina JH, Izquierdo I (1992) Amnesia by post training infusion of glutamate receptor antagonists into the amygdala, hippocampus and entorhinal cortex. Behav Neural Biol 58:76–80

    Google Scholar 

  • Kahneman D (1973) Attention and effort. Prentice Hall, Eaglewood Cliffs, N.J.

    Google Scholar 

  • Kim M, Campeau S, Falls WA, Davis M (1993) Infusion of the non-NMDA receptor antagonist CNQX into the amygdala blocks the expression of fear potentiated startle. Behav Neural Biol 59:5–8

    Google Scholar 

  • Layer RT, Uretszy NJ, Wallace LJ (1993) Effects of the AMPA/kainate receptor antagonist DNQX in the nucleus accumbens on drug induced conditioned place preference. Brain Res 617:267–273

    Google Scholar 

  • Liang KC, Hon W, Davis M (1994) Pre- and post-training infusion ofN-methyl-d-aspartate receptor antagonists into the amygdala impair memory in an inhibitory avoidance task. Behav Neurosci 108:241–253

    Google Scholar 

  • Lyford GL, Jarrard LE (1991) Effects of the competitive NMDA antagonist CPP on performance of a place and cue radial maze task. Psychobiology 19:157–160

    Google Scholar 

  • Misztal M, Danysz W (1995) Comparison of glutamate antagonists in continuous multiple trial and single trial dark avoidance. Behav Pharmacol 6:550–561

    Google Scholar 

  • Morris RGM (1989) Synaptic plasticity and learning: selective impairment of learning in rats and blockade of long-term potentiation in vivo by theN-methyl-d-aspartate receptor antagonist, AP5. J Neurosci 9:304–3057

    Google Scholar 

  • Parada J, Czuczwar SJ, Turski WA (1992) NBQX does not affect learning and memory tasks in mice — a comparison with d-CPPene and ifenprodil. Cognit Brain Res 1:67–71

    Google Scholar 

  • Poling A, Cleary J, Jackson K, Wallace S (1981)d-Amphetamine and phencyclidine alone and in combination: effects on fixed ratio and inter-response-time-greater-than-t responding of rats. Pharmacol Biochem Behav 15:357–361

    Google Scholar 

  • Pontecorvo MJ, Clissold DB, White MF, Ferkany JW (1991)N-Methyl-d-aspartate antagonists and working memory performance: comparison with the effects of scopolamine, propranalol, diazepam and phenylisopropyladenosine. Behav Neurosci 105:521–531

    Google Scholar 

  • Quillfeldt JA, Schmitz PK, Walz R, Bianchin M, Zanatta MS, Medina JH, Izquierdo I (1994) CNQX infused into entorhinal cortex blocks memory expression, and AMPA reverses the effect. Pharmacol Biochem Behav 48:437–440

    Google Scholar 

  • Ratkowsky DA (1990) Handbook of nonlinear regression models. Marcel Dekker, New York

    Google Scholar 

  • Sanger DJ (1992) NMDA antagonists disrupt timing behaviour in rats. Behav Pharmacol 3:593–600

    Google Scholar 

  • Sanger DJ, Blackman DE (1975) The effects of tranquillising drugs on timing behaviour in rats. Psychopharmacologia 44:153–156

    Google Scholar 

  • Sanger DJ, Jackson A (1988) Effects of phencyclidine and otherN-methyl-d-aspartate antagonists on the schedule-controlled behavior of rats. J Pharmacol Exp Ther 248:1215–1221

    Google Scholar 

  • Sheardown MJ, Nielsen EO, Hansen AJ, Jacobsen P, Honore T (1990) 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline — a neuroprotectant for cerebral ischemia. Science 247:571–574

    Google Scholar 

  • Smith SE, Darmuller N, Meldrum BS (1991) The non-N-methyl-d-aspartate receptor antagonists GYKI 52466 and NBQX are anticonvulsant in two animal models of reflex epilepsy. Eur J Pharmacol 201:179–183

    Google Scholar 

  • Spencer DG, Emmett-Oglesby MW (1985) Parallel processing strategies in the application of microcomputers to the behavioral laboratory. Behav Res Methods Instrum Comput 17:294–300

    Google Scholar 

  • Stephens DN, Voet B (1994) Differential effects of anxiolytic and non-anxiolytic benzodiazepine receptor ligands on performance of a differential reinforcement of low rate (DRL) schedule. Behav Pharmacol 5:4–14

    Google Scholar 

  • Stephens DN, Meldrum BS, Weidmann R, Schneider C, Grutzner M (1986) Does the excitatory amino acid antagonist 2-APH exhibit anxiolytic activity? Psychopharmacology 90:166–169

    Google Scholar 

  • Stephens DN, Andrews JS, Turski L, Schneider HH (1991a) Excitatory amino acids and anxiety. In: Briley M, File SE (eds) New concepts in anxiety. Macmillan Press, Basingstoke, pp 366–381

    Google Scholar 

  • Stephens DN, Duka T, Andrews JS (1991b) Benzodiazepines, β-carbolines and memory. In: Weinman J, Hunter J (eds) Memory: neurochemical and abnormal perspectives. Harwood Academic Publishers, Chur (Switzerland), pp 11–42

    Google Scholar 

  • Swedberg MDB, Jacobsen F, Honore T (1995) Anticonvulsant, anxiolytic and discriminative effects of the AMPA antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX). J Pharmacol Exp Ther 274:1113–1121

    Google Scholar 

  • Tan S, Kirk RC, Abraham WC, McNaughton N (1989) Effects of the NMDA antagonists CPP and MK-801 on delayed conditional discrimination. Psychopharmacology 98:556–560

    Google Scholar 

  • Tonkiss J, Rawlins JNP (1991) The competitive NMDA receptor antagonist AP5, but not the non-competitive antagonist MK801, induces a delay-related impairment in spatial working memory in rats. Exp Brain Res 85:349–358

    Google Scholar 

  • Tonkiss J, Morris RGM, Rawlins JNP (1988) Intaventricular infusion of the NMDA receptor antagonist AP5 impanirs performance on a non-spatial operant DRL task in the rat. Exp Brain Res 73:181–188

    Google Scholar 

  • Turski L, Jacobsen P, Honore T, Stephens DN (1992) Relief of experimental spasticity and anxiolytic/anticonvulsant actions of the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate antagonist 2,3-dihydroxyy-6-nitro-7-sulfamoyl-benzo(F) quinoxaline. J Pharmacol Exp Ther 260:742–747

    Google Scholar 

  • Upchurch M, Wehner JM (1990) Effects ofN-methyl-d-aspartate antagonism on spatial learning in mice. Psychopharmacology 100:209–214

    Google Scholar 

  • Ward L, Mason SE, Abraham WC (1990) Effects of the NMDA antagonists CPP and MK 801 on radial maze performance in rats. Pharmacol Biochem Behav 35:785–790

    Google Scholar 

  • Watkins JC, Krosgaard-Larsen P, Honore T (1990) Structure-activity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists. Trends Pharmacol Sci 11:25–33

    Google Scholar 

  • Welzl H, Berz S Battig K (1991) The effects of the non-competitive NMDA receptor antagonist MK801 on DRL performance in rats. Psychobiology 19:211–216

    Google Scholar 

  • Wiley JA, Balster RL (1992) Preclinical evaluation ofN-methyl-d-aspartate antagonists for antianxiety effects: a review. In: Kamenka J-M, Domino EF (eds) Multiple sigma and PCP receptor ligands: mechanisms for neuromodulation and neuroprotection. NPP Books, Ann Arbor, Michigan, pp 801–815

    Google Scholar 

  • Wogar MA, Bradshaw CM, Szabadi E (1992) Impaired acquisition of temporal differentiation performance following lesions of the ascending 5-hydroxytryptaminergic pathways. Psychopharmacology 107:373–378

    Google Scholar 

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

    Google Scholar 

  • Zorumski CF, Yamada KA, Price MT, Olney JW (1993) A benzodiazepine recognition site associated with the non-NMDA glutamate receptor. Neuron 10:61–67

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Experimental Psychology, School of Biological Sciences, University of Sussex, Falmer, BN1 9QG, Brighton, UK

    D. N. Stephens

  2. Research Laboratories of Schering AG, Berlin, Germany

    B. J. Cole

Authors
  1. D. N. Stephens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. J. Cole
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stephens, D.N., Cole, B.J. AMPA antagonists differ from NMDA antagonists in their effects on operant DRL and delayed matching to position tasks. Psychopharmacology 126, 249–259 (1996). https://doi.org/10.1007/BF02246455

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02246455

Key words

Search

Navigation