Skip to main content
SpringerLink
Log in

Behavioural and neurochemical interactions of the AMPA antagonist GYKI 52466 and the non-competitive NMDA antagonist dizocilpine in rats

  • Full Papers
  • Published:
Journal of Neural Transmission / General Section JNT Aims and scope Submit manuscript

Summary

The behavioural and neurochemical effects of the N-methyl-D-aspartate (NMDA) antagonist dizocilpine and the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonist GYKI 52466, given alone or in combination, were investigated in rats. Locomotor activity was increased by dizocilpine (0.2 mg/kg), but not by GYKI 52466 (2.4 mg/kg). Dizocilpine-induced hyperlocomotion was reduced by co-administration of GYKI 52466. In dizocilpine-treated rats dopamine (DA) metabolism (measured as DOPAC [dihydroxyphenylacetic acid] or DOPAC/DA in post mortem brain tissue) was increased in the prefrontal cortex and nucleus accumbens. In GYKI 52466-treated rats serotonin was reduced in the prefrontal cortex and nucleus accumbens while DA metabolism was not affected. In rats treated with dizocilpine plus GYKI 52466, DA metabolism was increased only in the prefrontal cortex, but not in the nucleus accumbens, when compared with vehicle-treated animals. These data confirm that AMPA and NMDA antagonists do not have synergistic effects on locomotor activity. A differential role of NMDA and AMPA antagonists in the control of mesolimbic DA neurons will be discussed here.

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

  • Bischoff C, Tiedtke PI (1992) Competitive and non-competitive NMDA receptor antagonists in spatial learning tasks. Eur J Pharmacol 213: 269–273

    PubMed  Google Scholar 

  • Block F, Schwarz M (1994) The depressant effect of GYKI 52466 on spinal reflex transmission is mediated via non-NMDA and benzodiazepine receptors. Eur J Pharmacol 256: 149–153

    PubMed  Google Scholar 

  • Browne SE, McCulloch J (1994) AMPA receptor antagonists and local cerebral glucose utilization in the rat. Brain Res 641: 10–20

    PubMed  Google Scholar 

  • Bubser M, Koch M (1994) Prepulse inhibition of the acoustic startle response of rats is reduced by 6-hydroxydopamine lesions of the medial prefrontal cortex. Psychopharmacology 113: 487–492

    PubMed  Google Scholar 

  • Bubser M, Keseberg U, Notz PK, Schmidt WJ (1992) Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats. Eur J Pharmacol 229: 75–82

    PubMed  Google Scholar 

  • Carlsson M, Carlsson A (1990) Interactions between glutamatergic and monoaminergic systems within the basal ganglia — implications for schizophrenia and Parkinson's disease. Trends Neurosci 13: 272–276

    PubMed  Google Scholar 

  • Chapman AG, Swan JH, Patel S, Graham JL, Meldrum BS (1990) Cerebroprotective and anticonvulsant action of competive and non-competive NMDA antagonists. In: Lubec G, Rosenthal GA (eds) Amino acids: Chemistry, biology and medicine. ESCOM, Leiden, pp 219–232

    Google Scholar 

  • Danysz W, Essmann U, Bresink I, Wilke R (1994) Glutamate antagonists have different effects on spontaneous locomotor activity in rats. Pharmacol Biochem Behav 48: 111–118

    PubMed  Google Scholar 

  • French ED, Ceci A (1990) Non-competitive N-methyl-D-aspartate antagonists are potent activators of ventral tegmental A10 dopamine neurons. Neurosci Lett 119: 159–162

    PubMed  Google Scholar 

  • Gill R, Lodge D (1992) The neuroprotective effects of a combination of MK-801 and NBQX in focal ischemia. Br J Pharmacol 107 [Suppl]: p 59

    Google Scholar 

  • Hauber W (1994) Effects of the AMPA antagonist GYKI 52466 on delayed alternation and spatial discrimination learning of rats in a T-maze. In: Eisner N, Breer H (eds) Sensory Transduction: Proceedings of the 22th Göttingen Neurobiology Conference. Thieme, Stuttgart, p 759

    Google Scholar 

  • Hauber W, Andersen R (1993) The non-NMDA glutamate receptor antagonist GYKI 52466 counteracts locomotor stimulation and anti-cataleptic activity induced by the NMDA receptor antagonist dizocilpine. Naunyn Schmiedebergs Arch Pharmacol 348: 486–490

    PubMed  Google Scholar 

  • Hauber W, Waldenmeier MT (1994) The AMPA receptor antagonist GYKI 52466 reverses the anticataleptic effects of the competitive NMDA receptor antagonist CGP 37849. Eur J Pharmacol 256: 339–342

    PubMed  Google Scholar 

  • Heffner TG, Hartman JA, Sciden LS (1980) A rapid method for the regional dissection of the rat brain. Pharmacol Biochem Behav 13: 453

    PubMed  Google Scholar 

  • Honoré T (1991) Inhibitors of kainate and AMPA ionophore receptors. In: Meldrum BS (ed) Excitatory amino acid antagonists. Blackwell Scientific, Oxford, pp 180–194

    Google Scholar 

  • Honoré T, Davies SN, Drejer J, Fletcher EJ, Jakobsen P, Lodge D, Nielsen FE (1988) Quinoxalinediones: potent competitive non-NMDA glutamate receptor antagonists Science 241: 701

    PubMed  Google Scholar 

  • Imperato A, Honoré T, Jensen LH (1990a) Dopamine release in the nucleus caudatus and in the nucleus accumbens is under glutamatergic control through non-NMDA receptors: a study in freely-moving rats. Brain Res 530: 223–228

    PubMed  Google Scholar 

  • Kaddis FG, Wallace LJ, Uretsky NJ (1993) AMPA/kainate antagonists in the nucleus accumbens inhibit locomotor stimulatory response to cocaine and dopamine agonists. Pharmacol Biochem Behav 46: 703–708

    PubMed  Google Scholar 

  • Kilpatrick IC, Jones MW, Phillipson OT (1986) A semiautomated analysis method for catecholamines, indoleamines, and some prominent metabolites in microdissected regions of the nervous system: an isocratic HPLC technique employing coulometric detection and minimal sample preparation. J Neurochem 46: 1865–1876

    PubMed  Google Scholar 

  • Klockgether T, Turski L, Honoré T, Zhang Z, Gash DM, Kurlan R Greenamyre JT (1991) The AMPA receptor antagonist NBQX has antiparkinsonian effects in monoamine-depleted rats and MPTP-treated monkeys. Ann Neurol 30: 717–723

    PubMed  Google Scholar 

  • Löscher W, Hönack (1994) Over-additive anticonvulsant effect of memantine and NBQX in kindled rats. Eur J Pharmacol 259: R3-R5

    PubMed  Google Scholar 

  • Löscher W, Hönack D (1993) Effects of the novel 5-HT1A receptor antagonist, (+)- WAY 100135, on stereotyped behaviour induced by the NMDA receptor antagonist dizocilpine in rats. Eur J Pharmacol 242: 99–104

    PubMed  Google Scholar 

  • Löscher W, Annies R, Hönack D (1991) The N-methyl-D-aspartate receptor antagonist MK-801 induces increases in dopamine and serotonin metabolism in several brain regions of rats. Neurosci Lett 128: 191–194

    PubMed  Google Scholar 

  • Löscher W, Rundfeldt C, Hönack D (1993) Low doses of NMDA receptor antagonists synergistically increase the anticonvulsant effect of the AMPA receptor antagonist NBQX in the kindling model of epilepsy. Eur J Neurosci 5: 1545–1550

    PubMed  Google Scholar 

  • Löschmann PA, Lange KW, Kunow M, Rettig KJ, Jähnig P, Honoré T, Turski L, Wachtel H, Jenner P, Marsden CD (1991) Synergism of the AMPA-antagonist NBQX and the NMDA-antagonist CPP with L-Dopa in models of Parkinson's disease. J Neural Transm [PD Sect] 3: 203–213

    Google Scholar 

  • Nicholls DG (1993) The glutamatergic nerve terminal. Eur J Biochem 212: 613–631

    PubMed  Google Scholar 

  • Ornstein PL, Arnold MB, Augenstein NK, Lodge D, Leander JD, Schoepp DD (1993) (3SR, 4aRS, 6RS, 8aRS)-6-[2(1H-tetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid: a structurally novel, systemically active, competitive AMPA receptor antagonist. J Med Chem 36: 2046–2048

    PubMed  Google Scholar 

  • Ouagazzal A, Nieoullon A, Amalric M (1993) Effects of dopamine D1 and D2 receptor blockade on MK-801-induced hyperlocomotion in rats. Psychopharmacology 111: 427–434

    PubMed  Google Scholar 

  • Ouardouz M, Durand J (1991) GYKI 52466 antagonizes glutamate responses but not NMDA and kainate responses in rat abducens motoneurones. Neurosci Lett 125: 5–8

    PubMed  Google Scholar 

  • Papa SM, Engber TM, Boldry RC, Chase TN (1993) Opposite effects of NMDA and AMPA receptor blockade on catalepsy induced by dopamine receptor antagonists. Eur J Pharmacol 232: 247–253

    PubMed  Google Scholar 

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

    Google Scholar 

  • Rao TS, Kim HS, Lehmann J, Martin LL, Wood PL (1990) Interactions of phencyclidine receptor agonist MK-801 with dopaminergic system: regional studies in the rat. J Neurochem 54: 1157

    PubMed  Google Scholar 

  • Rogawski MA (1993) Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines. Trends Pharmacol Sci 14: 325–331

    PubMed  Google Scholar 

  • Schmidt WJ, Bubser M (1989) Anticataleptic effects of the N-methyl-D-aspartate antagonist MK-801 in rats. Pharmacol Biochem Behav 32: 621–623

    PubMed  Google Scholar 

  • Schmidt WJ, Bubser M, Hauber W (1992) Behavioural pharmacology of glutamate in the basal ganglia. J Neural Transm [Suppl] 38: 65–89

    Google Scholar 

  • Smith SE, Dürmüller 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

    PubMed  Google Scholar 

  • Starr MS, Starr BS (1993) Facilitation of dopamine D1 receptor-but not dopamine D1/D2 receptor-dependent locomotion by glutamate antagonists in the reserpine-treated mouse. Eur J Pharmacol 250: 239–246

    PubMed  Google Scholar 

  • Tarnawa I, Farkas S, Berzsenyi P, Pataki S, Andrási F (1989) Electrophysiological studies with a 2,3-benzodiazepine muscle relaxant: GYKI 52466. Eur J Pharmacol 167: 193–199

    PubMed  Google Scholar 

  • Willetts J, Balster RL, Leander JD (1990) The behavioral pharmacology of NMDA receptor antagonists. In: Lodge D, Collingridge GL (eds) The pharmacology of excitatory amino acids. A special report 1991. (Trends Pharmacol Sci, pp 62–68)

  • Willins DL, Wallace LJ, Miller DD, Uretsky NJ (1992) α-Amino-3-hydroxy-5-methylisoxalone-4-propionate/kainate receptor antagonists in the nucleus accumbens and ventral pallidum decrease the hypermotility response to psychostimulant drugs. J Pharmacol Exp Ther 260: 1145–1151

    PubMed  Google Scholar 

  • Willins DL, Narayanan S, Wallace LJ, Uretsky NJ (1993) The role of dopamine and AMPA/kainate receptors in the nucleus accumbens in the hypermotility response to MK-801. Pharmacol Biochem Behav 46: 881–887

    PubMed  Google Scholar 

  • Witkin JM (1993) Blockade of the locomotor stimulant effects of cocaine and methamphetamine by glutamate antagonists. Life Sci 53: 405–410

    Google Scholar 

  • Wolf ME, White FJ, Hu XT (1993) Behavioral sensitization to MK-801 (dizocilpine): neurochemical and electrophysiological correlates in the mesoaccumbens dopamine system. Behav Pharmacol 4: 429–442

    PubMed  Google Scholar 

  • Yamaguchi S, Donevan SD, Rogawski MA (1993) Anticonvulsant activity of AMPA/kainate antagonists: comparison of GYKI 52466 and NBQX in maximal electroshock and chemoconvulsant Scizure models. Epilepsy Res 15: 179–184

    PubMed  Google Scholar 

  • Zadow B, Schmidt WJ (1994) The AMPA antagonists NBQX and GYKI 52466 do not counteract neuroleptic-induced catalepsy. Naunyn Schmiedebergs Arch Pharmacol 349: 61–65

    PubMed  Google Scholar 

Download references

Author information

Author notes

  1. M. Bubser

    Present address: Netherlands Institute for Brain Research, Amsterdam, The Netherlands

Authors and Affiliations

  1. Department of Neuropharmacology, Zoological Institute, University of Tübingen, Tübingen

    M. Bubser & T. Tzschentke

  2. Department of Animal Physiology, Biological Institute, University of Stuttgart, Stuttgart, Germany

    W. Hauber

Authors
  1. M. Bubser
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Tzschentke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W. Hauber
    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

Bubser, M., Tzschentke, T. & Hauber, W. Behavioural and neurochemical interactions of the AMPA antagonist GYKI 52466 and the non-competitive NMDA antagonist dizocilpine in rats. J. Neural Transmission 101, 115–126 (1995). https://doi.org/10.1007/BF01271550

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01271550

Keywords

Search

Navigation