Motor responses to dopamine D1 and D2 agonists in the reserpine-treated mouse are affected differentially by the NMDA receptor antagonist MK 801

  • P. Goodwin
  • B. S. Starr
  • M. S. Starr
Full Papers


The akinesia induced by reserpine in mice was effectively reversed by the dopamine D1 receptor agonists SKF 38393 (5–30 mg/kg IP) and CY 208-243 (1–5 mg/kg IP), and by the mixed D1/D2 agonist pergolide (5 mg/kg SC), but less well by the D2 agonists lisuride, PHNO, LY 171555 and RU 24213 (each at 5 mg/kg SC) and not at all by the NMDA receptor antagonist MK 801 (0.1–10 mg/kg IP). MK 801 potentiated D1-dependent locomotion, but always suppressed rearing and grooming. D2-dependent locomotion was inhibited by MK 801. The D2 agonist RU 24213 was antagonised by as little as 6.25 μg/kg MK 801, while PHNO and LY 171555 were antagonised by 0.1 mg/kg MK 801. Lisuride was not inhibited by up to 1.6 mg/kg MK 801.

Importantly, all animals showed signs of incapacitation with MK 801 in certain elements of their behaviour, most notably ataxia and hind limb abduction. Thus whilst NMDA receptor blockade can facilitate the restoration of movement by dopamine D1 (though not D2) agonists in monoamine-depleted mice, the fluency of the motor response is adversely affected.


Motor behaviour dopamine MK 801 reserpine 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abbott B, Starr BS, Starr MS (1991) CY 208-243 behaves as a typical D-1 agonist in the reserpine-treated mouse. Pharmacol Biochem Behav 38: 259–263Google Scholar
  2. Arnt J, Hyttel J, Peregaard J (1987) Dopamine D-1 receptor agonists combined with the selective D-2 agonist quinpirole facilitate the expression of oral stereotyped behaviour in rats. Eur J Pharmacol 133: 137–145Google Scholar
  3. Braun AR, Chase TN (1986) Obligatory D-1/D-2 receptor interaction in the generation of dopamine agonist related behaviours. Eur J Pharmacol 131: 301–306Google Scholar
  4. Carlsson M, Carlsson A (1989a) The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice. J Neural Transm 75: 221–226Google Scholar
  5. Carlsson M, Carlsson A (1989b) Dramatic synergism between MK-801 and clonidine with respect to locomotor stimulatory effect in monoamine-depleted mice. J Neural Transm 77: 65–71Google Scholar
  6. 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: 272–276Google Scholar
  7. Carlsson M, Svensson A (1990) The non-competitive NMDA antagonists MK-801 and PCP, as well as the competitive NMDA antagonist SDZ EAA494 (D-CPPene) interact synergistically with clonidine to promote locomotion in monoamine-depleted mice. Life Sci 47: 1729–1736Google Scholar
  8. Clineschmidt BV, Martin GE, Bunting PR, Papp NL (1982) Central sympathomimetic activity of (+)-5-methyl-10,11-dihydroxy-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK 801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties. Drug Dev Res 2: 135–142Google Scholar
  9. Crossman AR, Peggs D, Boyce S, Luquin MR, Sambrook MA (1989) Effect of the NMDA antagonist MK-801 on MPTP-induced parkinsonism in the monkey. Neuropharmacology 28: 1271–1273Google Scholar
  10. Euvrard C, Ferland L, Di Paolo T, Beaulieu M, Labrie F, Oberlander O, Raynaud JP, Boissier JP (1980) Activity of two new potent dopaminergic agonists at the striatal and anterior pituitary levels. Neuropharmacology 19: 379–386Google Scholar
  11. Fuxe K, Agnati LF, Ogren S-O, Kohler C, Calza L, Benfenati F, Goldstein M, Andersson K, Eneroth P (1983) The heterogeneity of the dopamine systems in relation to the actions of dopamine agonists. Acta Pharm Suecica [Suppl] 2: 60–78Google Scholar
  12. Gershanik O, Heikkila RE, Duvoisin RC (1983) Effects of dopamine depletion on rotational behaviour to dopamine agonists. Brain Res 261: 358–360Google Scholar
  13. Girault J-A, Halpain S, Greengard P (1990) Excitatory amino acid antagonists and Parkinson's disease. Trends Neurosci 13: 325–326Google Scholar
  14. Hata N, Nishikawa T, Umino A, Takahashi K (1990) Evidence for involvement of N-methyl-D-aspartate receptor in tonic inhibitory control of dopaminergic transmission in rat medial frontal cortex. Neurosci Lett 120: 101–104Google Scholar
  15. Herrera-Marschitz M, Ungerstedt U (1984) Evidence that striatal efferents relate to different dopamine receptors. Brain Res 323: 269–278Google Scholar
  16. Hiramatsu M, Cho AK, Nabeshima T (1989) Comparison of the behavioural and biochemical effects of the NMDA receptor antagonists MK-801 and phencyclidine. Eur J Pharmacol 166: 359–366Google Scholar
  17. Imperato A, Scrocco MG, Bacchi S, Angelucci L (1990) NMDA receptors and in vivo dopamine release in the nucleus accumbens and caudatus. Eur J Pharmacol 187: 555–556Google Scholar
  18. Klockgether T, Turski L (1989) Excitatory amino acids and the basal ganglia: implications for the therapy of Parkinson's disease. Trends Neurosci 12: 285–286Google Scholar
  19. Leviel V, Gobert A, Guibert B (1990) The glutamate-mediated release of dopamine in the rat striatum: further characterization of the dual excitatory-inhibitory function. Neuroscience 39: 305–312Google Scholar
  20. Liljequist S, Ossowska K, Grabowska-Anden M, Anden N-E (1991) Effect of the NMDA receptor antagonist, MK-801, on locomotor activity and on the metabolism of dopamine in various brain areas of mice. Eur J Pharmacol 195: 55–61Google Scholar
  21. Martin GE, Williams M, Pettibone DJ, Yarbrough GG, Clineschmidt BV, Jones JH (1984) Pharmacologic profile of a novel potent direct-acting dopamine agonist (+)-4-propyl-9-hydroxy-naphthoxazine [(+)-PHNO]. J Pharmacol Exp Ther 230: 569–576Google Scholar
  22. Morelli M, Di Chiara G (1990) MK-801 potentiates dopaminergic D1 but reduces D2 responses in the 6-hydroxydopamine model of Parkinson's disease. Eur J Pharmacol 182: 611–612Google Scholar
  23. Olney JW, Price MT, Labruyene J, Salles KS, Friedrich G, Mueller M, Silverman E (1987) Anti-parkinson agents are phencyclidine agonists and N-methyl-D-aspartate antagonists. Eur J Pharmacol 142: 319–320Google Scholar
  24. Scatton B, Lehmann J (1982) N-methyl-D-aspartate-type receptors mediate striatal3H-acetylcholine release evoked by excitatory amino acids. Nature 297: 422–424Google Scholar
  25. Schmidt WJ, Bubser M (1989) Anticataleptic effect of the N-methyl-D-aspartate antagonist MK 801 in rats. Pharmacol Biochem Behav 32: 621–623Google Scholar
  26. Schmidt WJ, Bubser M, Hauber W (1990) Anticataleptic effects of NMDA receptor antagonists. Eur J Neurosci [Suppl] 3: 118Google Scholar
  27. Setler P, Sarau HM, Zirkle CL, Saunders HL (1978) The central effects of a novel dopamine agonist. Eur J Pharmacol 50: 419–430Google Scholar
  28. Starr BS, Starr MS (1986) Differential effects of dopamine D1 and D2 agonists and antagonists on velocity of movement, rearing and grooming in the mouse. Neuroscience 25: 455–463Google Scholar
  29. Starr MS, Starr BS (1989) Behavioural synergism between the dopamine agonists SKF 38393 and LY 171555 in dopamine-depleted mice: antagonism by sulpiride reveals only stimulant postsynaptic D2 receptors. Pharmacol Biochem Behav 33: 41–44Google Scholar
  30. Starr BS, Starr MS, Kilpatrick IC (1987) Behavioural role of dopamine D1 receptors in the reserpine-treated mouse. Neuroscience 22: 179–188Google Scholar
  31. Tiedtke PI, Bischoff C, Schmidt WJ (1990) MK-801-induced stereotypy and its antagonism by neuroleptic drugs. J Neural Transm (Gen Sect) 81: 173–182Google Scholar
  32. Tricklebank MD, Singh L, Oles RJ, Preston C, Iversen SD (1989) The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur J Pharmacol 167: 127–135Google Scholar
  33. Tsuruta K, Frey EA, Grewe CW, Cote TE, Eskay RL, Kebabian JW (1981) Evidence that LY 141865 specifically stimulates the D-2 dopamine receptor. Nature 292: 463–465Google Scholar
  34. Wong EHF, Kemp JA, Priestly T, Knight AR, Woodruff GN, Iversen LL (1988) The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci 83: 7104Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • P. Goodwin
    • 1
  • B. S. Starr
    • 2
  • M. S. Starr
    • 1
  1. 1.Department of PharmacologySchool of PharmacyLondonUK
  2. 2.Psychology Division, School of Health and Human SciencesHatfield PolytechnicUK

Personalised recommendations