On central muscle relaxants, strychnine-insensitive glycine receptors and two old drugs: zoxazolamine and HA-966

  • B. A. McMillen
  • H. L. Williams
  • H. Lehmann
  • P. D. Shepard
Full Papers

Summary

Zoxazolamine is in the centrally-acting muscle relaxant class of drugs, which reportedly act by decreasing CNS interneuronal activity. These drugs, but not anxiolytics, decrease dopaminergic turnover and induce a pacemakerlike discharge pattern in dopaminergic neurons. A mechanism for these effects was not found in previous reports. We observed that (+)-HA-966, an inhibitor of the glycine modulatory site on the NMDA receptor, has a similar effect on dopaminergic impulse flow, which suggested that this may be the possible site of action of classical muscle relaxants. However, a competitive antagonist of NMDA receptors, NPC-12626, had little effect on impulse flow. Binding of 20 nM [3H]-glycine to cortical synaptosomal membranes was inhibited by (+)-HA-966, IC 50=3.16 μM, but only poorly by zoxazolamine, IC 50=474 μM, and chlorzoxazone, a related drug, caused no displacement. The drugs were then tested for protection from amphetamine neurotoxicity. Neither 50 mg/kg zoxazolamine nor 30 mg/kg (+)-HA-966 prevented (+)-amphetamine (0.1 mmol/kg plus 10 mg/kg iprindole) depletion of striatal dopamine (DA), but 3.0 mg/kg of MK-801, a non-competitive NMDA receptor antagonist, did protect DA content. Since baclofen induces a regular firing rate in DA neurons, zoxazolamine and (+)-HA-966 were tested for displacement of 10 nM [3H]-1-baclofen from cortical synaptosomal GABAb receptors, but were ineffective. Thus, the effects of these muscle relaxants on DA neurons are mediated by a mechanism other than strychnine-insensitive glycine or GABAb receptors.

Keywords

Muscle relaxants excitatory amino acids GABA dopamine neurotoxicity amphetamine 

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References

  1. Bonta IL, De Vos CJ, Grijsen H, Hillen FC, Noach EL, Sim AW (1971) 1-Hydroxy-3-amino-pyrrolidone-2 (HA-966): a new GABA-like compound, with potential use in extrapyramidal diseases. Br J Pharmacol 43: 514–535Google Scholar
  2. Bunney BS, Walters JR, Roth RH, Aghajanian GK (1973) Dopaminergic neurons: effect of antipsychotic drugs and amphetamine on single cell activity. J Pharmacol Exp Ther 185: 560–571Google Scholar
  3. Bunney BS, Sesack SR, Silva NL (1987) Midbrain dopaminergic systems. Neurophysiology and electrophysiological pharmacology. In: Meltzer HY (ed) Psychopharmacology: the third generation of progress. Raven Press, New York, pp 113–126Google Scholar
  4. Danysz W, Fadda E, Wroblewski JT, Costa E (1989) Different modes of action of 3-amino-1-hydroxy-2-pyroolidone (HA-966) and 7-chlorokynurenic acid in the modulation of N-methyl-D-aspartate-sensitive glutamate receptors. Mol Pharmacol 36: 912,x1916Google Scholar
  5. Ferkany JW, Kyle DJ, Willets J, Rzeszotarski Wj, Guzewska ME, Ellenberger SR, Jones SM, Sacaan AI, Snell LD, Borosky S, Jones BE, Johnson KM, Balster RL, Burchett K, Kawasaki K, Hoch DB, Dingledine R (1989) Pharmacological profile of NPC 12626, a novel, competitive N-methyl-D-aspartate receptor antagonist. J Pharmacol Exp Ther 250: 100–109Google Scholar
  6. Fletcher EJ, Lodge D (1988) Glycine reverses antagonism of N-methyl-D-aspartate (NMDA) by 1-hydroxy-3-aminopyrrolidone-2 (HA-966) but not by D-2-amino-5-phosphonovalerate (D-AP 5) on rat cortical slices. Eur J Pharmacol 151: 161–162Google Scholar
  7. Foster AC, Kemp JA (1989) HA-966 antagonizes N-methyl-D-aspartate receptors through a selective action with the glycine modulatory site. J Neurosci 9: 2191–2196Google Scholar
  8. Fuller RW, Hemrick-Luecke S (1980) Long-lasting depletion of striatal dopamine by a single injection of amphetamine in iprindole-treated rats. Science 209: 305–307Google Scholar
  9. Fuller RW, Hemrick-Luecke S, Ornstein PL (1990) LY 274614, an antagonist of N-methyl-D-aspartate (NMDA) receptors protects against amphetamine-induced neurotoxicity toward striatal dopamine neurons in rats. Soc Neurosci Abstr 16: 799Google Scholar
  10. Gonon FG (1988) Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopaminergic neurons as studied byin vivo electrochemistry. Neuroscience 24: 19–28Google Scholar
  11. Grace AA, Bunney BS (1980 a) Effects of baclofen on nigral dopaminergic cell activity following acute and chronic haloperidol treatment. Brain Res Bull 5 [Suppl 2]: 537–546Google Scholar
  12. Grace AA, Bunney BS (1980 b) Nigral dopamine neurons: intracellular recording and identification with L-DOPA injection and histofluorescence. Science 210: 654–656Google Scholar
  13. Grace AA, Bunney BS (1984) The control of firing pattern in nigral dopamine neurons: burst firing. J Neurosci 4: 2877–2890Google Scholar
  14. Hill DR, Bowery NG (1981) [3H]-baclofen and [3H]-GABA bind to bicuculline-insensitive GABAb sites in brain. Nature 290: 149–152Google Scholar
  15. Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325: 529–531Google Scholar
  16. Karbon EW, Duman R, Enna SJ (1983) Biochemical identification of multiple GABAb binding sites: association with noradrenergic terminals in rat forebrain. Brain Res 274: 393–396Google Scholar
  17. Keith RA, Mangano TJ, Meiners BA, Stumpo RJ, Klika AB, Patel J, Salama AI (1989) HA-966 acts at a modulatory glycine site to inhibit N-methyl-D-asparate-evoked neurotransmitter release. Eur J Pharmacol 166: 393–400Google Scholar
  18. King EE, Unna KR (1954) The action of mephenesin and other interneuron depressants on the brain stem. J Pharmacol Exp Ther 111: 293–301Google Scholar
  19. Kishimoto H, Simon JR, Aprison MH (1981) Determination of the equilibrium dissociation constants and number of glycine binding sites in several areas of the rat central nervous system, using a sodium-independent system. J Neurochem 37: 1015–1024Google Scholar
  20. Matthews RT, McMillen BA, Speciale SG, Jarrah H, Shore PA, Sanghera MK, Shepard PD, German DC (1984) Effects of zoxazolamine and related centrally acting muscle relaxants on nigrostriatal dopaminergic neurons. Brain Res Bull 12: 479–486Google Scholar
  21. McMillen BA, Scott SM, Williams HL, Sanghera MK (1987) Effects of gepirone, an arylpiperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission. Naunyn-Schmiedebergs Arch Pharmacol 335: 454–464Google Scholar
  22. McMillen BA, Chamberlain JK, DaVanzo JP (1988) Effects of housing and muricidal behavior on serotonergic receptors and interactions with novel anxiolytic drugs. J Neural Transm 71: 123–132Google Scholar
  23. Scherer RW, Ferkany JW, Enna SJ (1988) Evidence for pharmacologically distinct subsets of GABAb receptors. Brain Res Bull 21: 439–443Google Scholar
  24. Shepard PD, Bunney BS (1988) Effects of apamin on the discharge properties of putative dopamine-containing neurons in vitro. Brain Res 463: 380–384Google Scholar
  25. Shepard PD, German DC (1988) Electrophysiological and pharmacological evidence for the existence of distinct subpopulations of nigrostriatal dopaminergic neurons in the rat. Neuroscience 27: 537–546Google Scholar
  26. Shepard PD, Lehmann H (1992) (±)HA-966 inhibits the activity of nigral-dopaminecontaining neurons through a non-NMDA receptor-mediated mechanism. J Pharmacol Exp Ther 261: 387–394Google Scholar
  27. Shepard PD, Lehmann-Romeyn H, Kogan JH, Roth RH, Bunney BS (1990) HA-966 inhibits the activity of mesencephalic dopamine-containing neurons through a non-NMDA receptor-mediated mechanism. Soc Neurosci Abstr 16: 1044Google Scholar
  28. Singh L, Donald AE, Foster AC, Hutson PH, Iversen LL, Iversen SD, Kemp JA, Leeson PD, Marshall GR, Oles RJ, Priestley T, Thorn L, Tricklebank MD, Vass CA, Williams BJ (1990 a) Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist, but (−)HA-966 is a potent γ-butyrolactone-like sedative. Proc Natl Acad Sci USA 87: 347–351Google Scholar
  29. Singh L, Menzies R, Tricklebank MD (1990 b) The dicriminative stimulus properties of (+)HA-966, an antagonist at the glycine/N-methyl-D-aspartate receptor. Eur Pharmacol 186: 129–132Google Scholar
  30. Sokal RR, Rohlf FJ (1969) Biometry. The principles and practice of statistics in biological research. WH Freeman, San FranciscoGoogle Scholar
  31. Steranka LR (1982) Long-term decreases in striatal dopamine, 3, 4-dihydroxyphenylacetic acid, and homovanillic acid after a single injection of amphetamine in iprindole-treated rats: time course and time-dependent interactions with amfonelic acid. Brain Res 234: 123–136Google Scholar
  32. Tung CS, Grenhoff J, Svensson TH (1991) Kynurenate blocks the acute effcts of haloperidol on midbrain dopamine neurons recorded in vivo. J Neural Transm [Gen Sect] 84: 53–64Google Scholar
  33. Turski L, Schwarz M, Turski WA, Klockgether T, Sontag K-H, Collins JF (1985) Muscle relaxant properties of excitatory amino acid antagonists. Neurosci Lett 53: 321–326Google Scholar
  34. Turski L, Klockgether T, Sontag K-H, Herrling PL, Watkins JC (1987) Muscle relaxant and anticonvulsant activity of 3((±-2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid, a novel N-methyl-D-aspartate antagonist, in rodents. Neurosci Lett 73: 143–148Google Scholar
  35. van Valkenburg CFM, Noach El (1978) Electrical stimulation of the nigrostriatal pathway after HA-966 block of striatal dopamine release. Eur J Pharamcol 48: 171–177Google Scholar
  36. Waldmeier PC (1991) The GABAb antagonist, CGP 35348, antagonizes the effects of baclofen, γ-butyrolactone and HA-966 on rat striatal dopamine synthesis. Naunyn-Schmiedebergs Arch Pharmacol 343: 173–178Google Scholar
  37. Watkins JC, Olverman HJ (1987) Agonists and antagonists for excitatory amino acid receptors. Trends Neurosci 10: 265–268Google Scholar
  38. Zar JH (1984) Biostatistical analysis. Prentice-Hall, Englewood Cliffs, NJGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • B. A. McMillen
    • 1
  • H. L. Williams
    • 1
  • H. Lehmann
    • 2
    • 3
  • P. D. Shepard
    • 2
    • 3
  1. 1.Department of Pharmacology, School of MedicineEast Carolina UniversityGreenville
  2. 2.Maryland Psychiatric Research CenterUSA
  3. 3.The University of Maryland School of MedicineBaltimoreUSA

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