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


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.


Muscle relaxants excitatory amino acids GABA dopamine neurotoxicity amphetamine 


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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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