ON CENTRAL MUSCLE-RELAXANTS, STRYCHNINE-INSENSITIVE GLYCINE RECEPTORS AND 2 OLD DRUGS - ZOXAZOLAMINE AND HA-966

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 pacemaker-like 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 [H-3]-glycine to cortical synaptosomal membranes was inhibited by (+)-HA-966, IC 50 = 3.16-mu-M, but only poorly by zoxazolamine, IC 50 = 474-mu-M, 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 [H-3]-1-baclofen from cortical synaptosomal GABA(b) 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 GABA(b) receptors.