Antimyoclonic action of clonazepam: the role of serotonin.

Clonazepam (5-(2-chlorophenyl)-1,3-dihydro-7-nitro 2H-1,4 benzodiazepin-2-one) (2 mg/kg) reduced a p,p'-DDT-induced myoclonus in mice by 50%. This antimyoclonic action of clonazepam was counteracted by the serotonin (5-HT) receptor blockers methysergide, metergoline and cinnanserin and potentiated by the 5-HT uptake inhibitors fluoxetine and chlorimipramine. Clonazepam (4 mg/kg) reduced plasma tryptophan by 27%, but had no effect on brain tryptopham, 5-HT, 5-hydroxyindoleacetic acid, 5-HT synthesis and 3H-5-HT receptor binding. Clonazepam (10(-5) M) inhibited brain synaptosomal 3H-5-HT uptake by 23% and increased 3H-5-HT release by 24%. However, 2-8 mg/kg of clonazepam administered intraperitoneally had no effect on 5-HT uptake or release. gamma-Aminobutyric acid (GABA) agonists (muscimol, acetylenic GABA, amino-oxyacetic acid) and the GABA antagonists bicuculline and isoniazid had no effect on p,p'-DDT-induced myoclonus. Furthermore, bicuculline did not counteract the antimyoclonic effect of clonazepam. We suggest that the antimyoclonic action of clonazepam is mediated by enhancement of serotonergic rather than GABAergic neurotransmission.