The relationship of DDT myoclonus and antimyoclonic agents to the concentration of cGMP in the cerebellum was investigated. Intragastric administration of 600 mg/kg DDT increased mouse cerebellar cGMP levels about 4 fold. Antimyoclonic agents, such as L-5HTP plus fluoxetine, clonazepam, phenoxybenzamine, prostaglandin E2 and harmaline, all counteracted the elevation of cerebellar cGMP induced by DDT. Cinnanserin, a 5-HT receptor blocker, did not counteract the reduction of cerebellar cGMP produced by L-5HTP plus fluoxetine, clonazepam, and phenoxybenzamine, although cinnanserin abolished the antimyoclonic actions of these agents. Destruction of the inferior olive-climbing fiber pathway by 3-acetylpyridine in rats did not prevent the elevation of cerebellar cGMP levels by DDT. L-5HTP, clonazepam and phenoxybenzamine still significantly counteracted DDT-induced elevation of cerebellar cGMP levels in the inferior olive lesioned rats, although these agents no longer had any antimyoclonic action in these animals. These data indicate that 1) DDT-induced elevation of cerebellar cGMP and DDT-induced myoclonus are not related, and 2) antimyoclonic agents counteract DDT-induced elevation of cerebellar cGMP levels via pathways other than the olivo-cerebellar tract.