The neuropharmacological basis for tremor and hyperexcitability produced by p,p'-DDT and chlordecone was compared in a series of experiments. Pretreatment with phenytoin, an anticonvulsant that decreases membrane excitability by holding sodium channels in the inactivation state, was used to study the functional significance of brain neurochemical changes produced by p,p'-DDT and chlordecone. Phenytoin selectively enhanced chlordecone-induced tremor and significantly increased chlordecone-induced changes in brainstem MHPG, the major metabolite of the neurotransmitter norepinephrine. Regional levels of norepinephrine were not affected by p,p'-DDT or chlordecone. Phenytoin blocked tremor induced by p,p'-DDT, as well as increases in brainstem MHPG. Subsequent experiments found that systemic administration of phenoxybenzamine attenuated the tremor and hyperexcitability produced by chlordecone and p,p'-DDT. These data suggest that tremor and hyperexcitability produced by p,p'-DDT and chlordecone are produced by different mechanisms, but are mediated by a common neural pathway. A facilitatory noradrenergic influence, perhaps from pathways descending from the locus coeruleus to the ventral horn, appears to be activated by both agents. Subsequent studies found that systemic administration of alpha-1-noradrenergic receptor antagonists attenuated the tremorigenic effects of p,p'-DDT, while yohimbine, an alpha-2-receptor antagonist, exacerbated the effects of p,p'-DDT. That p,p'-DDT and chlordecone act by different mechanisms is supported by experiments showing that intraventricular administration of calcium into the lateral cerebroventricles exacerbated the effects of chlordecone, but decreased those produced by p,p'-DDT. Furthermore, pretreatment with difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, attenuated the effects of chlordecone, but had no effect in rats treated with p,p'-DDT. Putrescine, the product formed by ornithine decarboxylase, reversed the effects of DFMO on chlordecone. Future studies will emphasize the neural substrate responsible for the modification of tremor and startle reflexes mediated at the level of the brainstem.
