Lithium (Li) is used widely in the treatment of certain mental disorders and both cholinergic agonists and cholinesterase inhibitors are being used and/or proposed for treatment of the same mental conditions. In addition, these cholinergic agents are employed in various other fields of medicine and patients receiving Li and/or cholinomimetic agents may also be exposed to anticholinesterase insecticides environmentally. Relevant to the above, the applicants recently observed that subcutaneous (sc) administration of a single dose of the cholinergic agonist, pilocarpine or the cholinesterase inhibitor, physostigmine to adult rats treated 24 hr previously with a single sc injection of lithium chloride results in a dramatic acute neurotoxis syndrome consisting of sustained seizure activity plus fulminant degeneration of neurons in numerous brain regions. This neurotoxic syndrome does not occur from administration of these cholinergic agents without Li pretreatment of from Li by itself. Administering atropine in the interval between Li and pilocarpine prevents the neurotoxic syndrome. The applicants propose a series of experiments aimed at clarifying the mechanism(s) underlying this neurotoxic syndrome and at evaluating, in experimental animals, the nature and degree of risk that combined exposure of humans to Li and cholinomimetic agents may entail. We will employ a combination of neurochemical quantitative microhistochemical, ultrastructural, autoradiographic, immunocytochemical, electrophysiological, neuropharmacological and selective lesioning methods.
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