Organophosphates (OPs) including parathion and malathion are widely used as pesticides. Intoxication by high-dose or long-term exposure to OPs is a global health concern. OPs irreversibly inhibit cholinesterase, elevate the acetylcholine level and cause various cholinergic symptoms (e.g., cardiovascular hypofunction, motor excitements, and convulsions). However, the mechanism of OPs intoxication, especially its effects on motor functions, still not fully understood. Here, using paraoxon, an active metabolite of parathion, we performed behavioral and immunohistochemistry studies to clarify the mechanisms for paraoxon-induced tremor. Paraoxon (0.15-0.6 mg/kg, i.p.) induced a dose-dependent kinetic tremor. Expression analysis of Fos protein, a biomarker of neural excitation, in 48 brain different regions revealed that a tremorgenic dose (0.6 mg/kg, i.p.) of paraoxon region-specifically activates 6 brain regions (sensory cortex, hippocampus, dorsolateral striatum, globus pallidus, medial habenula and inferior olive). In addition, paraoxon-induced tremor and Fos expression in the inferior olive were inhibited by mecamylamine (nicotinic receptor antagonist), but not by trihexyphenidyl (muscarinic receptor antagonist). Finally, electrical lesion of the inferior olive suppressed paraoxon-induced tremor. Our results show that paraoxon provokes kinetic tremor at least partly by activating the inferior olive neurons via nicotinic acetylcholine receptors.
