Mechanism Underlying Organophosphate Paraoxon-Induced Kinetic Tremor
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Organophosphates (OPs) inhibit cholinesterase and hyperactivate the acetylcholinergic nervous system in the brain, causing motor disorders (e.g., tremor and seizures). Here, we performed behavioral and immunohistochemical studies in mice and rats to investigate the tremorgenic mechanism of paraoxon, an active metabolite of parathion. Treating animals with paraoxon (0.15–0.6 mg/kg, i.p.) elicited kinetic tremor in a dose-dependent manner. Expressional analysis of Fos protein, a biomarker of neural excitation, revealed that a tremorgenic dose of paraoxon (0.6 mg/kg) significantly and region-specifically elevated Fos expression in the cerebral cortex (e.g., sensory cortex), hippocampal CA1, globus pallidus, medial habenula, and inferior olive (IO) among 48 brain regions examined. A moderate increase in Fos expression was also observed in the dorsolateral striatum while the change was not statistically significant. Paraoxon-induced tremor was inhibited by the nicotinic acetylcholine (nACh) receptor antagonist mecamylamine (MEC), but not affected by the muscarinic acetylcholine receptor antagonist trihexyphenidyl (THP). In addition, paraoxon-induced Fos expression in the IO was also antagonized by MEC, but not by THP, and lesioning of the IO markedly suppressed tremorgenic action of paraoxon. The present results suggest that OPs elicit kinetic tremor at least partly by activating IO neurons via nACh receptors.
KeywordsOrganophosphate pesticides Paraoxon Tremor Fos protein expression Inferior olive
This study was supported in part by a research grant from the Smoking Research Foundation (YO) and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (YO:17K08324, SS:16K21501).
Compliance with Ethical Standards
The experimental protocols were approved by the Experimental Animal Research Committee at the Osaka University of Pharmaceutical Sciences.
Conflict of Interest
The authors declare that there is no conflict of interest.
- Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates, 3rd edn. Academic Press, San DiegoGoogle Scholar
- Iha HA, Kunisawa N, Tokudome K, Mukai T, Kinboshi M, Shimizu S, Ohno Y (2016) Immunohistochemical analysis of Fos protein expression for exploring brain regions (foci) related to central nervous system (CNS) disorders and drug actions. In: Philippu A (ed) In vivo neuropharmacology and neurophysiology. Springer, New York, pp 389–408Google Scholar
- Ohno Y, Okano M, Masui A, Imaki J, Egawa M, Yoshihara C, Tatara A, Mizuguchi Y, Sasa M, Shimizu S (2012) Region-specific elevation of D1 receptor-mediated neurotransmission in the nucleus accumbens of SHR, a rat model of attention deficit/hyperactivity disorder. Neuropharmacology 63:547–554CrossRefGoogle Scholar
- Yelamos F, Diez F, Martin C, Blanco JL, Garcia MJ, Lardelli A, Pena JF (1992) Acute organophosphate insecticide poisonings in the province of Almeria. A study of 187 cases. Med Clin (Barc) 98:681–684Google Scholar