Role of muscarinic signal transduction and CREB phosphorylation in dichlorvos-induced memory deficits in rats: An acetylcholine independent mechanism

Abstract

The present study was designed to explore the alternative mechanism (other than AChE inhibition) for chronic, low-level exposure to dichlorvos, an organophosphate, in vivo. Dichlorvos, at a dose of 1.0 and 6.0 mg/kg body weight (b.wt.) for 12 weeks, showed impairment in neurobehavioral indices viz. rota rod, passive avoidance and water maze tests. Though high dose of dichlorvos had a detrimental effect on acetylcholinesterase activity, no significant inhibition was seen with low dose of dichlorvos. Western blot analysis and immunofluorescence studies showed a significant reduction in the expression of M 1, M 2 and M 3 muscarinic receptor subtypes in high dose group animals, whereas in low dose group animals only the M 2 receptor subtype was reduced significantly. Further, the signal transduction cascade linked to these receptor subtypes was affected in high dose group animals whereas in low dose group only adenylyl cyclase-linked signaling pathway was impaired. Finally, the phosphorylation of CREB, a memory enhancing transcription factor, was significantly reduced in both low dose and high dose group animals. Thus, the present study reveals the significance of M 2 muscarinic receptor linked adenylyl cyclase signaling pathway and phosphorylation of CREB in the development of neurobehavioral impairments after chronic low-level exposure to dichlorvos.