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

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.