Muscarinic M(1) receptor and cannabinoid CB(1) receptor do not modulate paraoxon-induced seizures

One of the major signs of severe organophosphate poisoning is seizures. Previous studies have shown that both muscarinic agonist- and organophosphate-induced seizures require activation of muscarinic acetylcholine receptors in the central nervous system. Seizures induced by the muscarinic agonist pilocarpine require the M(1) receptor and are modulated by cannabinoid CB(1) receptors. In this study, we determined whether M(1) and CB(1) receptors also regulated seizures induced by the organophosphate paraoxon. We found no differences in seizures induced by paraoxon in wild-type (WT) and M(1) knockout (KO) mice, indicating that in contrast to pilocarpine seizures, M(1) receptors are not required for paraoxon seizures. Furthermore, we found that pilocarpine administration resulted in seizure-independent activation of ERK in the hippocampus in a M(1) receptor-dependent manner, while paraoxon did not induce seizure-independent activation of ERK in the mouse hippocampus. This shows that pilocarpine and paraoxon activated M(1) receptors in the hippocampus to different extents. There were no differences in seizures induced by paraoxon in WT and CB(1) KO mice, and neither CB(1) agonist nor antagonist administration had significant effects on paraoxon seizures, indicating that, in contrast to pilocarpine seizures, paraoxon seizures are not modulated by CB(1) receptors. These results demonstrate that there are fundamental molecular differences in the regulation of seizures induced by pilocarpine and paraoxon.