ORGANOPHOSPHORUS COMPOUNDS PREFERENTIALLY AFFECT 2ND-MESSENGER SYSTEMS COUPLED TO M2 M4 RECEPTORS IN RAT FRONTAL-CORTEX/

Recent reports indicate that organophosphate insecticides, In addition to inhibiting acetylcholinesterase activity, can bind directly at a s ubset of muscarinic receptors, which also bind cis-methyldioxolane wit h high affinity. Muscarinic receptors are known to act through at leas t two second messenger systems, either the stimulation of phosphoinosi tide turnover (mediated through the M1 and M3 receptor subtypes) or th e inhibition of cAMP formation (mediated through the M2 and M4 recepto r subtypes). We have investigated the action of the active forms of pa rathion, malathion, and chlorpyrifos (paraoxon, malaoxon, and chlorpyr ifos oxon, respectively) on these second messenger systems in cortical slices from adult male Long-Evans rats. Paraoxon, malaoxon, and chlor pyrifos oxon (10(-8) to 10(-4) M) inhibited forskolin-stimulated cAMP formation in a concentration-dependent manner. The effect on cAMP form ation was blocked by the muscarinic antagonist atropine (10 mu M). The se results suggest that paraoxon, malaoxon, and chlorpyrifos oxon can act as agonists at the M2 and/or M4 subset of muscarinic receptors. In addition, chlorpyrifos may have another site of action. In contrast, none of the organophosphates had any effect on basal or carbachol-stim ulated phosphoinositide hydrolysis. The differential activity on these two second messenger systems make it unlikely that the observed effec ts on cAMP formation are due to increases in endogenous acetylcholine resulting from inhibition of acetylcholinesterase.