EFFECT OF REPEATED ORGANOPHOSPHATE ADMINISTRATION ON CARBACHOL-STIMULATED PHOSPHOINOSITIDE HYDROLYSIS IN THE RAT-BRAIN

The effects of repeated exposure to two organophosphates on the turnov er of phosphoinositides, the second messenger system coupled to the M1 and M3 Subtypes of muscarinic receptors, were examined in the rat hip pocampus. Repeated diisopropylfluorophosphate (DFP) exposure (0.2-0.8 mg/kg, SC) decreased brain acetylcholinesterase activity and muscarini c receptor density. The incorporation of [H-3]myoinositol into brain s lices was also decreased. Phosphoinositide turnover was measured as th e accumulation of [H-3]inositol phosphates (IP) in the presence of lit hium. DFP did not affect basal IP accumulation, but decreased carbacho l-stimulated IP accumulation in the hippocampus after 0.4 and 0.8 mg/k g. The effects of repeated disulfoton administration (2.0 mg/kg, IP) w ere also examined in the hippocampus. Similar to DFP, repeated disulfo ton exposure decreased acetylcholinesterase activity, receptor density , and carbachol-stimulated IP accumulation. The incorporation of myoin ositol, however, was increased in disulfoton-treated rats. These data indicate that repeated organophosphate exposure results in a functiona l decrease in muscarinic receptor activity, as well as changes in myoi nositol incorporation into phospholipids.