The effects of repeated exposure to two organophosphates on the turnover of phosphoinositides, the second messenger system coupled to the M1 and M3 subtypes of muscarinic receptors, were examined in the rat hippocampus. Repeated diisopropylfluorophosphate (DFP) exposure (0.2-0.8 mg/kg, SC) decreased brain acetylcholinesterase activity and muscarinic receptor density. The incorporation of (3H)myoinositol into brain slices was also decreased. Phosphoinositide turnover was measured as the accumulation of (3H)inositol phosphates (IP) in the presence of lithium. DFP did not affect basal IP accumulation, but decreased carbachol-stimulated IP accumulation in the hippocampus after 0.4 and 0.8 mg/kg. The effects of repeated disulfoton administration (2.0 mg/kg, IP) were also examined in the hippocampus. Similar to DFP, repeated disulfoton exposure decreased acetylcholinesterase activity, receptor density, and carbachol-stimulated IP accumulation. The incorporation of myoinositol, however, was increased in disulfoton-treated rats. These data indicate that repeated organophosphate exposure results in a functional decrease in muscarinic receptor activity, as well as changes in myoinositol incorporation into phospholipids.