The phosphoinositide cycle is an important second messenger system that may be involved in the therapeutic action of lithium. Elderly patients taking lithium often experience beneficial effects at lower doses and serum levels than their younger counterparts. To investigate age-related differences in lithium's effects on the phosphoinositide system, neostriatal slices from 3-, 10-, and 24- to 26-month-old Fischer 344 rats were labeled with [3H]-myoinositol and exposed for a 25-minute incubation period to oxotremorine-M and varying lithium chloride concentrations. Inositol phosphatase accumulation was significantly greater in 10- and 24- to 26-month-old than in 3-month-old rats. Further investigations may clarify the underlying mechanisms for such age-related differences.