Receptor-activated hydrolysis of [3H]inositol-labeled phosphoinositides was evaluated in brain slices of 6-month-old (6M) and 24-month-old (24M) F344 rats that had been fed ad libitum (AL) or restricted (60% of normal) diet (RD). The muscarinic cholinergic agonist, carbachol, and the dopamine receptor agonist, SKF3893, stimulated significantly lower accumulation of [3H]inositol phosphates in striatal and cortical slices of the 24M AL rats compared to the 6M AL group. This observation suggests a decreased capacity of the aged brain to respond to receptor-activated phosphoinositide hydrolysis. Furthermore, the 24M RD tissues gave significantly higher responses to carbachol (p < .01) or SKF38393 (p < .01) compared to the 24M AL group. The 24M RD responses were not significantly different from corresponding responses in the 6M AL rats, implying complete prevention of the aging effect in the diet-restricted animals up to at least 24 months of age. Concomitant observations of decreased phosphoinositide labeling in the 24M AL tissues and prevention of this decrease in diet restriction may contribute to the observed effects of aging on inositol phosphate formation.