Previous research has suggested that age-related decline in physiological functions may be the result of substantial alterations in membrane molecular structure. The purpose of the present experiments was to elucidate the role of cholesterol domains in the age-related decline in receptor-G-protein interactions in striatal synaptosomes. We observed a significant age-related deficit in muscarinic cholinergic stimulated Low-Km GTPase activity and its age-related susceptibility to cholesterol treatment in range of 10(-10)-10(-5) M. Treatment of synaptosomes from old rats with cholesterol in range of 10(-8)-10(-6) M restored the Low-Km GTPase activity up to the level seen in young animals and reached a maximum at 10(-7) M. In synaptosomes from young rats, however, cholesterol treatment did not have any effect on striatal Low-Km GTPase activity. We observed significant alterations in the membrane lipid composition of striatal synaptosomes as a function of age. Our results suggested a significant interaction of age and cholesterol treatment on physical properties of striatal synaptosomes. Thus, the present results of experiments in vitro support our previous results of experiments in vivo and suggested an interaction of cholesterol domains with muscarinic-cholinergic receptor G-protein alpha subunit coupling/uncoupling through regulation of physical properties of striatal synaptosomes.