Possible alterations in muscarinic cholinergic (mACh) signal transduction in senescence were studied in rat neostriata. Acetylcholine (ACh) activation of striatal muscarinic heteroreceptors by carbachol or oxotremorine enhances K(+)-evoked release of dopamine from perifused striata of 6- but not 24-month-old rats. Present experiments determined the effects of simultaneous activation or activation/inhibition of more than one second messenger on K(+)-evoked release of DA from perifused striatal slices from these age groups. Combinations of carbachol (500 microns), which stimulates inositol-1,4,5-bisphosphate (IP3) production and inhibits cyclic AMP production, with oxotremorine (500 microns), which inhibits cyclic AMP production, in the presence of 30 mM KCl (in a modified Krebs-Ringer medium) reduced the age-related reduction in mAChR enhancement of DA release (analyzed by HPLC coupled to electrochemical detection; 5 min fractions were collected on ice in perchloric acid; flow rate 120 microliters/min). Combinations of these agonists with the putative second messenger arachidonic acid (10 microM), also enhanced K(+)-evoked release of DA in the striatal tissue from the 24-month group. IP3 activation was lower in the striatal tissue from old animals than those from young under all conditions, but cross-activation/inhibition actually may have lowered the IP3 threshold necessary for enhanced DA release to occur. In a subsequent experiment, pre-loading striatal tissue from young animals with either carbachol or oxotremorine under basal release conditions reduced the responding when the basal release medium was switched to one containing 30 mM KCl and combinations of the agonists.(ABSTRACT TRUNCATED AT 250 WORDS)