The activation of phospholipase C (PLC) was examined in membranes of rat cerebral cortex simultaneously exposed to monoaminergic receptor and muscarinic receptor agonists after the treatment of membranes with two alkylating agents, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (100 microM EEDQ) and propylbenzilylcholine (10 nM PrBCM). Treatment of membranes with PrBCM results in a selective inactivation of M3 muscarinic receptors, while treatment with EEDQ results in a relative sparing of M1 muscarinic receptors. Stimulation of PLC by GTP gamma S alone in rat cortical membranes had an apparent EC50 of about 0.4 microM, but in the presence of carbachol (1 mM) was 0.09 microM. Treatment of rat cortical membranes with EEDQ or PrBCM did not modify the concentration-response curves for GTP gamma S alone, but the ability of carbachol (1 mM) to shift the EC50 of GTP gamma S was lost in PrBCM-treated membranes. We have previously shown that dopamine, working through D1-like dopamine receptors, alters the PLC response to carbachol by preventing this shift in the apparent EC50 for GTP gamma S16. When we reproduced these experiments in EEDQ- and PrBCM-treated membranes, only in EEDQ-treated membranes was dopamine able to inhibit the PLC response to carbachol. The results indicate that the post-receptor mechanisms of PLC activation are distinct for the putative M1 as opposed to M3 muscarinic receptors in rat cortical membranes. Further, there appears to be a specific interaction between D1 and M3 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)