M1 muscarinic receptors contribute to, whereas M4 receptors inhibit, dopamine D1 receptor-induced [3H]-Cyclic AMP accumulation in rat striatal slices

In rat striatal slices labelled with [H-3]-adenine and in the presence of 1 mM 3-isobutyl-1-methylxantine (IBMX), cyclic [H-3]-AMP ([H-3]-cAMP) accumulation induced by the dopamine D-1 receptor agonist SKF-81297 (1 mu M; 177 +/- 13% of basal) was inhibited by the general muscarinic agonist carbachol (maximum inhibition 72 +/- 3%, IC50 0.30 +/- 0.06 mu M). The muscarinic toxin 7 (MT-7), a selective antagonist at muscarinic M-1 receptors, reduced the effect of SKF-81297 by 40 +/- 7% (IC50 251 +/- 57 pM) and enhanced the inhibitory action of a submaximal (1 mu M) concentration of carbachol (69 +/- 4% vs. 40 +/- 7% inhibition, IC50 386 +/- 105 pM). The toxin MT1, agonist at M-1 receptors, stimulated [H-3]-cAMP accumulation in a modest but significant manner (137 +/- 11% of basal at 400 nM), an action additive to that of D-1 receptor activation and blocked by MT-7 (10 nM). The effects of MT-7 on D-1 receptor-induced [H-3]-cAMP accumulation and the carbachol inhibition were mimicked by the PKC inhibitors Ro-318220 (200 nM) and G-6976 (200 nM). Taken together our results indicate that in addition to the inhibitory role of M-4 receptors, in rat striatum acetylcholine stimulates cAMP formation through the activation of M-1 receptors and PKC stimulation.