Muscarinic Inhibition of Hippocampal and Striatal Adenylyl Cyclase is Mainly Due to the M4 Receptor

The five muscarinic acetylcholine receptors (M1–M5) are differentially expressed in the brain. M2 and M4 are coupled to inhibition of stimulated adenylyl cyclase, while M1, M3 and M5 are mainly coupled to the phosphoinositide pathway. We studied the muscarinic receptor regulation of adenylyl cyclase activity in the rat hippocampus, compared to the striatum and amygdala. Basal and forskolin-stimulated adenylyl cyclase activity was higher in the striatum but the muscarinic inhibition was much lower. Highly selective muscarinic toxins MT1 and MT2—affinity order M1 ≥ M4 >> others—and MT3—highly selective M4 antagonist—did not show significant effects on basal or forskolin-stimulated cyclic AMP production but, like scopolamine, counteracted oxotremorine inhibition. Since MTs have negligible affinity for M2, M4 would be the main subtype responsible for muscarinic inhibition of forskolin-stimulated enzyme. Dopamine stimulated a small fraction of the enzyme (3.1% in striatum, 1.3% in the hippocampus). Since MT3 fully blocked muscarinic inhibition of dopamine-stimulated enzyme, M4 receptor would be responsible for this regulation.