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. [ABSTRACT FROM AUTHOR]