Pirenzepine-insensitive muscarinic autoreceptors regulate acetylcholine release in human neocortex

The release of [³H]acetylcholine ([³H]ACh) and its modulation mediated by autoreceptors were investigated in synaptosomes prepared from fresh human cerebral cortex prelabelled with [³H]choline ([³H]Ch) and depolarized in superfusion with 15 mM KCl. The K⁺-evoked release of tritium was almost totally accounted for by unmetabolized [³H]ACh and was largely calcium-dependent. Exogenous ACh decreased the depolarization-evoked release of [³H]ACh in a concentration-dependent manner (EC₅₀ = 1.5 μM). The inhibitory effect of ACh on [³H]ACh release was counteracted by the non-selective muscarinic antagonist atropine. In contrast, the selective M₁ receptor antagonist pirenzepine was ineffective. It is concluded that muscarinic autoreceptors regulating the release of ACh are present on cholinergic nerve terminals of human cerebral cortex and appear to belong to a pirenzepine-insensitive subtype.