Stimulation of acetylcholine synthesis by blockade of presynaptic muscarinic inhibitory autoreceptors: Observations in rat and human brain preparations and comparison with the effect of choline

The central presynaptic muscarinic inhibitory autoreceptor has been monitored by measuring the effects of muscarinic agents on acetylcholine (ACh) synthesis by rat and human neocortical tissue prisms. Quinuclidinyl benzilate (QNB), the antimuscarinic which of 20 tested caused the most marked stimulation of ACh synthesis in rat, significantly increased ACh synthesis in human prisms over a range of concentrations of 0.1 μM–10 μM. This data provides the first evidence that human brain contains presynaptic muscarinic receptors. However, the most marked effect of QNB was to increase synthesis to only 112% of control (value without drug) which was much less than in rat (to 140% of control). ACh synthesis is reduced to 50% of control in neocortex from Alzheimer patients so none of the antimuscarinics tested seem to be potentially capable of appreciably reversing this deficit. A high concentration of choline (10 mM) stimulated synthesis in rat prisms to about the same extent as QNB. Moreover, the ACh precursor was at least as effective in stimulating synthesis in human prisms (including those from a patient with Alzheimer's disease). This suggests that an elevated intracellular concentration of choline is likely to be much more effective than an antimuscarinic agent in stimulating synthesis in Alzheimer brain.