Evaluation of autoreceptor-mediated control of [(3)H]acetylcholine release in rat and human neocortex.

In order to assess the autoinhibitory control of endogenous acetylcholine (ACh) in rat and human neocortex, slices of these tissues were prelabelled with [3H]choline, superfused continuously and stimulated electrically using various frequencies in the presence or absence of drugs. The autoinhibitory feedback control of [3H]ACh release was operative – despite the absence of blockers of ACh esterase – at stimulation frequencies ≥3 Hz in rat and ≥6 Hz in human neocortex tissue. At these frequencies the muscarinic antagonist atropine (0.1 µM) disinhibited the release of [3H]ACh in both species. Estimation of the biophase concentration of ACh near the autoreceptor in the rat neocortex from concentration-response curves of the muscarinic agonist oxotremorine revealed that at 3 Hz about 25% of the autoreceptors were activated by endogenously released ACh. This estimation is consistent with an increase in [3H]ACh release to about 120% of control values by complete blockade of autoreceptors with atropine. The observation that in human neocortical tissue presynaptic autoinhibition of [3H]ACh release is operative at stimulation frequencies ≥6 Hz suggests that selective blockade of autoinhibition may also increase ACh release in the cortex of Alzheimer’s disease patients, without additional blockade of the enzyme acetylcholinesterase.