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

Abstract 

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.