We examined the effects of tacrine (9-amino-l,2,3,4-tetrahydroacridine) on endogenous acetylcholine (ACh) release from rat hippocampal slices. Tacrine (more than 1 μM) increased the measurable amount of basal ACh release. On the other hand, in the presence of physostigmine (50 μM; under this condition, cholinesterase activity was inhibited), tacrine did not enhance the basal ACh release. Tacrine at more than 100μM increased the submaximal electrical stimulation-evoked release of ACh in both the absence and presence of physostigmine (50 μM). This effect of tacrine was abolished by a combination of atropine (100 nM) and physostigmine. These results indicate that a high-dose of tacrine increases cholinergic neurotransmission not only by inhibition of cholinesterase but also by increasing ACh release through an atropine-like effect, perhaps by blockade of part of the process of muscarinic autoinhibition.
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