The existence in the mammalian CNS of release-inhibiting
muscarinic autoreceptors is well established. In contrast, few reports have focused on nicotinic
autoreceptors mediating enhancement of
acetylcholine (ACh) release. Moreover, it is unclear under what conditions the function of one type of
autoreceptor prevails over that of the other. Rat cerebrocortex slices, prelabeled with [3H]
choline, were stimulated electrically at 3 or 0.1 Hz. The release of [3H]ACh evoked at both frequencies was inhibited by
oxotremorine, a
muscarinic receptor agonist, and stimulated by
atropine, a
muscarinic antagonist.
Nicotine, ineffective at 3 Hz, enhanced [3H]ACh release at 0.1 Hz;
mecamylamine, a nicotinic antagonist, had no effect at 3 Hz but inhibited [3H]ACh release at 0.1 Hz. The
cholinesterase inhibitor neostigmine decreased [3H]ACh release at 3 Hz but not at 0.1 Hz; in the presence of
atropine,
neostigmine potentiated [3H]ACh release, an effect blocked by
mecamylamine. In synaptosomes depolarized with 15 mM KCl, ACh inhibited [3H]ACh release; this inhibition was reversed to an enhancement when the external [Ca2+] was lowered. The same occurred when, at 1.2 mM Ca2+, external [K+] was decreased.
Oxotremorine still inhibited [3H]ACh release at 0.1 mM Ca2+. When
muscarinic receptors were inactivated with
atropine, the K+ (15 mM)-evoked release of [3H]ACh (at 0.1 mM Ca2+) was potently enhanced by ACh acting at
nicotinic receptors (EC50 approximately 0.6 microM). In conclusion, synaptic ACh concentration does not seem to determine whether
muscarinic or nicotinic
autoreceptors are activated. Although
muscarinic autoreceptors prevail under normal conditions, nicotinic
autoreceptors appear to become responsive to endogenous ACh and to exogenous
nicotinic agents under conditions mimicking impairment of ACh release. Our data may explain in part the reported efficacy of
cholinesterase inhibitors (and
nicotinic agonists) in
Alzheimer's disease.