Physostigmine stimulates phosphoinositide breakdown in the rat neostriatum

The reversible acetylcholinesterase inhibitor, physostigmine, stimulated in a dose-dependent manner the accumulation of [3H]inositol monophosphate ([3H]IP1) in lithium-treated neostriatal slices. The muscarinic agonists, carbachol and oxotremorine, also stimulated [3H]IP1 accumulation. Atropine completely blocked the physostigmine-induced accumulation but had no effect on the basal accumulation. Tetrodotoxin partially inhibited the physostigmine-induced [3H]IP1 accumulation but had no effect on the carbachol-induced accumulation. 4-Aminopyridine stimulated the basal [3H]IP1 accumulation and potentiated the physostigmine-induced accumulation. This potentiation was blocked by tetrodotoxin. The physostigmine dose-response curve for the stimulation of [3H]IP1 accumulation was similar to its dose-response curve to inhibit acetylcholinesterase activity in the neostriatum. The results suggest that, under our experimental conditions, the acetylcholine released spontaneously from intrinsic cholinergic neurons does not activate the striatal muscarinic receptors coupled to phosphoinositide breakdown unless the intrinsic acetylcholinesterases are inhibited.