Effects of neostigmine and atropine on basal and handling-induced acetylcholine output from ventral hippocampus.

The involvement of muscarinic autoreceptors in the regulation of hippocampal acetylcholine levels during acetylcholinesterase inhibition was examined by perfusing the acetylcholinesterase inhibitor neostigmine bromide (10, 100 or 1000 nM) alone and in the presence of the muscarinic receptor antagonist atropine methylnitrate (10 microM), in resting and behaviourally-activated animals. In resting animals, local perfusion of neostigmine caused a dose-dependent increase in acetylcholine levels. Coadministration of atropine did not affect basal levels in the presence of 10 nM neostigmine, but increased acetylcholine levels approximately four and 11-fold in the presence of 100 nM and 1000 nM neostigmine, respectively. In animals which were behaviourally activated by handling, acetylcholine levels increased two- to three-fold in the presence of all neostigmine concentrations. However, the handling-induced increase in acetylcholine levels was somewhat smaller with 1000 nM neostigmine as compared to 10 nM neostigmine. Atropine had no effect on handling-induced acetylcholine output in the presence of 10 nM neostigmine, but caused greater and longer increases in the presence of 100 nM and 1000 nM neostigmine. These data indicate that acetylcholine levels are greatly reduced by autoinhibition at higher levels of acetylcholine esterase inhibition. The handling-evoked increase in acetylcholine levels is only moderately affected by the level of acetylcholinesterase inhibition, despite the participation of autoreceptors in the handling effect at higher levels of acetylcholinesterase inhibition.