The effect of the cholinesterase inhibitor neostigmine on hippocampal noradrenaline (NA) release was studied using in vivo microdialysis. Local application of neostigmine significantly increased the release of NA. The effect was potentiated by coperfusion of the nicotinic antagonist mecamylamine but was completely blocked by the muscarinic antagonist atropine. The neostigmine-evoked NA release was not affected by the M2-selective muscarinic antagonist gallamine but was completely blocked by the M1-selective muscarinic antagonist pirenzepine. While muscarinic antagonists had no effect on the resting release of NA, mecamylamine increased it. Our data indicate that acetylcholine can stimulate the hippocampal NA release via M1 muscarinic receptors and that a population of nicotinic receptors mediate inhibitory tone on hippocampal NA release. The fact that neostigmine is able to enhance both cholinergic and noradrenergic neurotransmission may help to understand the beneficial effect of cholinesterase inhibitors in Alzheimer's disease.