The present study demonstrated that administration of nicotine prevented glutamate-induced motor neuronal death in primary cultures of the rat spiral cord. The nicotine-induced neuroprotection was inhibited by either dihydro-beta-erythroidin (DHPE) or alpha-bungarotoxin (alpha BT), suggesting that it is mediated through both alpha 4 beta 2 and alpha 7 nicotinic acetylcholine receptors (nAChRs). Both alpha 4 beta 2 and alpha 7 nAChRs were identified on rat spinal motor neurons by immunohistochemical methods. We also demonstrated that galantamine, an acetylcholinesterase inhibitor with allosteric nAChR-potentiating ligand properties, prevented glutamate-induced motor neuronal death. These results suggest that stimulation of nAChR may be used as a treatment for ALS. (c) 2005 Elsevier Inc. All rights reserved.