N-methyl-D-aspartate (NMDA) antagonists have been investigated for therapeutic potential for a variety of neurological disorders. However, many NMDA antagonists produce undesirable psychotropic side effects in humans and neurotoxic effects in animals. In addition, NMDA antagonist-mediated neurotoxicity in the rat is exacerbated by co-exposure to cholinergic agonists. Olney, et al. (2004 SFN abstract 219.6) recently reported that anti-Alzheimer’s AChEI's exacerbate NMDA antagonist neurotoxicity. We assessed the neurotoxicity of four NMDA antagonists (MK-801, dextromethorphan, felbamate, or memantine) combined with two AChEIs (pyridostigmine and physostigmine) in adult female rats. Toxicity was assessed using Fluoro-Jade B (FJ-B) staining in the posterior cingulate and retrosplenial corticies (PC/RSC), areas highly sensitive to this toxicity. Memantine (25 mg/kg) was unexpectedly neurotoxic. For all NMDA antagonists, neither AChEI increased FJ-B staining. However, memantine and dextromethorphan were unexpect...