Neuronal Degeneration in the Cingulate Gyrus: NMDA Antagonists and Anticholinesterases

Abstract

Abstract : Neurotoxic mechanisms and interactions between NMDA antagonists and acetylcholinesterase inhibitors (AChEIs)/cholingeric agonists were investigated using patch clamp recordings in rat brain slices of posterior cingulate/retrosplenial cortices (PCC/RSC), Functional Observational Battery monitoring, and Fluoro-Jade B (FJ-B) neurodegeneration staining. We obtained direct evidence that NMDA-mediated excitatory postsynaptic currents (EPSCs) in interneurons are blocked by NMDA antagonists (MK-801), the first direct evidence for their hypothesized neurotoxic mechanism. Physostigmine and pilocarpine suppressed GABAergic inhibitory postsynaptic currents; MK-801 was additive to them. In vivo, MK-801 is more neurotoxic in older than younger rats: in PCC/RSC slices, NMDA-mediated EPSCs were more rapidly suppressed by MK-801 in adults, suggesting a mechanism for age differences. Ethanol had more complex effects, and younger rats were more sensitive. In vivo, MK-801 alone produced FJ-B-positive neurodegeneration in the PCC/RSC, whereas, when used alone, AChEIs pyridostigmine and physostigmine did not. These findings are relevant to prevention of nerve agent exposures: NMDA antagonist drugs (e.g. for pain, neuroprotection, or recreation (e.g., ethanol)) could be co-administered with AChEIs (e.g., for soman prophylaxis). To avoid unexpected synergistic neurotoxicity in humans, the potential for serious neurotoxic interactions must be carefully explored in animals.