Pathomorphologic effects of N‐methyl‐D‐aspartate antagonists in the rat posterior ingulate/retrosplenial cerebral cortex: A review

This review discusses available information on the neurotoxicity of N‐methyl‐D‐aspartate (NMDA) antagonists in the posterior cingulate/retrosplenial (PC/RS) cortex of rats. NMDA antagonists block the NMDA receptor, a central nervous system ionotropic glutamate receptor, and are neuroprotective since they reduce injury in animal models of ischemia. There is interest in the development and use of NMDA antagonists in treating human cerebrovascular diseases. However, with certain NMDA antagonists, dose‐dependent vacuolization of neurons in the neuroanatomically localized PC/RS cortex occurs as a side effect in rats. NMDA antagonists that cause vacuolization also appear to induce heat shock protein expression and heightened glucose metabolism in the same cortical region. Electron microscopy has shown that after treatment with MK‐801 (dizocilpine maleate), a prototypic noncompetitive NMDA antagonist, the onset of vacuolization is very rapid. Additional studies with MK‐801 have indicated that susceptibility to vacuolization increases between 30 and 90 days of age. Histologic time course studies have demonstrated that as the dose of MK‐801 is increased, some vacuolated neurons become necrotic. Necrotic neurons are readily evident by light microscopy in routine preparations. At a given dose of MK‐801, neuronal necrosis is more extensive in female rats than male rats. Furthermore, necrosis increases along an anterior to posterior gradient within the susceptible PC/RS cortex. A number of compounds with varied central nervous system (CNS) pharmacologic activity (anticholinergics, GABAmimetics, antipsychotics, and general anesthetics) partially or completely prevent neuronal vacuolization. These data suggest a complex pathogenesis for NMDA antagonist‐mediated neurotoxicity and indicate variables which require consideration when designing and interpreting studies with these compounds. Since recent reports have described failure of some NMDA antagonists to produce these side effects, the issues discussed in this review may or may not apply to all NMDA antagonists.