NEURONAL INJURY PRODUCED BY NMDA ANTAGONISTS CAN BE DETECTED USING HEAT-SHOCK PROTEINS AND CAN BE BLOCKED WITH ANTIPSYCHOTICS

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, inclu ding ketamine, MK-801, and phencyclidine (PCP), induce the HSP70 heat shock or stress gene in pyramidal neurons in rat posterior cingulate a nd retrosplenial cortex. PCP also induces HSP70 in many other pyramida l neurons in brain including neocortex, insular cortex, piriform corte x, hippocampus, and basal nuclei of the amygdala. Several neurotransmi tter antagonists, including haloperidol, clozapine, SCH-22390, diazepa m, and muscimol, inhibited induction of HSP70 produced by PCP. Baclofe n had no effect. Nifedipine blocked induction of HSP70 by PCP in cingu late, neocortex, and insular cortex but only partially blocked HSP70 i n piriform cortex and amygdala. These data suggest that phencyclidine injures pyramidal neurons via dopamine D-1, D-2, D-4, sigma, and other receptors. Gamma-aminobutyric acid (GABA) agonists ameliorate the inj ury. A model is proposed whereby NMDA receptor blockade on GABA neuron s decreases inhibitory inputs onto cortical pyramidal neurons and make s them more vulnerable to injury from a variety of excitatory inputs. It is possible that psychosis produced by PCP and other NMDA antagonis ts correlates with overactivity and eventual injury to cingulate pyram idal neurons.