HALOPERIDOL PREVENTS KETAMINE-INDUCED AND PHENCYCLIDINE-INDUCED HSP70PROTEIN EXPRESSION BUT NOT MICROGLIAL ACTIVATION

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, inclu ding ketamine and phencyclidine (PCP), produce abnormal intracellular vacuoles in posterior cingulate and retrosplenial cortical neurons in the rat, Ketamine also induces 70-kDa heat shock protein (HSP70) expre ssion in pyramidal neurons in the posterior cingulate and retrosplenia l cortex and, as shown by this study, activates microglia in the retro splenial cortex of the rat, Whereas HSP70 protein expression was induc ed with ketamine doses of 40 mg/kg (ip) and higher, doses of 80 mg/kg and higher were required to activate microglia, HSP70-positive neurons were observed in 30- to 90-day-old rats but not in younger, 10- to 20 -day-old animals following ketamine (80 mg/kg, ip), Pretreatment with the antipsychotic drug haloperidol at doses of 1.0 mg/kg and above abo lished all HSP70 immunostaining produced by ketamine (80 mg/kg), Howev er, a single dose of haloperidol (5 mg/kg, im) did not decrease the nu mber of microglia activated in retrosplenial cortex by ketamine (80-14 0 mg/kg), Similarly, PCP (10 and 50 mg/kg, ip)-induced microglial acti vation in the posterior cingulate and retrosplenial cortex of adult ra ts was not blocked by haloperidol (10 mg/kg, im, 1 h prior to PCP), Th ese results suggest that ketamine and PCP injure neurons in the poster ior cingulate and retrosplenial cortex of adult rats, Though haloperid ol may afford some protection against this injury since it inhibits in duction of HSP70 expression, the failure to prevent microglial activat ion suggests that single doses of haloperidol do not completely protec t neurons from NMDA antagonist toxicity. (C) 1996 Academic Press, Inc.