Haloperidol prevents ketamine- and phencyclidine-induced HSP70 protein 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) expression in pyramidal neurons in the posterior cingulate and retrosplenial cortex and, as shown by this study, activates microglia in the retrosplenial cortex of the rat. Whereas HSP70 protein expression was induced 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 abolished all HSP70 immunostaining produced by ketamine (80 mg/kg). However, a single dose of haloperidol (5 mg/kg, im) did not decrease the number of microglia activated in retrosplenial cortex by ketamine (80-140 mg/kg). Similarly, PCP (10 and 50 mg/kg, ip)-induced microglial activation in the posterior cingulate and retrosplenial cortex of adult rats was not blocked by haloperidol (10 mg/kg, im, 1 h prior to PCP). These results suggest that ketamine and PCP injure neurons in the posterior cingulate and retrosplenial cortex of adults rats. Though haloperidol may afford some protection against this injury since it inhibits induction of HSP70 expression, the failure to prevent microglial activation suggests that single doses of haloperidol do not completely protect neurons from NMDA antagonist toxicity.
Nakki
R
R
Department of Neurology, University of California and Veterans Affairs Medical Center, San Francisco, 94121, USA.
Nickolenko
J
J
Chang
J
J
Sagar
S M
SM
Sharp
F R
FR
D000818:Animals; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology*; D007150:Immunohistochemistry; D007649:Ketamine / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects*; D010622:Phencyclidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018840:HSP70 Heat-Shock Proteins; D007649:Ketamine; D010622:Phencyclidine; D006220:Haloperidol