Haloperidol prevents induction of the hsp70 heat shock gene in neurons injured by phencyclidine (PCP), MK801, and ketamine.
The non-competitive NMDA receptor antagonists, PCP (phencyclidine), MK801, and ketamine produce psychosis in humans and abnormal vacuoles in posterior cingulate and retrosplenial rat cortical neurons. We show that PCP (> or = 5 mg/kg), MK801 (> or = 0.1 mg/kg), and ketamine (> 20 mg/kg) induce hsp70 mRNA and HSP70 heat shock protein in these vacuolated, injured neurons, and PCP also induces hsp70 in injured neocortical, piriform, and amygdala neurons. The PCP, MK801, and ketamine drug induced injury occurs in 30 day and older rats, but not in 0-20 day old rats, and is prevented by prior administration of the antipsychotic drugs haloperidol and rimcazole. Since haloperidol and rimcazole block dopamine and sigma receptors, and since M1 muscarinic cholinergic receptor antagonists also prevent the injury produced by PCP, MK801, and ketamine, future studies will be needed to determine whether dopamine, sigma, M1, or other receptors mediate the injury.
Sharp
F R
FR
Department of Neurology, University of California, San Francisco.
Butman
M
M
Wang
S
S
Koistinaho
J
J
Graham
S H
SH
Sagar
S M
SM
Noble
L
L
Berger
P
P
Longo
F M
FM
D000679:Amygdala / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D002227:Carbazoles / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007649:Ketamine / Q000494:pharmacology*; D007700:Kinetics; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D010622:Phencyclidine / Q000494:pharmacology*; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D015183:Restriction Mapping
D002227:Carbazoles; D006360:Heat-Shock Proteins; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D007649:Ketamine; D016291:Dizocilpine Maleate; C034931:rimcazole; D010622:Phencyclidine; D006220:Haloperidol