Fluoxetine prevents PCP- and MK801-induced HSP70 expression in injured limbic cortical neurons of rats.
BACKGROUND
N-Methyl-D-aspartate (NMDA) receptor antagonists, including phencyclidine (PCP) and dizocilpine (MK801), cause schizophrenialike psychosis in humans, and produce vacuolated neurons in the cingulate and retrosplenial cortices of the rat brain. Since psychotically depressed patients and schizophrenic depressed patients may require treatment with selective serotonin reuptake inhibitors (SSRIs), it is of interest to examine the relationship between SSRIs and NMDA antagonist neurotoxicity.


METHODS
The neurotoxicity of PCP and MK801 was assessed using heat shock protein (HSP70) immunocytochemistry and HSP70 Western blots because HSP70 is expressed in the injured, vacuolated neurons. Female rats were given fluoxetine (0, 5, 10, and 20 mg/kg IP) followed 1 hour later by MK801 (1 mg/kg IP) or PCP (50 mg/kg IP).


RESULTS
Pretreatment with fluoxetine (20 mg/kg IP) 1 hour before MK801 prevented the induction of HSP70 by MK801 in the cingulate and retrosplenial cortices. Pretreatment with fluoxetine (10 or 20 mg/kg IP) 1 hour before PCP also prevented the HSP70 induction by PCP.


CONCLUSIONS
Fluoxetine prevents the neurotoxicity of NMDA receptor antagonists in rat brain. This suggests the possibility that SSRIs could modulate psychosis, and may provide a model for examining the link between the hallucinogenic properties of PCP and lysergic acid diethylamide.
Tomitaka
M
M
Department of Neurology, University of Cincinnati, Ohio 45267-0525, USA.
Tomitaka
S
S
Rajdev
S
S
Sharp
F R
FR
D000818:Animals; D015153:Blotting, Western; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D008163:Luminescent Measurements; D010622:Phencyclidine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012565:Schizophrenic Psychology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D005473:Fluoxetine; D018840:HSP70 Heat-Shock Proteins; D010622:Phencyclidine; D017367:Selective Serotonin Reuptake Inhibitors