Fluoxetine prevents PCP- and MK801-induced HSP70 expression in injured limbic cortical neurons of rats.

NMDA receptor antagonists like PCP and MK801 produce schizophrenia-like psychosis in humans and damage neurons in the cingulate and retrosplenial cortices of rat brains. Pretreating female rats with the SSRI fluoxetine (20 mg/kg) one hour before MK801 prevented the expression of heat shock protein HSP70, a marker of neuronal injury, in those brain regions. Fluoxetine at 10 or 20 mg/kg also prevented HSP70 induction by PCP. Fluoxetine prevents the neurotoxicity of NMDA receptor antagonists in rat brain, suggesting SSRIs could modulate psychosis and offering a model to study the link between PCP's hallucinogenic properties and those of LSD.

Study at a glance

Abstract

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. 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). 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. 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.