Non-competitive NMDA receptor antagonists like phencyclidine, ketamine, and MK801 cause psychosis in humans and damage the cingulate-retrosplenial cortex in adult rodents. This damage can be prevented by GABA-receptor agonists and antipsychotics such as haloperidol and clozapine. Injecting MK801 into the anterior thalamus reproduces the cortical injury, while injecting GABA-receptor agonists there prevents injury from systemic MK801. The authors suggest that inhibiting NMDA receptors on GABAergic thalamic reticular nucleus neurons may activate thalamocortical circuits that cause injury in animals and psychosis in humans, potentially contributing to schizophrenia.
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.