Serotonergic agents that activate 5HT(2A) receptors prevent NMDA antagonist neurotoxicity

Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5 HT(2A) agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It is proposed that 5HT(2A) agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT(2A) agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogeniced activity to agonist action at 5HT(2C) receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT(2A) receptors.