Depleting serotonin in the forebrain of mice, specifically by destroying serotonin neurons projecting from the median raphe nucleus, made the animals hyperactive at baseline and increased their hyperactivity response to phencyclidine, a drug that can induce psychosis-like behaviors. The same lesion did not affect hyperactivity caused by amphetamine or a measure of sensorimotor gating called prepulse inhibition. Serotonin levels dropped by 68% in the hippocampus and 31% in the striatum. These results, consistent with earlier rat studies, suggest that serotonin release in the dorsal hippocampus normally dampens excessive behavioral stimulation. Disruption of this pathway may contribute to psychosis, and enhancing it could be a mechanism for antipsychotic drugs.
A reduced level of the alpha7-nicotinic acetylcholine receptor in certain brain areas may contribute to sensory and movement deficits in schizophrenia and might be a necessary condition for the disorder. This has led to interest in drugs that activate this receptor. In a mouse model, the drug anabasine, a selective alpha7-nicotinic receptor agonist, reduced popping behavior caused by MK-801 (a drug that mimics schizophrenia-like symptoms) at a dose that did not cause seizures. The findings suggest potential therapeutic benefit for schizophrenia, but also highlight the need to consider seizure risk.
Phencyclidine (PCP) produces a psychotic reaction in humans that closely resembles an acute episode of schizophrenia, making it a valuable model for the disorder. This review examines the behavioral and neurochemical effects of PCP in both humans and animals, comparing them with those of amphetamine where possible. It discusses the roles of dopamine and NMDA/PCP receptors in mediating PCP-induced psychosis and emphasizes the importance of selecting behavioral models that capture the expression of psychosis rather than just the motor effects of psychotomimetic drugs.