Mice lacking the serotonin-1A (5-HT(1A)) receptor showed enhanced hyperactivity in response to amphetamine, a model of the hyperdopaminergic state linked to psychosis. The response to MK-801, which models NMDA receptor hypoactivity, was unchanged. The effect of the hallucinogen 5-MeO-DMT was markedly reduced in the knockout mice. No changes were seen in sensory gating deficits induced by apomorphine, nor in the density of dopamine transporters or D1/D2 receptors. These results suggest that 5-HT(1A) receptors play a role in hallucinations and modulating dopamine activity, extending insight into their possible involvement in schizophrenia.
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.