Phencyclidine-induced locomotor hyperactivity is enhanced in mice after stereotaxic brain serotonin depletion.

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.

Study at a glance

Abstract

The aim of this study was to investigate the role of forebrain serotonin projections in behavioural models with relevance to schizophrenia. Mice received stereotaxic micro-injections of the serotonin neurotoxin 5,7-dihydroxytryptamine into the median raphe nucleus (MRN). Two weeks later, MRN-lesioned mice were hyperactive at baseline and showed enhanced locomotor hyperactivity induced by phencyclidine. In contrast, no lesion effect was observed on the locomotor hyperactivity induced by amphetamine treatment or on prepulse inhibition. Lesioned mice showed a 68% depletion of serotonin in the hippocampus and 31% depletion in the striatum. These data confirm previous studies in rats that selective serotonin depletion in the brain enhances the effect of phencyclidine, but not amphetamine, on locomotor activity. This enhanced action of phencyclidine is likely to be mediated by the absence of serotonin-mediated behavioural inhibition in the hippocampus, leaving the psychostimulant effects of phencyclidine unopposed. Taken together with previous studies in rats, these studies in mice suggest that serotonin release in the dorsal hippocampus constitutes a behavioural inhibitory pathway normally involved in dampening excessive behavioural stimulation. Dysfunction of this pathway could be involved in psychosis and its stimulation could be a potential mechanism of action of antipsychotic drugs.