Mice lacking the serotonin Htr 2B receptor gene present an antipsychotic-sensitive schizophrenic-like phenotype

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Abstract

Impulsivity and hyperactivity share common ground with numerous mental disorders, including schizophrenia. Recently, a population-specific serotonin 2B (5-HT 2B) receptor stop codon (ie, HTR2B Q20∗) was reported to segregate with severely impulsive individuals, whereas 5-HT 2B mutant (Htr 2B -/-) mice also showed high impulsivity. Interestingly, in the same cohort, early-onset schizophrenia was more prevalent in HTR2B Q∗20 carriers. However, the putative role of 5-HT 2B receptor in the neurobiology of schizophrenia has never been investigated. We assessed the effects of the genetic and the pharmacological ablation of 5-HT 2B receptors in mice subjected to a comprehensive series of behavioral test screenings for schizophrenic-like symptoms and investigated relevant dopaminergic and glutamatergic neurochemical alterations in the cortex and the striatum. Domains related to the positive, negative, and cognitive symptom clusters of schizophrenia were affected in Htr 2B -/- mice, as shown by deficits in sensorimotor gating, in selective attention, in social interactions, and in learning and memory processes. In addition, Htr 2B -/- mice presented with enhanced locomotor response to the psychostimulants dizocilpine and amphetamine, and with robust alterations in sleep architecture. Moreover, ablation of 5-HT 2B receptors induced a region-selective decrease of dopamine and glutamate concentrations in the dorsal striatum. Importantly, selected schizophrenic-like phenotypes and endophenotypes were rescued by chronic haloperidol treatment. We report herein that 5-HT 2B receptor deficiency confers a wide spectrum of antipsychotic-sensitive schizophrenic-like behavioral and psychopharmacological phenotypes in mice and provide first evidence for a role of 5-HT 2B receptors in the neurobiology of psychotic disorders.

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Pitychoutis, P. M., Belmer, A., Moutkine, I., Adrien, J., & Maroteaux, L. (2015). Mice lacking the serotonin Htr 2B receptor gene present an antipsychotic-sensitive schizophrenic-like phenotype. Neuropsychopharmacology, 40(12), 2764–2773. https://doi.org/10.1038/npp.2015.126

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