Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype.
Impulsivity and hyperactivity share common ground with numerous mental disorders, including schizophrenia. Recently, a population-specific serotonin 2B (5-HT2B) receptor stop codon (ie, HTR2B Q20*) was reported to segregate with severely impulsive individuals, whereas 5-HT2B mutant (Htr2B(-/-)) 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-HT2B receptor in the neurobiology of schizophrenia has never been investigated. We assessed the effects of the genetic and the pharmacological ablation of 5-HT2B 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 Htr2B(-/-) mice, as shown by deficits in sensorimotor gating, in selective attention, in social interactions, and in learning and memory processes. In addition, Htr2B(-/-) mice presented with enhanced locomotor response to the psychostimulants dizocilpine and amphetamine, and with robust alterations in sleep architecture. Moreover, ablation of 5-HT2B 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-HT2B 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-HT2B receptors in the neurobiology of psychotic disorders.
INSERM UMR S-839, Université Pierre et Marie Curie-Paris6, Institut du Fer à Moulin, Paris, France.|Department of Biology and Center for Tissue Regeneration and Engineering, University of Dayton, Dayton, OH, USA.
Pothitos M
PM
Pitychoutis
INSERM UMR S-839, Université Pierre et Marie Curie-Paris6, Institut du Fer à Moulin, Paris, France.
Arnauld
A
Belmer
INSERM UMR S-839, Université Pierre et Marie Curie-Paris6, Institut du Fer à Moulin, Paris, France.
Imane
I
Moutkine
INSERM UMR S-975, Universite Pierre et Marie Curie-Paris6, Paris, France.
Joëlle
J
Adrien
INSERM UMR S-839, Université Pierre et Marie Curie-Paris6, Institut du Fer à Moulin, Paris, France.
Luc
http://orcid.org/0000-0002-9499-8603
L
Maroteaux
D000661:Amphetamine / Q000627:therapeutic use*; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D003213:Conditioning, Psychological / Q000187:drug effects; D003463:Cues; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D005239:Fear / Q000187:drug effects; D007266:Inhibition, Psychological; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D044403:Receptor, Serotonin, 5-HT2B / Q000172:deficiency* / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics*; D055139:Sensory Gating / Q000187:drug effects; D012919:Social Behavior; D014851:Wakefulness / Q000187:drug effects
D014150:Antipsychotic Agents; D044403:Receptor, Serotonin, 5-HT2B; D016291:Dizocilpine Maleate; D000661:Amphetamine