title: Characterization of 5-HT(1A/1B)-/- mice: an animal model sensitive to anxiolytic treatments.
abstract: Selective serotonin (5-HT) re-uptake inhibitors (SSRIs) are commonly used in the treatment of generalized anxiety disorder in Humans. However, because only few animal models display overt anxious-like behavior, detailed preclinical studies of the anxiolytic properties of antidepressants are still lacking. Here, we studied the neurochemical and behavioral effects of a double 5-HT(1A/1B) receptor knockout in mice (5-HT(1A/1B)-/-) as compared to their wild-type littermates (5-HT(1A/1B)+/+). It is known that single deletion of either 5-HT(1A) or 5-HT(1B) receptor induces behavioral changes that are not correlated with differences in brain serotonergic tone. Deletion of both receptors resulted in (i) higher emotionality of animals, as observed in three unconditioned paradigms of anxiety (open field, elevated plus maze and novelty suppressed feeding tests); (ii) a ≈200% increase in the mean spontaneous firing rate of 5-HT neurons in the dorsal raphe nucleus (DRN) compared to 5-HT(1A/1B)+/+ mice; (iii) elevated basal dialysate levels of 5-HT in the DRN and frontal cortex; (iv) an exaggerated response to acute paroxetine administration in microdialysis experiments, and (v) increased basal core body temperature. These findings suggest that the deletion of both autoreceptors induces a strong anxious-like behavioral state associated with increased 5-HT neurotransmission. Interestingly, 5-HT(1A/1B)-/- mice are still sensitive to the acute administration of diazepam. Moreover, while deletion of both receptors impacted on the response to acute SSRI treatment in the forced swim test, anxiolytic-like effects of a chronic SSRI treatment were still observed in 5-HT(1A/1B)-/- mice. Thus, the 5-HT(1A/1B)-/- mouse model could be of great interest to unveil the mechanisms of action of the anxiolytic effects of SSRIs.
authors.affiliation: Univ Paris-Sud EA 3544, Faculté de Pharmacie, 5, rue JB Clément, Châtenay-Malabry Cedex F-92296, France. jean-philippe.guilloux@u-psud.fr
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Guilloux
authors.forename: Denis J P
authors.initials: DJ
authors.lastname: David
authors.forename: Lin
authors.initials: L
authors.lastname: Xia
authors.forename: Hai Thanh
authors.initials: HT
authors.lastname: Nguyen
authors.forename: Quentin
authors.initials: Q
authors.lastname: Rainer
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Guiard
authors.forename: Christelle
authors.initials: C
authors.lastname: Repérant
authors.forename: Thierry
authors.initials: T
authors.lastname: Deltheil
authors.forename: Miklos
authors.initials: M
authors.lastname: Toth
authors.forename: René
authors.initials: R
authors.lastname: Hen
authors.forename: Alain M
authors.initials: AM
authors.lastname: Gardier
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D001833:Body Temperature Regulation; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017374:Paroxetine / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000502:physiology*; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D014151:Anti-Anxiety Agents; D017374:Paroxetine; D012333:RNA, Messenger; D044282:Receptor, Serotonin, 5-HT1A; D044302:Receptor, Serotonin, 5-HT1B; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493231:Slc6a4 protein, mouse