title: S32212, a novel serotonin type 2C receptor inverse agonist/α2-adrenoceptor antagonist and potential antidepressant: II. A behavioral, neurochemical, and electrophysiological characterization.
abstract: The present studies characterized the functional profile of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide) (S32212), a combined serotonin (5-HT)(2C) receptor inverse agonist and α(2)-adrenoceptor antagonist that also possesses 5-HT(2A) antagonist properties (J Pharmacol Exp Ther 340:750-764, 2012). Upon parenteral and/or oral administration, dose-dependent (0.63-40.0 mg/kg) actions were observed in diverse procedures. Both acute and subchronic administration of S32212 reduced immobility time in a forced-swim test in rats. Acutely, it also suppressed marble burying and aggressive behavior in mice. Long-term administration of S32212 was associated with rapid (1 week) and sustained (5 weeks) normalization of sucrose intake in rats exposed to chronic mild stress and with elevated levels of mRNA encoding brain-derived neurotrophic factor in hippocampus and amygdala (2 weeks). S32212 accelerated the firing rate of adrenergic perikarya in the locus coeruleus and elevated dialysis levels of noradrenaline in the frontal cortex and hippocampus of freely moving rats. S32212 also elevated the frontocortical levels of dopamine and acetylcholine, whereas 5-HT, amino acids, and histamine were unaffected. These neurochemical actions were paralleled by "promnemonic" properties: blockade of scopolamine-induced deficits in radial maze performance and social recognition and reversal of delay-induced impairments in social recognition, social novelty discrimination, and novel object recognition. It also showed anxiolytic actions in a Vogel conflict procedure. Furthermore, in an electroencephalographic study of sleep architecture, S32212 enhanced slow-wave and rapid eye movement sleep, while decreasing waking. Finally, chronic administration of S32212 neither elevated body weight nor perturbed sexual behavior in male rats. In conclusion, S32212 displays a functional profile consistent with improved mood and cognitive performance, together with satisfactory tolerance.
authors.affiliation: Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125 Chemin de Ronde, 78290 Croissy/Seine, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Dekeyne
authors.forename: Mauricette
authors.initials: M
authors.lastname: Brocco
authors.forename: Florence
authors.initials: F
authors.lastname: Loiseau
authors.forename: Alain
authors.initials: A
authors.lastname: Gobert
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rivet
authors.forename: Benjamin
authors.initials: B
authors.lastname: Di Cara
authors.forename: Thomas I
authors.initials: TI
authors.lastname: Cremers
authors.forename: Gunnar
authors.initials: G
authors.lastname: Flik
authors.forename: Kevin C F
authors.initials: KC
authors.lastname: Fone
authors.forename: David J G
authors.initials: DJ
authors.lastname: Watson
authors.forename: Mariusz
authors.initials: M
authors.lastname: Papp
authors.forename: Trevor
authors.initials: T
authors.lastname: Sharp
authors.forename: Florence
authors.initials: F
authors.lastname: Serres
authors.forename: Raymond
authors.initials: R
authors.lastname: Cespuglio
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.forename: Johnny S W
authors.initials: JS
authors.lastname: Chan
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lavielle
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
mesh_terms: D000109:Acetylcholine / Q000032:analysis; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology*; D000374:Aggression / Q000187:drug effects; D000679:Amygdala / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D004298:Dopamine / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D006624:Hippocampus / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000032:analysis; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D012601:Scopolamine / Q000494:pharmacology; D012726:Sexual Behavior, Animal / Q000187:drug effects; D012890:Sleep / Q000187:drug effects / Q000502:physiology; D013550:Swimming
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D007211:Indoles; C571288:N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)-1,2-dihydro-3-H-benzo(e)indole-3-carboxamide; D010879:Piperazines; D044405:Receptor, Serotonin, 5-HT2C; D012601:Scopolamine; D000109:Acetylcholine; D004298:Dopamine; D009638:Norepinephrine