title: Synergistic antidepressant-like action of gaboxadol and escitalopram.
abstract: According to current theories on the etiopathogenesis and pathophysiology of depression, both GABAergic and monoaminergic transmitter systems are perturbed. Consequently, the present study addressed the putative antidepressant action of the sedative-hypnotic GABAA receptor agonist, gaboxadol, separately and in combination with the selective serotonin reuptake inhibitor (SSRI) escitalopram. The rat chronic mild stress model was used to test the chronic antidepressant properties of gaboxadol in this depression model. Sucrose intake used as a read-out on anhedonic-like behavior indicated that the drug response rate for gaboxadol (5 mg/kg/day, i.p.) was similar to that measured for escitalopram (5 mg/kg/day, i.p.), however, the rate increased when the two drugs were co-administered, suggesting a synergistic action. Using in vivo electrophysiological recordings in dorsal raphe nucleus (DRN) of anesthetised rats, the present results showed that one week treatment with gaboxadol (5 mg/kg/day, i.p.) or with escitalopram (5 mg/kg/day, i.p.), followed by a 24 h washout period, did not affect DRN 5-HT neuronal firing per se, but in rats treated with both drugs for one week, the firing rate of DRN 5-HT neurons was significantly increased. Immunohistochemical estimations of cell proliferation in the hippocampal dentate gyrus did not reveal any effect of gaboxadol on chronic mild stressed rats, indicating that neurogenesis per se is not systematically associated with recovery from anhedonic-like behavior. Taken together, our data reveal for the first time an antidepressant action of gaboxadol and indicate a synergistic mechanism, regarding rapid onset of action and efficacy, when co-administered with escitalopram.
authors.affiliation: Centre for Psychiatric Research, Aarhus University Hospital, Skovagervej 2, 8240 Risskov, Denmark.
authors.forename: Trine
authors.initials: T
authors.lastname: Christensen
authors.forename: Cécile
authors.initials: C
authors.lastname: Bétry
authors.forename: Ouissame
authors.initials: O
authors.lastname: Mnie-Filali
authors.forename: Adeline
authors.initials: A
authors.lastname: Etievant
authors.forename: Bjarke
authors.initials: B
authors.lastname: Ebert
authors.forename: Nasser
authors.initials: N
authors.lastname: Haddjeri
authors.forename: Ove
authors.initials: O
authors.lastname: Wiborg
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D015283:Citalopram / Q000494:pharmacology / Q000627:therapeutic use*; D018891:Dentate Gyrus / Q000187:drug effects / Q000473:pathology; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004351:Drug Resistance; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D058785:GABA-A Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D011903:Raphe Nuclei / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D009435:Synaptic Transmission / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D015283:Citalopram; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; D017367:Selective Serotonin Reuptake Inhibitors; C015542:gaboxadol