title: The α2C-adrenoceptor antagonist, ORM-10921, exerts antidepressant-like effects in the Flinders Sensitive Line rat.
abstract: Depression involves deficits in monoaminergic neurotransmission. Differential roles for α2A, B and C subtypes of the α2-adrenoceptor (AR) are evident, with selective α2C-AR antagonists purported to have antidepressant and procognitive properties. However, this has not been demonstrated in a genetic animal model of depression. The role of the α2C-AR in modulating two key depression-related behaviours in the Flinders Sensitive Line (FSL) rat was studied using a dose-response analysis following subcutaneous administration with the selective α2C-AR antagonist ORM-10921 (0.03; 0.3 mg/kg), the nonselective α2-AR antagonist idazoxan (3 mg/kg), or vehicle once daily for 14 days. Behaviour in the novel object recognition test, forced swim test (FST) and locomotor activity test was assessed. To ratify the validity of the FSL model, the reference tricyclic antidepressant imipramine (15 mg/kg, intraperitoneally) was used as a comparator drug in the FST. FSL rats demonstrated significantly increased immobility and recognition memory deficits versus Flinders Resistant Line controls, with imipramine significantly reversing said immobility. Similarly, ORM-10921 at both doses but not idazoxan significantly reversed immobility in the FST as well as attenuated cognitive deficits in FSL animals. We conclude that selective α2C-AR antagonism has potential as a novel therapeutic strategy in the treatment of depression and cognitive dysfunction.
authors.affiliation: aDivision of Pharmacology, School of Pharmacy and bCenter of Excellence for Pharmaceutical Sciences, North-West University (Potchefstroom Campus), Potchefstroom, South Africa cOrion Pharma, Orion Corporation, Nottingham, UK dOrion Pharma, Orion Corporation, Turku, Finland.
authors.forename: Madeleine M
authors.initials: MM
authors.lastname: Uys
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shahid
authors.forename: Jukka
authors.initials: J
authors.lastname: Sallinen
authors.forename: Brian H
authors.initials: BH
authors.lastname: Harvey
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology*; D060825:Cognitive Dysfunction / Q000188:drug therapy / Q000503:physiopathology; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019329:Idazoxan / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D054837:Quinolizidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D013550:Swimming
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000928:Antidepressive Agents; D001572:Benzofurans; C587546:ORM-10921; D054837:Quinolizidines; D007099:Imipramine; D019329:Idazoxan