RESEARCH REPORTSThe α2C-adrenoceptor antagonist, ORM-10921, exerts antidepressant-like effects in the Flinders Sensitive Line ratUys, Madeleine M.a; Shahid, Mohammedc; Sallinen, Jukkad; Harvey, Brian H.bAuthor Information 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 Correspondence to Brian H. Harvey, PhD, Center of Excellence for Pharmaceutical Sciences, MRC Unit on Stress and Anxiety Disorders, North-West University (Potchefstroom Campus), Hoffman Street, Potchefstroom 2520, South Africa E-mail: [email protected] Behavioural Pharmacology: February 2017 - Volume 28 - Issue 1 - p 9-18 doi: 10.1097/FBP.0000000000000261 Buy Metrics 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. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.