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.

Therapeutic Potential of Selectively Targeting the α2C-Adrenoceptor in Cognition, Depression, and Schizophrenia—New Developments and Future Perspective

“…Acute administration of highly subtype-selective α 2C -AR antagonists, JP-1302 ( 17 ), ORM-10921 ( 18 , 21 ) and ORM-12741 ( 19 ) to Sprague Dawley and Han-Wistar rats was found to decrease immobility in the FST (see Table 2 ), providing evidence that selective α 2C -AR antagonism harbors therapeutic antidepressant effects. Although the aforementioned findings were predominantly from acute studies, we recently reported that chronic ORM-10921 reduced FST immobility time in the FSL rat, a genetic rodent model of MDD ( 21 ). Moreover, these effects were not seen with the non-selective α 2 -AR antagonist idazoxan ( 21 ).…”

“…The α 2A -AR is, therefore, the main α 2 -AR regulating 5-HT release and possibly 5-HT synthesis. Nevertheless, selective antagonism of the α 2C -AR could result in meaningful increases in 5-HT release and region-specific 5-HT synthesis (e.g., provoking serotonergic behaviours in Flinders Sensitive Line (FSL) rats ( 21 )), which may be of importance in various neuropsychiatric illnesses characterized by altered serotonergic neurotransmission, such as obsessive compulsive disorder, MDD, and schizophrenia. Confirmation of these findings using highly selective α 2C -AR subtype ligands and in appropriate animal models is, therefore, warranted (e.g., FSL rats; 21 ).…”

“…Although the aforementioned findings were predominantly from acute studies, we recently reported that chronic ORM-10921 reduced FST immobility time in the FSL rat, a genetic rodent model of MDD ( 21 ). Moreover, these effects were not seen with the non-selective α 2 -AR antagonist idazoxan ( 21 ). These findings constitute the first findings for an antidepressant-like effect of an α 2C -AR antagonist within a translational and pathological construct-driven approach ( 16 ).…”

“…The Novel Object Recognition Test (NORT) (see Cognitive Deficits Associated With MDD and Schizophrenia ) measures recognition memory and is reliant on hippocampal function, while both this cognitive parameter ( 120 , 121 ) and hippocampal function has been shown to be deficient in patients with MDD ( 93 ). Recently, an important role for the α 2C -AR in this test has been demonstrated in the FSL rat, using the selective α 2C -AR antagonist ORM-10921 in a chronic treatment paradigm ( 21 ). This study found that selective α 2C -AR antagonism reversed deficits in novel object recognition memory in FSL rats, constituting the first findings for a pro-cognitive effect of a selective α 2C -AR antagonist using an illness-specific construct-driven translational model of MDD.…”

“…Before the availability of sufficiently subtype-selective ligands, evidence from transgenic mouse studies have indicated a potential therapeutic role for selective antagonism of the α 2C -AR in MDD, schizophrenia and associated cognitive impairment ( 16 ). More recently, the availability of highly selective α 2C -AR antagonists for use in preclinical research has produced evidence confirming the antipsychotic-like, antidepressant-like, and pro-cognitive effects of this treatment strategy in animal models of schizophrenia and MDD ( 17 – 21 ). Genetic studies have also highlighted the potential involvement of the α 2C -AR in these neuropsychiatric illnesses, with evidence that genetic polymorphism of the α 2C -AR is associated with dysfunction in MDD ( 22 ), ADHD ( 23 ), and schizophrenia ( 24 ).…”