Therapeutic Potential of Selectively Targeting the α_2C-Adrenoceptor in Cognition, Depression, and Schizophrenia-New...

α_2A- and α_2C-adrenoceptors (ARs) are the primary α₂-AR subtypes involved in central nervous system (CNS) function. These receptors are implicated in the pathophysiology of psychiatric illness, particularly those associated with affective, psychotic, and cognitive symptoms. Indeed, non-selective α₂-AR blockade is proposed to contribute toward antidepressant (e.g., mirtazapine) and atypical antipsychotic (e.g., clozapine) drug action. Both α_2C- and α_2A-AR share autoreceptor functions to exert negative feedback control on noradrenaline (NA) release, with α_2C-AR heteroreceptors regulating non-noradrenergic transmission (e.g., serotonin, dopamine). While the α_2A-AR is widely distributed throughout the CNS, α_2C-AR expression is more restricted, suggesting the possibility of significant differences in how these two receptor subtypes modulate regional neurotransmission. However, the α_2C-AR plays a more prominent role during states of low endogenous NA activity, while the α_2A-AR is relatively more engaged during states of high noradrenergic tone. Although augmentation of conventional antidepressant and antipsychotic therapy with non-selective α₂-AR antagonists may improve therapeutic outcome, animal studies report distinct yet often opposing roles for the α_2A- and α_2C-ARs on behavioral markers of mood and cognition, implying that non-selective α₂-AR antagonism may compromise therapeutic utility both in terms of efficacy and side-effect liability. Recently, several highly selective α_2C-AR antagonists have been identified that have allowed deeper investigation into the function and utility of the α_2C-AR. ORM-13070 is a useful positron emission tomography ligand, ORM-10921 has demonstrated antipsychotic, antidepressant, and pro-cognitive actions in animals, while ORM-12741 is in clinical development for the treatment of cognitive dysfunction and neuropsychiatric symptoms in Alzheimer's disease. This review will emphasize the importance and relevance of the α_2C-AR as a neuropsychiatric drug target in major depression, schizophrenia, and associated cognitive deficits. In addition, we will present new prospects and future directions of investigation.