Abstract
α2A- and α2C-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 α2C- and α2A-AR share autoreceptor functions to exert negative feedback control on noradrenaline (NA) release, with α2C-AR heteroreceptors regulating non-noradrenergic transmission (e.g., serotonin, dopamine). While the α2A-AR is widely distributed throughout the CNS, α2C-AR expression is more restricted, suggesting the possibility of significant differences in how these two receptor subtypes modulate regional neurotransmission. However, the α2C-AR plays a more prominent role during states of low endogenous NA activity, while the α2A-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 α2A- and α2C-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 α2C-AR antagonists have been identified that have allowed deeper investigation into the function and utility of the α2C-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 α2C-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.
Highlights
The α2-adrenoceptor (AR) plays an important role in modulating the release of noradrenaline (NA) and various other important neurotransmitters in the central nervous system (CNS), providing a solid construct why drugs that target these receptors have clinical utility in several major neuropsychiatric disorders [1]
The aforementioned findings were predominantly from acute studies, we recently reported that chronic ORM-10921 reduced forced swim test (FST) immobility time in the Flinders Sensitive Line (FSL) rat, a genetic rodent model of major depressive disorder (MDD) [21]
This study found that selective α2C-AR antagonism reversed deficits in novel object recognition memory in FSL rats, constituting the first findings for a pro-cognitive effect of a selective α2C-AR antagonist using an illness-specific construct-driven translational model of MDD
Summary
The α2-adrenoceptor (AR) plays an important role in modulating the release of noradrenaline (NA) and various other important neurotransmitters in the central nervous system (CNS), providing a solid construct why drugs that target these receptors have clinical utility in several major neuropsychiatric disorders [1]. The α2- (and α1-) AR plays a prominent role in the functioning of the prefrontal cortex (PFC) and as such mediates the effect of normal, aroused, and stressed NA levels on memory and other cognitive processes [2] To this end α2-AR antagonists mianserin and mirtazapine have seen widespread use in the therapy of major depressive disorder (MDD), while almost all atypical antipsychotics display moderate to potent levels of α2-AR antagonism, which has been suggested to underlie the atypical profile of antipsychotics such as clozapine, quetiapine, risperidone, and asenapine [3, 4]. Before the availability of sufficiently subtype-selective ligands, evidence from transgenic mouse studies have indicated a potential therapeutic role for selective antagonism of the α2C-AR in MDD, schizophrenia and associated cognitive impairment [16]. Prefrontal cortical networks regulating various aspects of attention, cognition, and emotion require optimal catecholamine signaling, including stimulation of postsynaptic α2-ARs by NA to regulate “top-down” control of the
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