Uys Madeleine Monique, Shahid Mohammed, Harvey Brian Herbert
Division of Pharmacology, Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.
Orion Pharma, Orion Corporation, Nottingham, United Kingdom.
Front Psychiatry. 2017 Aug 14;8:144. doi: 10.3389/fpsyt.2017.00144. eCollection 2017.
α- and α-adrenoceptors (ARs) are the primary α-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 α-AR blockade is proposed to contribute toward antidepressant (e.g., mirtazapine) and atypical antipsychotic (e.g., clozapine) drug action. Both α- and α-AR share autoreceptor functions to exert negative feedback control on noradrenaline (NA) release, with α-AR heteroreceptors regulating non-noradrenergic transmission (e.g., serotonin, dopamine). While the α-AR is widely distributed throughout the CNS, α-AR expression is more restricted, suggesting the possibility of significant differences in how these two receptor subtypes modulate regional neurotransmission. However, the α-AR plays a more prominent role during states of low endogenous NA activity, while the α-AR is relatively more engaged during states of high noradrenergic tone. Although augmentation of conventional antidepressant and antipsychotic therapy with non-selective α-AR antagonists may improve therapeutic outcome, animal studies report distinct yet often opposing roles for the α- and α-ARs on behavioral markers of mood and cognition, implying that non-selective α-AR antagonism may compromise therapeutic utility both in terms of efficacy and side-effect liability. Recently, several highly selective α-AR antagonists have been identified that have allowed deeper investigation into the function and utility of the α-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-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.
α1和α2肾上腺素能受体（ARs）是参与中枢神经系统（CNS）功能的主要α-AR亚型。这些受体与精神疾病的病理生理学有关，特别是那些与情感、精神病性和认知症状相关的疾病。事实上，非选择性α-AR阻断被认为有助于抗抑郁药（如米氮平）和非典型抗精神病药（如氯氮平）的药物作用。α1和α2-AR都具有自身受体功能，对去甲肾上腺素（NA）释放发挥负反馈控制，α2-AR异受体调节非去甲肾上腺素能传递（如5-羟色胺、多巴胺）。虽然α1-AR广泛分布于整个中枢神经系统，但α2-AR的表达更为局限，这表明这两种受体亚型调节区域神经传递的方式可能存在显著差异。然而，α2-AR在内源性NA活性较低的状态下发挥更突出的作用，而α1-AR在去甲肾上腺素能张力较高的状态下相对更活跃。虽然用非选择性α-AR拮抗剂增强传统抗抑郁药和抗精神病药治疗可能改善治疗效果，但动物研究报告α1和α2-AR在情绪和认知行为标志物上具有不同但往往相反的作用，这意味着非选择性α-AR拮抗作用可能在疗效和副作用方面损害治疗效用。最近，已鉴定出几种高选择性α2-AR拮抗剂，这使得对α2-AR的功能和效用有了更深入的研究。ORM-13070是一种有用的正电子发射断层扫描配体，ORM-10921在动物中已显示出抗精神病、抗抑郁和促认知作用，而ORM-12741正在进行治疗阿尔茨海默病认知功能障碍和神经精神症状的临床开发。本综述将强调α2-AR作为重度抑郁症、精神分裂症和相关认知缺陷的神经精神药物靶点的重要性和相关性。此外，我们将介绍新的前景和未来的研究方向。
