Ballesteros-Yáñez Inmaculada, Castillo Carlos A, Merighi Stefania, Gessi Stefania
Department of Inorganic and Organic Chemistry and Biochemistry, School of Medicine, University of Castilla-La Mancha, Ciudad Real, Spain.
Department of Nursing, Physiotherapy and Occupational Therapy, School of Nursing and Physiotherapy, University of Castilla-La Mancha, Toledo, Spain.
Front Pharmacol. 2018 Jan 10;8:985. doi: 10.3389/fphar.2017.00985. eCollection 2017.
Adenosine receptors (AR) are a family of G-protein coupled receptors, comprised of four members, named A, A, A, and A receptors, found widely distributed in almost all human body tissues and organs. To date, they are known to participate in a large variety of physiopathological responses, which include vasodilation, pain, and inflammation. In particular, in the central nervous system (CNS), adenosine acts as a neuromodulator, exerting different functions depending on the type of AR and consequent cellular signaling involved. In terms of molecular pathways and second messengers involved, A and A receptors inhibit adenylyl cyclase (AC), through G proteins, while A and A receptors stimulate it through G proteins. In the CNS, A receptors are widely distributed in the cortex, hippocampus, and cerebellum, A receptors are localized mainly in the striatum and olfactory bulb, while A and A receptors are found at low levels of expression. In addition, AR are able to form heteromers, both among themselves (e.g., A/A), as well as with other subtypes (e.g., A/D), opening a whole range of possibilities in the field of the pharmacology of AR. Nowadays, we know that adenosine, by acting on adenosine A and A receptors, is known to antagonistically modulate dopaminergic neurotransmission and therefore reward systems, being A receptors colocalized in heteromeric complexes with D receptors, and A receptors with D receptors. This review documents the present state of knowledge of the contribution of AR, particularly A and A, to psychostimulants-mediated effects, including locomotor activity, discrimination, seeking and reward, and discuss their therapeutic relevance to psychostimulant addiction. Studies presented in this review reinforce the potential of A agonists as an effective strategy to counteract psychostimulant-induced effects. Furthermore, different experimental data support the hypothesis that A/D heterodimers are partly responsible for the psychomotor and reinforcing effects of psychostimulant drugs, such as cocaine and amphetamine, and the stimulation of A receptor is proposed as a potential therapeutic target for the treatment of drug addiction. The overall analysis of presented data provide evidence that excitatory modulation of A and A receptors constitute promising tools to counteract psychostimulants addiction.
腺苷受体（AR）是一类G蛋白偶联受体家族，由四个成员组成，分别命名为A1、A2A、A2B和A3受体，广泛分布于几乎所有人体组织和器官中。迄今为止，已知它们参与多种生理病理反应，包括血管舒张、疼痛和炎症。特别是在中枢神经系统（CNS）中，腺苷作为一种神经调节剂，根据AR的类型以及随之涉及的细胞信号传导发挥不同的功能。就所涉及的分子途径和第二信使而言，A1和A3受体通过G蛋白抑制腺苷酸环化酶（AC），而A2A和A2B受体则通过G蛋白刺激它。在中枢神经系统中，A1受体广泛分布于皮质、海马体和小脑中，A2A受体主要定位于纹状体和嗅球，而A2B和A3受体的表达水平较低。此外，AR能够自身之间（例如A1/A2A）以及与其他亚型（例如A2A/D2）形成异聚体，为AR药理学领域开启了一系列可能性。如今，我们知道腺苷通过作用于腺苷A2A和A2B受体，已知可拮抗调节多巴胺能神经传递，进而调节奖赏系统，因为A2A受体与D2受体共定位于异聚体复合物中，A2B受体与D3受体共定位于异聚体复合物中。本综述记录了AR，特别是A2A和A2B，对精神兴奋剂介导的效应（包括运动活性、辨别、寻求和奖赏）的贡献的当前知识状态，并讨论它们与精神兴奋剂成瘾的治疗相关性。本综述中呈现的研究强化了A2A激动剂作为抵消精神兴奋剂诱导效应的有效策略的潜力。此外，不同的实验数据支持这样的假设，即A2A/D2异二聚体部分负责精神兴奋剂药物（如可卡因和苯丙胺）的精神运动和强化作用，并且刺激A2A受体被提议作为治疗药物成瘾的潜在治疗靶点。对所呈现数据的整体分析提供了证据，表明对A2A和A2B受体进行兴奋性调节构成了对抗精神兴奋剂成瘾的有前景的工具。
