Wright Sherie R, Zanos Panos, Georgiou Polymnia, Yoo Ji-Hoon, Ledent Catherine, Hourani Susanna M, Kitchen Ian, Winsky-Sommerer Raphaelle, Bailey Alexis
Sleep, Chronobiology and Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, UK.
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Belgium.
Addict Biol. 2016 Jul;21(4):811-25. doi: 10.1111/adb.12259. Epub 2015 May 15.
Addiction to psychostimulants is a major public health problem with no available treatment. Adenosine A2A receptors (A2A R) co-localize with metabotropic glutamate 5 receptors (mGlu5 R) in the striatum and functionally interact to modulate behaviours induced by addictive substances, such as alcohol. Using genetic and pharmacological antagonism of A2A R in mice, we investigated whether A2A R-mGlu5 R interaction can regulate the locomotor, stereotypic and drug-seeking effect of methamphetamine and cocaine, two drugs that exhibit distinct mechanism of action. Genetic deletion of A2A R, as well as combined administration of sub-threshold doses of the selective A2A R antagonist (SCH 58261, 0.01 mg/kg, i.p.) with the mGlu5 R antagonist, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (0.01 mg/kg, i.p.), prevented methamphetamine- but not cocaine-induced hyperactivity and stereotypic rearing behaviour. This drug combination also prevented methamphetamine-rewarding effects in a conditioned-place preference paradigm. Moreover, mGlu5 R binding was reduced in the nucleus accumbens core of A2A R knockout (KO) mice supporting an interaction between these receptors in a brain region crucial in mediating addiction processes. Chronic methamphetamine, but not cocaine administration, resulted in a significant increase in striatal mGlu5 R binding in wild-type mice, which was absent in the A2A R KO mice. These data are in support of a critical role of striatal A2A R-mGlu5 R functional interaction in mediating the ambulatory, stereotypic and reinforcing effects of methamphetamine but not cocaine-induced hyperlocomotion or stereotypy. The present study highlights a distinct and selective mechanistic role for this receptor interaction in regulating methamphetamine-induced behaviours and suggests that combined antagonism of A2A R and mGlu5 R may represent a novel therapy for methamphetamine addiction.
精神兴奋剂成瘾是一个严重的公共卫生问题，目前尚无有效治疗方法。腺苷A2A受体（A2A R）与代谢型谷氨酸5受体（mGlu5 R）在纹状体中共定位，并在功能上相互作用，以调节成瘾物质（如酒精）诱导的行为。我们利用小鼠中A2A R的基因和药理学拮抗作用，研究了A2A R-mGlu5 R相互作用是否能调节甲基苯丙胺和可卡因的运动、刻板行为及觅药效应，这两种药物具有不同的作用机制。A2A R的基因缺失，以及亚阈值剂量的选择性A2A R拮抗剂（SCH 58261，0.01 mg/kg，腹腔注射）与mGlu5 R拮抗剂3-((2-甲基-4-噻唑基)乙炔基)吡啶（0.01 mg/kg，腹腔注射）联合给药，可预防甲基苯丙胺而非可卡因诱导的多动和刻板竖毛行为。这种药物组合还可在条件性位置偏爱范式中预防甲基苯丙胺的奖赏效应。此外，在A2A R基因敲除（KO）小鼠的伏隔核核心中，mGlu5 R结合减少，这支持了这些受体在介导成瘾过程的关键脑区中存在相互作用。慢性给予甲基苯丙胺而非可卡因，可导致野生型小鼠纹状体中mGlu5 R结合显著增加，而A2A R KO小鼠中则无此现象。这些数据支持纹状体A2A R-mGlu5 R功能相互作用在介导甲基苯丙胺的行走、刻板行为及强化效应中起关键作用，但对可卡因诱导的运动亢进或刻板行为无此作用。本研究突出了这种受体相互作用在调节甲基苯丙胺诱导行为中的独特和选择性机制作用，并表明A2A R和mGlu5 R的联合拮抗作用可能代表一种治疗甲基苯丙胺成瘾的新疗法。
