Grup de Recerca en Neurobiologia del Comportament (GRNC), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
J Psychopharmacol. 2011 Apr;25(4):550-64. doi: 10.1177/0269881110389210. Epub 2011 Jan 24.
Adenosine is an endogenous purine nucleoside that plays a neuromodulatory role in the central nervous system. A2a adenosine receptors have been involved in reward-related processes, inflammatory phenomena and neurotoxicity reactions. In the present study, we investigated the role of A2a adenosine receptors on the acute pharmacological effects, reinforcement and neuroinflammation induced by MDMA administration. First, the acute effects of MDMA on body temperature, locomotor activity and anxiety-like responses were measured in A2a knockout mice and wild-type littermates. Second, MDMA reinforcing properties were evaluated using the intravenous self-administration paradigm. Finally, we assessed striatal astrogliosis and microgliosis as markers of MDMA neurotoxicity. Our results showed that acute MDMA produced a biphasic effect on body temperature and increased locomotor activity and anxiogenic-like responses in both genotypes. However, MDMA reinforcing properties were dramatically affected by the lack of A2a adenosine receptors. Thus, wild-type mice maintained MDMA self-administration under a fixed ratio 1 reinforcement schedule, whereas the operant response appeared completely abolished in A2a knockout mice. In addition, the MDMA neurotoxic regime produced an enhanced inflammatory response in striatum of wild-type mice, revealed by a significant increase in glial expression, whereas such activation was attenuated in mutant mice. This is the first report indicating that A2a adenosine receptors play a key role in reinforcement and neuroinflammation induced by the widely used psychostimulant.
腺苷是一种内源性嘌呤核苷，在中枢神经系统中发挥神经调质作用。A2a 腺苷受体参与与奖励相关的过程、炎症现象和神经毒性反应。在本研究中，我们研究了 A2a 腺苷受体在 MDMA 给药引起的急性药理作用、强化作用和神经炎症中的作用。首先，在 A2a 敲除小鼠和野生型同窝仔鼠中测量 MDMA 对体温、运动活性和焦虑样反应的急性影响。其次，使用静脉内自我给药范式评估 MDMA 的强化特性。最后，我们评估纹状体星形胶质细胞增生和小胶质细胞增生作为 MDMA 神经毒性的标志物。我们的结果表明，急性 MDMA 对体温产生双相作用，并增加两种基因型的运动活性和焦虑样反应。然而，A2a 腺苷受体的缺失显著影响 MDMA 的强化特性。因此，野生型小鼠在固定比率 1 强化方案下维持 MDMA 自我给药，而 A2a 敲除小鼠的操作反应完全被消除。此外，MDMA 神经毒性方案在野生型小鼠的纹状体中产生增强的炎症反应，表现为胶质表达显著增加，而在突变小鼠中这种激活被减弱。这是第一个表明 A2a 腺苷受体在广泛使用的精神兴奋剂引起的强化和神经炎症中发挥关键作用的报告。
