Soria Guadalupe, Castañé Anna, Ledent Catherine, Parmentier Marc, Maldonado Rafael, Valverde Olga
Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
Neuropsychopharmacology. 2006 May;31(5):978-87. doi: 10.1038/sj.npp.1300876.
Adenosine is an endogenous purine nucleoside, which acts as a neuromodulator in the central nervous system. A2A adenosine and D2 dopamine receptors are colocalized in the same neurons in discrete brain areas, and the dopaminergic transmission plays a crucial role in the addictive properties of drugs of abuse, such as cocaine. In the present study, we have investigated the specific role of A2A adenosine receptors in cocaine-induced behavioral responses related to its addictive properties. For this purpose, we have evaluated the acute locomotor effects produced by cocaine and the development of locomotor sensitization by repeated cocaine administration. In addition, we have also examined cocaine acute rewarding properties using the conditioned place preference. Finally, we used the intravenous drug self-administration paradigm to investigate the acquisition of an operant response maintained by cocaine self-administration and the reinforcing efficacy of the drug in these knockout animals. Acute cocaine induced a similar increase of locomotor activity in mice lacking A2A adenosine receptors and wild-type littermates. Cocaine-induced locomotor sensitization and conditioned place preference were also maintained in A2A knockout mice. Nevertheless, these knockout mice showed a lower rate of cocaine self-administration than wild-type mice in both fixed ratio 1 and 3 schedules of reinforcement. Moreover, a reduction in the maximal effort to obtain a cocaine infusion was found in A2A knockout mice under a progressive ratio schedule. In addition, a vertical shift of the cocaine dose-response curve was observed in mice lacking A2A adenosine receptors in comparison with wild-type littermates. Our study demonstrates that A2A adenosine receptors play an important role in cocaine addictive properties, and these receptors seem to be required to develop the addictive effects of this drug.
腺苷是一种内源性嘌呤核苷，在中枢神经系统中作为神经调质发挥作用。A2A 腺苷受体和 D2 多巴胺受体在离散脑区的同一神经元中共定位，多巴胺能传递在滥用药物（如可卡因）的成瘾特性中起关键作用。在本研究中，我们研究了 A2A 腺苷受体在与可卡因成瘾特性相关的行为反应中的具体作用。为此，我们评估了可卡因产生的急性运动效应以及重复给予可卡因后运动敏化的发展。此外，我们还使用条件性位置偏爱试验检测了可卡因的急性奖赏特性。最后，我们采用静脉注射药物自我给药范式，研究了在这些基因敲除动物中，由可卡因自我给药维持的操作性反应的习得以及该药物的强化效力。急性给予可卡因后，缺乏 A2A 腺苷受体的小鼠和野生型同窝小鼠的运动活性增加程度相似。可卡因诱导的运动敏化和条件性位置偏爱在 A2A 基因敲除小鼠中也得以维持。然而，在固定比率 1 和 3 的强化程序中，这些基因敲除小鼠的可卡因自我给药率均低于野生型小鼠。此外，在渐进比率程序下，发现 A2A 基因敲除小鼠获取一次可卡因注射的最大努力程度降低。另外，与野生型同窝小鼠相比，缺乏 A2A 腺苷受体的小鼠的可卡因剂量 - 反应曲线发生了垂直位移。我们的研究表明，A2A 腺苷受体在可卡因成瘾特性中起重要作用，这些受体似乎是该药物产生成瘾效应所必需的。
