Castañé Anna, Soria Guadalupe, Ledent Catherine, Maldonado Rafael, Valverde Olga
Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, C/Doctor Aiguader 80, 08003 Barcelona, Spain.
Neuropharmacology. 2006 Sep;51(3):631-40. doi: 10.1016/j.neuropharm.2006.05.005. Epub 2006 Jun 21.
The non-selective A2A antagonist caffeine has been reported to modify nicotine-induced locomotor and reinforcing effects. In the present study, we have investigated the specific role of A2A adenosine receptors in the behavioural responses induced by nicotine by using genetically modified mice lacking A2A adenosine receptors. Acute nicotine administration induced a similar decrease of locomotor activity in A2A knockout mice and wild-type littermates. Acute antinociceptive responses elicited by nicotine in the tail-immersion and hot-plate tests were unaffected in these mutant mice. The rewarding properties of nicotine were then investigated using the place-conditioning paradigm. Nicotine-induced conditioned place preference was suppressed in A2A knockout mice. Accordingly, in vivo microdialysis studies revealed that the extracellular levels of dopamine in the nucleus accumbens were not increased after nicotine administration in mutant mice. Wild-type and A2A knockout mice were trained in conditioned taste aversion procedure in which drinking a saccharin or saline solution was paired with nicotine or saline injections. A similar reduction in the intake of nicotine-paired solution in this paradigm was obtained in both genotypes. Finally, the administration of the nicotinic antagonist mecamylamine in nicotine-dependent mice precipitated a similar withdrawal syndrome in both genotypes. Together, the present results identify A2A adenosine receptors as an important factor that contributes to the rewarding properties of nicotine.
据报道，非选择性A2A拮抗剂咖啡因可改变尼古丁诱导的运动和强化作用。在本研究中，我们通过使用缺乏A2A腺苷受体的转基因小鼠，研究了A2A腺苷受体在尼古丁诱导的行为反应中的具体作用。急性给予尼古丁后，A2A基因敲除小鼠和野生型同窝小鼠的运动活动均出现类似程度的下降。在尾部浸入和热板试验中，尼古丁引发的急性抗伤害感受反应在这些突变小鼠中未受影响。然后使用条件性位置偏好范式研究尼古丁的奖赏特性。在A2A基因敲除小鼠中，尼古丁诱导的条件性位置偏好受到抑制。相应地，体内微透析研究表明，突变小鼠给予尼古丁后，伏隔核中多巴胺的细胞外水平并未升高。对野生型和A2A基因敲除小鼠进行条件性味觉厌恶训练，在此过程中，饮用糖精或盐溶液与注射尼古丁或盐水配对。在这两种基因型中，该范式下与尼古丁配对的溶液摄入量均出现类似程度的减少。最后，在尼古丁依赖的小鼠中给予烟碱拮抗剂美加明，两种基因型均出现类似的戒断综合征。总之，本研究结果表明A2A腺苷受体是促成尼古丁奖赏特性的一个重要因素。
