Soria Guadalupe, Mendizábal Victoria, Touriño Clara, Robledo Patricia, 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. 2005 Sep;30(9):1670-80. doi: 10.1038/sj.npp.1300707.
Acute rewarding properties are essential for the establishment of cocaine addiction, and multiple neurochemical processes participate in this complex behavior. In the present study, we used the self-administration paradigm to evaluate the role of CB1 cannabinoid receptors in several aspects of cocaine reward, including acquisition, maintenance, and motivation to seek the drug. For this purpose, both CB1 receptor knockout mice and wild-type littermates were trained to intravenously self-administer cocaine under different schedules. Several cocaine training doses (0.32, 1, and 3.2 mg/kg/infusion) were used in the acquisition studies. Only 25% of CB1 knockout mice vs 75% of their wild-type littermates acquired a reliable operant responding to self-administer the most effective dose of cocaine (1 mg/kg/infusion), and the number of sessions required to attain this behavior was increased in knockout mice. Animals reaching the acquisition criteria were evaluated for the motivational strength of cocaine as a reinforcer under a progressive ratio schedule. The maximal effort to obtain a cocaine infusion was significantly reduced after the genetic ablation of CB1 receptors. A similar result was obtained after the pharmacological blockade of CB1 receptors with SR141716A in wild-type mice. Moreover, the cocaine dose-response curve was flattened in the knockout group, suggesting that the differences observed between genotypes were related to changes in the reinforcing efficacy of the training dose of cocaine. Self-administration for water and food was not altered in CB1 knockout mice in any of the reinforcement schedules used, which emphasizes the selective impairment of drug reinforcement in these knockout mice. Finally, cocaine effects on mesolimbic dopaminergic transmission were evaluated by in vivo microdialysis in these mice. Acute cocaine administration induced a similar enhancement in the extracellular levels of dopamine in the nucleus accumbens of both CB1 knockout and wild-type mice. This work clearly demonstrates that CB1 receptors play an important role in the consolidation of cocaine reinforcement, although are not required for its acute effects on mesolimbic dopaminergic transmission.
急性奖赏特性对于可卡因成瘾的形成至关重要，多种神经化学过程参与了这一复杂行为。在本研究中，我们使用自我给药范式来评估CB1大麻素受体在可卡因奖赏的多个方面所起的作用，包括获取、维持以及寻求药物的动机。为此，我们训练CB1受体基因敲除小鼠和野生型同窝小鼠在不同给药方案下静脉内自我给药可卡因。在获取研究中使用了几种可卡因训练剂量（0.32、1和3.2毫克/千克/输注）。只有25%的CB1基因敲除小鼠与75%的野生型同窝小鼠学会了对自我给药最有效剂量的可卡因（1毫克/千克/输注）做出可靠的操作性反应，并且基因敲除小鼠达到这一行为所需的实验次数增加。达到获取标准的动物在累进比率方案下被评估可卡因作为强化物的动机强度。CB1受体基因缺失后，获取一次可卡因输注的最大努力显著降低。在野生型小鼠中用SR141716A对CB1受体进行药理学阻断后也得到了类似结果。此外，基因敲除组的可卡因剂量-反应曲线变平，这表明不同基因型之间观察到的差异与可卡因训练剂量的强化效力变化有关。在所用的任何强化方案中，CB1基因敲除小鼠对水和食物的自我给药均未改变，这强调了这些基因敲除小鼠中药物强化的选择性损伤。最后，通过对这些小鼠进行体内微透析来评估可卡因对中脑边缘多巴胺能传递的影响。急性给予可卡因在CB1基因敲除小鼠和野生型小鼠的伏隔核细胞外多巴胺水平上均诱导了类似的升高。这项工作清楚地表明，CB1受体在可卡因强化巩固中起重要作用，尽管其对中脑边缘多巴胺能传递的急性作用并不需要CB1受体。
