Lack of CB1 cannabinoid receptor impairs cocaine self-administration
Lack of CB1 cannabinoid receptor impairs cocaine self-administration
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DOI：
10.1038/sj.npp.1300707
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发表时间：
2005-09-01
影响因子：
7.6
通讯作者：
Valverde, O
中科院分区：
文献类型：
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作者：
Soria, G;Mendizábal, V;Valverde, O
急性奖励特性对于可卡因成瘾的建立至关重要，多种神经化学过程参与了这种复杂的行为。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励的几个方面的作用，包括获取、维持和寻求药物的动机。为此，CB1 受体敲除小鼠和野生型同窝小鼠都经过训练，在不同的时间表下静脉自我注射可卡因。习得研究中使用了几种可卡因训练剂量（0.32、1 和 3.2 mg/kg/输注）。与 75% 的野生型同窝小鼠相比，只有 25% 的 CB1 敲除小鼠获得了对自我施用最有效剂量的可卡因（1 毫克/千克/输注）做出可靠的操作反应，并且在敲除小鼠中实现这种行为所需的治疗次数有所增加。在渐进比例方案下，对达到获得标准的动物作为强化剂的可卡因的激励强度进行评估。 CB1 受体基因消除后，获得可卡因输注的最大努力显着减少。在野生型小鼠中用 SR141716A 药理学阻断 CB1 受体后，获得了类似的结果。此外，可卡因剂量反应曲线在基因敲除组中变平，表明基因型之间观察到的差异与可卡因训练剂量的增强功效的变化有关。在任何使用的强化方案中，CB1 敲除小鼠的水和食物的自我管理都没有改变，这强调了这些敲除小鼠中药物强化的选择性损害。最后，通过这些小鼠体内微透析评估可卡因对中脑边缘多巴胺能传递的影响。急性可卡因给药引起 CB1 敲除小鼠和野生型小鼠伏核细胞外多巴胺水平的类似增强。这项工作清楚地表明 CB1 受体在可卡因强化的巩固中发挥着重要作用，尽管其对中脑边缘多巴胺能传递的急性影响并不是必需的。
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.