Role of CB2 Cannabinoid Receptors in the Rewarding, Reinforcing, and Physical Effects of Nicotine
Role of CB2 Cannabinoid Receptors in the Rewarding, Reinforcing, and Physical Effects of Nicotine
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DOI：
10.1038/npp.2013.157
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发表时间：
2013-11-01
影响因子：
7.6
通讯作者：
Manzanares, Jorge
中科院分区：
文献类型：
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作者：
Navarrete, Francisco;Rodriguez-Arias, Marta;Manzanares, Jorge
本研究旨在探讨CB2大麻素受体(CB2R)参与尼古丁的奖赏、增强和兴奋作用。用CB2R拮抗剂AM630(1 mg/kg和3 mg/kg)对CB2R基因敲除小鼠(CB2KO)和野生型(WT)小鼠进行条件性位置偏爱(CPP)和静脉给药实验。用免疫组织化学方法检测腹侧被盖区(VTA)酪氨酸羟基酶(TH)、α3-和α4-烟碱型乙酰胆碱受体亚单位(NAChRs)的基因表达，以及CB2R是否与α3-和α4-nAChRs共存于伏隔核和VTA。在给予AM630(1 mg/kg和3 mg/kg)治疗的CB2KO小鼠和WT小鼠中，评估了慢性尼古丁暴露后的甲氨基乙胺催促戒断综合征。CB2KO小鼠没有表现出尼古丁诱导的位置条件反射，自身给药的尼古丁显著减少。此外，AM630还能阻断(3 mg/kg)尼古丁诱导的CPP，并减少(1 mg/kg和3 mg/kg)尼古丁的自身给药。在基线条件下，CB2KO小鼠VTA中TH、α3-nAChR和α4-nAChR的mRNA水平显著低于WT小鼠。共聚焦显微镜图像显示CB2R与α3-和α4-nAChRs共定位。尼古丁戒断的躯体迹象(后背、新郎、抓挠、牙齿颤抖和身体颤抖)在WT组显著增加，但在CB2KO小鼠中则没有。有趣的是，给药AM630阻止了尼古丁戒断综合症，并未能改变生理盐水处理的WT小鼠的基本行为。这些结果表明，CB2R在尼古丁的奖赏、增强和激励作用中发挥着相关的作用。该受体的药理操作值得进一步考虑，作为治疗尼古丁依赖的潜在新的有价值的靶点。
This study was aimed to evaluate the involvement of CB2 cannabinoid receptors (CB2r) in the rewarding, reinforcing and motivational effects of nicotine. Conditioned place preference (CPP) and intravenous self-administration experiments were carried out in knockout mice lacking CB2r (CB2KO) and wild-type (WT) littermates treated with the CB2r antagonist AM630 (1 and 3 mg/kg). Gene expression analyses of tyrosine hydroxylase (TH) and alpha 3-and alpha 4-nicotinic acetylcholine receptor subunits (nAChRs) in the ventral tegmental area (VTA) and immunohistochemical studies to elucidate whether CB2r colocalized with alpha 3-and alpha 4-nAChRs in the nucleus accumbens and VTA were performed. Mecamylamine-precipitated withdrawal syndrome after chronic nicotine exposure was evaluated in CB2KO mice and WT mice treated with AM630 (1 and 3 mg/kg). CB2KO mice did not show nicotine-induced place conditioning and selfadministered significantly less nicotine. In addition, AM630 was able to block (3 mg/kg) nicotine-induced CPP and reduce (1 and 3 mg/kg) nicotine self-administration. Under baseline conditions, TH, alpha 3-nAChR, and alpha 4-nAChR mRNA levels in the VTA of CB2KO mice were significantly lower compared with WT mice. Confocal microscopy images revealed that CB2r colocalized with alpha 3-and alpha 4-nAChRs. Somatic signs of nicotine withdrawal (rearings, groomings, scratches, teeth chattering, and body tremors) increased significantly in WT but were absent in CB2KO mice. Interestingly, the administration of AM630 blocked the nicotine withdrawal syndrome and failed to alter basal behavior in saline-treated WT mice. These results suggest that CB2r play a relevant role in the rewarding, reinforcing, and motivational effects of nicotine. Pharmacological manipulation of this receptor deserves further consideration as a potential new valuable target for the treatment of nicotine dependence.