Genetic Versus Pharmacological Assessment of the Role of Cannabinoid Type 2 Receptors in Alcohol Reward-Related Behaviors.
Genetic Versus Pharmacological Assessment of the Role of Cannabinoid Type 2 Receptors in Alcohol Reward-Related Behaviors.
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大麻素 2 型受体在酒精奖励相关行为中作用的遗传与药理学评估。
DOI：
10.1111/acer.12894
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Chester,JuliaA
中科院分区：
文献类型：
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作者：
Powers,MatthewS;Breit,KristenR;Chester,JuliaA
背景新的证据表明，内源性大麻素系统（ECS）参与调节滥用药物的奖励效应。最近，大麻素受体2（CB 2 R）被证明在大脑奖赏回路中表达，并参与调节酒精的奖赏效应。方法采用CB 2配体和CB 2 R基因敲除（KO）小鼠，在两种成熟的行为模型中评估CB 2 R参与酒精奖赏相关行为：限制性2瓶选择饮酒和条件性位置偏好（CPP）。对于药理学研究，小鼠在行为测试前30分钟接受媒介物、CB 2 R激动剂JWH-133（10和20 mg/kg）或CB 2 R拮抗剂AM 630（10和20 mg/kg）的预处理。对于遗传学研究，将CB 2 R KO小鼠与野生型（WT）同窝对照小鼠进行比较。结果与WT小鼠相比，CB 2 R KO小鼠显示酒精诱导的CPP幅度增加。CB 2 R的激动或拮抗作用均不影响酒精摄入量或CPP的表达，CPP获得试验期间CB 2 R的拮抗作用也不影响CPP.ConclusionsThe CB 2 R KO CPP数据为CB 2 Rs参与酒精奖励相关行为的调节这一假设提供了部分支持。然而，CB 2 Rs的药理学操作并没有改变酒精在这里使用的酒精寻求模型中的奖励作用。这些结果突出了使用寿命KO模型观察到的作用的药理学验证的重要性。鉴于药物开发的持续努力，未来的研究应继续探索CB 2 R作为治疗酒精使用障碍的潜在神经生物学靶点的作用。
BackgroundEmerging evidence suggests that the endocannabinoid system (ECS) is involved in modulating the rewarding effects of abused drugs. Recently, the cannabinoid receptor 2 (CB2R) was shown to be expressed in brain reward circuitry and is implicated in modulating the rewarding effects of alcohol.MethodsCB2 ligands and CB2R knockout (KO) mice were used to assess CB2R involvement in alcohol reward‐related behavior in 2 well‐established behavioral models: limited‐access 2‐bottle choice drinking and conditioned place preference (CPP). For the pharmacological studies, mice received pretreatments of either vehicle, the CB2R agonist JWH‐133 (10 and 20 mg/kg) or the CB2R antagonist AM630 (10 and 20 mg/kg) 30 minutes before behavioral testing. For the genetic studies, CB2R KO mice were compared to wild‐type (WT) littermate controls.ResultsCB2R KO mice displayed increased magnitude of alcohol‐induced CPP compared to WT mice. Neither agonism nor antagonism of CB2R affected alcohol intake or the expression of CPP, and antagonism of CB2R during CPP acquisition trials also did not affect CPP.ConclusionsThe CB2R KO CPP data provide partial support for the hypothesis that CB2Rs are involved in the modulation of alcohol reward‐related behaviors. However, pharmacological manipulation of CB2Rs did not alter alcohol's rewarding effects in the alcohol‐seeking models used here. These results highlight the importance of pharmacological validation of effects seen with lifetime KO models. Given the ongoing efforts toward medications development, future studies should continue to explore the role of the CB2R as a potential neurobiological target for the treatment of alcohol use disorders.