Rationale

Cannabinoid type 1 receptors (CB1Rs) are widely expressed within the brain’s reward circuits and are implicated in regulating drug induced behavioral adaptations. Understanding how CB1R signaling in discrete circuits and cell types contributes to drug-related behavior provides further insight into the pathology of substance use disorders.

Objective and methods

We sought to determine how cell type–specific expression of CB1Rs within striatal circuits contributes to cocaine-induced behavioral plasticity, hypothesizing that CB1R function in distinct striatal neuron populations would differentially impact behavioral outcomes. We crossed conditional Cnr1^fl/fl mice and striatal output pathway cre lines (Drd1a –cre; D1, Adora2a –cre; A2a) to generate cell type–specific CB1R knockout mice and assessed their performance in cocaine locomotor and associative behavioral assays.

Results

Both knockout lines retained typical locomotor activity at baseline. D1-Cre x Cnr1^fl/fl mice did not display hyperlocomotion in response to acute cocaine dosing, and both knockout lines exhibited blunted locomotor activity across repeated cocaine doses. A2a-cre Cnr1^fl/fl, mice did not express a preference for cocaine paired environments in a two-choice place preference task.

Conclusions

This study aids in mapping CB1R-dependent cocaine-induced behavioral adaptations onto distinct striatal neuron subtypes. A reduction of cocaine-induced locomotor activation in the D1- and A2a-Cnr1 knockout mice supports a role for CB1R function in the motor circuit. Furthermore, a lack of preference for cocaine-associated context in A2a-Cnr1 mice suggests that CB1Rs on A2a-neuron inhibitory terminals are necessary for either reward perception, memory consolidation, or recall. These results direct future investigations into CB1R-dependent adaptations underlying the development and persistence of substance use disorders.

中文翻译：

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A2a 神经元中的大麻素 1 型受体有助于可卡因与环境的关联

基本原理

大麻素 1 型受体 (CB1Rs) 在大脑的奖赏回路中广泛表达，并与调节药物诱导的行为适应有关。了解离散电路和细胞类型中的 CB1R 信号如何促成药物相关行为，可以进一步了解物质使用障碍的病理学。

目的和方法

我们试图确定纹状体回路中 CB1R 的细胞类型特异性表达如何促进可卡因诱导的行为可塑性，假设不同纹状体神经元群体中的 CB1R 功能会不同地影响行为结果。我们将条件 C nr1 ^fl/fl小鼠和纹状体输出通路 cre 系（Drd1a – cre；D1，Adora2a – cre ； A2a ）杂交以产生细胞类型特异性 CB1R 敲除小鼠，并评估它们在可卡因运动和关联行为测定中的表现。

结果

两个敲除线在基线时都保留了典型的运动活动。D1-Cre x Cnr1 ^fl/fl小鼠对急性可卡因给药没有表现出过度运动，并且两个基因敲除系在重复可卡因剂量下表现出迟钝的运动活动。A2a-cre Cnr1 ^fl/fl，小鼠在二选一地点偏好任务中没有表现出对可卡因配对环境的偏好。

结论

这项研究有助于将依赖 CB1R 的可卡因诱导的行为适应映射到不同的纹状体神经元亚型上。D1 和 A2a -Cnr1敲除小鼠中可卡因诱导的运动激活的减少支持 CB1R 功能在运动回路中的作用。此外，A2a- Cnr1小鼠对可卡因相关环境缺乏偏好表明，A2a-神经元抑制末端的 CB1R 对于奖赏感知、记忆巩固或回忆都是必要的。这些结果指导未来对物质使用障碍发展和持续存在的 CB1R 依赖性适应的调查。