Molecular Targets and Medication Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, 251 Bayview Blvd, NIDA IRP, BRC Suite 200, Baltimore, MD 21224, USA; Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Molecular Targets and Medication Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, 251 Bayview Blvd, NIDA IRP, BRC Suite 200, Baltimore, MD 21224, USA.
Eur Neuropsychopharmacol. 2021 Feb;43:38-51. doi: 10.1016/j.euroneuro.2020.11.019. Epub 2020 Dec 15.
Cannabinoids produce both rewarding and aversive effects in humans and experimental animals. However, the mechanisms underlying these conflicting findings are unclear. Here we examined the potential involvement of CB and CB receptors in cannabinoid action using transgenic CB-knockout (CB-KO) and CB-knockout (CB-KO) mice. We found that Δ-tetrahydrocannabinol (Δ-THC) induced conditioned place preference at a low dose (1 mg/kg) in WT mice that was attenuated by deletion of the CB receptor. At 5 mg/kg, no subjective effects of Δ-THC were detected in WT mice, but CB-KO mice exhibited a trend towards place aversion and CB-KO mice developed significant place preferences. This data suggests that activation of the CB receptor is rewarding, while CBR activation is aversive. We then examined the nucleus accumbens (NAc) dopamine (DA) response to Δ-THC using in vivo microdialysis. Unexpectedly, Δ-THC produced a dose-dependent decrease in extracellular DA in WT mice, that was potentiated in CB-KO mice. However, in CB-KO mice Δ-THC produced a dose-dependent increase in extracellular DA, suggesting that activation of the CBR inhibits DA release in the NAc. In contrast, Δ-THC, when administered systemically or locally into the NAc, failed to alter extracellular DA in rats. Lastly, we examined the locomotor response to Δ-THC. Both CB and CB receptor mechanisms were shown to underlie Δ-THC-induced hypolocomotion. These findings indicate that Δ-THC's variable subjective effects reflect differential activation of cannabinoid receptors. Specifically, the opposing actions of CB and CB receptors regulate cannabis reward and aversion, with CB-mediated effects predominant in mice.
大麻素在人类和实验动物中既产生奖赏作用，也产生厌恶作用。然而，这些相互矛盾的发现背后的机制尚不清楚。在这里，我们使用转基因 CB 敲除 (CB-KO) 和 CB 敲除 (CB-KO) 小鼠，研究了大麻素作用中潜在的 CB 和 CB 受体参与情况。我们发现，Δ-四氢大麻酚 (Δ-THC) 在 WT 小鼠中以低剂量（1mg/kg）诱导条件性位置偏好，而 CB 受体缺失则减弱了这种作用。在 5mg/kg 时，WT 小鼠未检测到 Δ-THC 的主观效应，但 CB-KO 小鼠表现出对位置的厌恶趋势，而 CB-KO 小鼠则产生了显著的位置偏好。这些数据表明，CB 受体的激活是奖赏性的，而 CBR 激活是厌恶性的。然后，我们使用活体微透析法检查了 Δ-THC 对伏隔核（NAc）多巴胺（DA）的反应。出乎意料的是，Δ-THC 在 WT 小鼠中产生了剂量依赖性的细胞外 DA 减少，而在 CB-KO 小鼠中则增强了这种作用。然而，在 CB-KO 小鼠中，Δ-THC 产生了剂量依赖性的细胞外 DA 增加，表明 CBR 的激活抑制了 NAc 中的 DA 释放。相反，Δ-THC 无论是全身给药还是局部给药到 NAc，都不能改变大鼠的细胞外 DA。最后，我们检查了 Δ-THC 对运动的反应。CB 和 CB 受体机制都参与了 Δ-THC 诱导的运动减少。这些发现表明，Δ-THC 的可变主观效应反映了大麻素受体的不同激活。具体而言，CB 和 CB 受体的相反作用调节大麻素的奖赏和厌恶，而 CB 介导的作用在小鼠中占主导地位。
