Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, USA.
Br J Pharmacol. 2019 May;176(9):1268-1281. doi: 10.1111/bph.14625. Epub 2019 Apr 3.
Endocannabinoids are critically involved in brain reward functions, mediated by activation of CB receptors, reflecting their high density in the brain. However, the recent discovery of CB receptors in the brain, particularly in the midbrain dopamine neurons, has challenged this view and inspired us to re-examine the roles of both CB and CB receptors in the effects of cannabis.
In the present study, we used the electrical intracranial self-stimulation paradigm to evaluate the effects of various cannabinoid drugs on brain reward in laboratory rats and the roles of CB and CB receptors activation in brain reward function(s).
Two mixed CB / CB receptor agonists, Δ -tetrahydrocannabinol (Δ -THC) and WIN55,212-2, produced biphasic effects-mild enhancement of brain-stimulation reward (BSR) at low doses but inhibition at higher doses. Pretreatment with a CB receptor antagonist (AM251) attenuated the low dose-enhanced BSR, while a CB receptor antagonist (AM630) attenuated high dose-inhibited BSR. To confirm these opposing effects, rats were treated with selective CB and CB receptor agonists. These compounds produced significant BSR enhancement and inhibition, respectively.
CB receptor activation produced reinforcing effects, whereas CB receptor activation was aversive. The subjective effects of cannabis depend on the balance of these opposing effects. These findings not only explain previous conflicting results in animal models of addiction but also explain why cannabis can be either rewarding or aversive in humans, as expression of CB and CB receptors may differ in the brains of different subjects.
内源性大麻素通过激活 CB 受体在大脑奖赏功能中起关键作用，这反映了它们在大脑中的高浓度。然而，最近在大脑中发现了 CB 受体，特别是在中脑多巴胺神经元中，这一观点受到了挑战，并激发我们重新审视大麻素在大麻素作用中的作用。
在本研究中，我们使用电颅内自我刺激范式来评估各种大麻素药物对实验室大鼠大脑奖赏的影响，以及 CB 和 CB 受体激活在大脑奖赏功能中的作用。
两种混合的 CB / CB 受体激动剂，Δ -四氢大麻酚（Δ -THC）和 WIN55,212-2，产生了双相作用 - 在低剂量时轻度增强脑刺激奖励（BSR），但在高剂量时抑制。CB 受体拮抗剂（AM251）预处理减弱了低剂量增强的 BSR，而 CB 受体拮抗剂（AM630）减弱了高剂量抑制的 BSR。为了证实这些相反的作用，用选择性 CB 和 CB 受体激动剂处理大鼠。这些化合物分别产生了显著的 BSR 增强和抑制作用。
CB 受体的激活产生了强化作用，而 CB 受体的激活则是厌恶的。大麻的主观效果取决于这些相反作用的平衡。这些发现不仅解释了以前在成瘾动物模型中的相互矛盾的结果，而且还解释了为什么大麻在人类中既可以是奖赏性的，也可以是厌恶的，因为不同个体的大脑中 CB 和 CB 受体的表达可能不同。
