Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, USA.
Nat Neurosci. 2011 Jul 24;14(9):1160-6. doi: 10.1038/nn.2874.
The presence and function of cannabinoid CB(2) receptors in the brain have been the subjects of much debate. We found that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB(2) receptor agonist, dose-dependently inhibited intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens extracellular dopamine in wild-type and CB(1) receptor knockout (CB(1)(-/-), also known as Cnr1(-/-)) mice, but not in CB(2)(-/-) (Cnr2(-/-)) mice. This inhibition was mimicked by GW405833, another CB(2) receptor agonist with a different chemical structure, and was blocked by AM630, a selective CB(2) receptor antagonist. Intra-accumbens administration of JWH133 alone dose-dependently decreased, whereas intra-accumbens administration of AM630 elevated, extracellular dopamine and locomotion in wild-type and CB(1)(-/-) mice, but not in CB(2)(-/-) mice. Intra-accumbens administration of AM630 also blocked the reduction in cocaine self-administration and extracellular dopamine produced by systemic administration of JWH133. These findings suggest that brain CB(2) receptors modulate cocaine's rewarding and locomotor-stimulating effects, likely by a dopamine-dependent mechanism.
大脑中大麻素 CB(2) 受体的存在和功能一直是争论的焦点。我们发现，全身性、鼻内或伏隔核内给予选择性 CB(2) 受体激动剂 JWH133，可剂量依赖性地抑制野生型和 CB(1) 受体敲除（CB(1)(-/-)，也称为 Cnr1(-/-)）小鼠的静脉可卡因自我给药、可卡因增强的运动和可卡因增强的伏隔核细胞外多巴胺，但不能抑制 CB(2)(-/-)（Cnr2(-/-)）小鼠。另一种具有不同化学结构的 CB(2) 受体激动剂 GW405833 模拟了这种抑制作用，而选择性 CB(2) 受体拮抗剂 AM630 则阻断了这种抑制作用。单独给予伏隔核内 JWH133 剂量依赖性地降低，而给予 AM630 剂量依赖性地增加，野生型和 CB(1)(-/-) 小鼠的细胞外多巴胺和运动，但不能增加 CB(2)(-/-) 小鼠的细胞外多巴胺和运动。伏隔核内给予 AM630 也阻断了全身性给予 JWH133 引起的可卡因自我给药减少和细胞外多巴胺增加。这些发现表明，大脑 CB(2) 受体调节可卡因的奖赏和运动刺激作用，可能通过多巴胺依赖的机制。
