Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
Eur J Pharmacol. 2010 Dec 1;648(1-3):133-8. doi: 10.1016/j.ejphar.2010.09.006. Epub 2010 Sep 18.
The objective was to examine the time course of the cannabinoid 1 receptor antagonist/inverse agonist rimonabant's ability to antagonize in vivo cannabinergic agonist effects. We used two behavioral procedures sensitive to the effects of ∆⁹-tetrahydrocannabinol (∆⁹-THC): rat drug discrimination (EXP-1) and suppression of fixed-ratio responding (FR) for food reinforcement (EXP-2). Two training doses of ∆⁹-THC (1.8 and 3 mg/kg) served as discriminative cues in two groups discriminating ∆⁹-THC from vehicle; injections were i.p. 20 min before session onset. Tests assessed the dose-response functions of ∆⁹-THC and the time course for rimonabant in its ability to block the discriminative stimulus effects of ∆⁹-THC. For antagonism testing, the training doses of ∆⁹-THC were used and the rimonabant dose was 1mg/kg. Tests were 20, 60, 120, and 240 min post rimonabant administration; ∆⁹-THC was always administered 20 min prior to testing. For EXP-2, only one response lever was activated and every 10th (FR-10) press on that lever resulted in food delivery. Once the response rate stabilized, tests occurred with ∆⁹-THC, rimonabant and combinations of the drugs. The ED(50) estimates for the dose-response functions were 0.38 (±0.28-0.51) and 0.50 (±0.40-0.63) mg/kg for the training doses of 1.8 and 3 mg/kg ∆⁹-THC, respectively. The time course studies suggested functional half-life estimates of 128.4 (±95.7-172.2) and 98.4 (±64.2-150.7) min by rimonabant for the two groups in EXP-1, respectively. Similarly, the functional half-life of rimonabant was 118.9 (±66.1-213.9) min in EXP-2. Thus, antagonism of ∆⁹-THC by rimonabant is relatively short lasting.
目的是研究大麻素 1 受体拮抗剂/反向激动剂利莫那班拮抗体内大麻素激动剂效应的时间过程。我们使用了两种对 ∆⁹-四氢大麻酚（∆⁹-THC）效应敏感的行为程序：大鼠药物辨别（EXP-1）和固定比例反应（FR）食物强化的抑制（EXP-2）。两个训练剂量的 ∆⁹-THC（1.8 和 3 mg/kg）作为两组辨别 ∆⁹-THC 与载体的辨别线索；注射在开始前 20 分钟进行。测试评估了 ∆⁹-THC 的剂量反应函数以及利莫那班阻断 ∆⁹-THC 辨别刺激效应的时间过程。对于拮抗作用测试，使用了训练剂量的 ∆⁹-THC，利莫那班的剂量为 1mg/kg。测试在利莫那班给药后 20、60、120 和 240 分钟进行；∆⁹-THC 总是在测试前 20 分钟给药。对于 EXP-2，只有一个反应杆被激活，每按压 10 次（FR-10）就会得到食物。一旦反应率稳定，就会进行 ∆⁹-THC、利莫那班和药物组合的测试。训练剂量为 1.8 和 3 mg/kg ∆⁹-THC 的剂量反应函数的 ED（50）估计值分别为 0.38（±0.28-0.51）和 0.50（±0.40-0.63）mg/kg。时间过程研究表明，利莫那班在 EXP-1 中的两个组的功能半衰期估计值分别为 128.4（±95.7-172.2）和 98.4（±64.2-150.7）分钟。类似地，利莫那班在 EXP-2 中的功能半衰期为 118.9（±66.1-213.9）分钟。因此，利莫那班拮抗 ∆⁹-THC 的作用相对短暂。
