Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
J Pharmacol Exp Ther. 2010 Jul;334(1):347-56. doi: 10.1124/jpet.110.168435. Epub 2010 Apr 7.
Marijuana-dependent individuals report using marijuana to alleviate withdrawal, suggesting that pharmacotherapy of marijuana withdrawal could promote abstinence. To identify potential pharmacotherapies for marijuana withdrawal, this study first characterized rimonabant-induced Delta(9)-tetrahydrocannabinol (Delta(9)-THC) withdrawal in rhesus monkeys by using drug discrimination and directly observable signs. Second, drugs were examined for their capacity to modify cannabinoid withdrawal. Monkeys receiving chronic Delta(9)-THC (1 mg/kg/12 h s.c.) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) under a fixed ratio schedule of stimulus-shock termination. The discriminative stimulus effects of rimonabant were dose-dependent (ED(50) = 0.25 mg/kg) and accompanied by head shaking. In the absence of chronic Delta(9)-THC treatment (i.e., in nondependent monkeys), a larger dose (3.2 mg/kg) of rimonabant produced head shaking and tachycardia. Temporary discontinuation of Delta(9)-THC treatment resulted in increased responding on the rimonabant lever, head shaking, and activity during the dark cycle. The rimonabant discriminative stimulus was attenuated fully by Delta(9)-THC (at doses larger than mg/kg/12 h) and the cannabinoid agonist CP 55940 [5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol], and partially by the cannabinoid agonist WIN 55212-2 [(R)-(+)-[2, 3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and the alpha(2)-adrenergic agonist clonidine. In contrast, a benzodiazepine (diazepam) and monoamine agonist (cocaine) did not attenuate the rimonabant discriminative stimulus. Head shaking was attenuated by all test compounds. These results show that the discriminative stimulus effects of rimonabant in Delta(9)-THC-treated monkeys are a more pharmacologically selective measure of cannabinoid withdrawal than rimonabant-induced head shaking. These results suggest that cannabinoid and noncannabinoid (alpha(2)-adrenergic) agonists are potentially useful therapeutics for marijuana dependence inasmuch as they attenuate the subjective experience of Delta(9)-THC withdrawal.
大麻依赖者报告说使用大麻来缓解戒断症状，这表明对大麻戒断的药物治疗可能会促进戒除。为了确定大麻戒断的潜在药物治疗方法，本研究首先通过药物辨别和直接观察到的迹象来描述大麻素拮抗剂利莫那班诱导的 Δ9-四氢大麻酚（Δ9-THC）戒断在恒河猴中的作用。其次，研究了药物改变大麻素戒断的能力。接受慢性 Δ9-THC（1 mg/kg/12 h sc）治疗的猴子根据刺激-休克终止的固定比率时间表辨别出大麻素拮抗剂利莫那班（1 mg/kg iv）。利莫那班的辨别刺激作用呈剂量依赖性（ED50=0.25 mg/kg），并伴有摇头。在没有慢性 Δ9-THC 治疗（即非依赖性猴子）的情况下，较大剂量（3.2 mg/kg）的利莫那班引起摇头和心动过速。停止 Δ9-THC 治疗会导致对利莫那班杠杆的反应增加、摇头和暗周期的活动增加。利莫那班的辨别刺激完全被 Δ9-THC（剂量大于 1 mg/kg/12 h）和大麻素激动剂 CP 55940[5-（1,1-二甲基庚基）-2- [5-羟基-2-（3-羟基丙基）环己基]苯酚]以及部分被大麻素激动剂 WIN 55212-2[（R）-（+）-[2,3-二氢-5-甲基-3-（4-吗啉基甲基）吡咯烷并[1,2,3-de]-1,4-苯并恶嗪-6-基]-1-萘基甲酮甲磺酸盐]和 α2-肾上腺素能激动剂可乐定减弱。相比之下，苯二氮䓬（地西泮）和单胺激动剂（可卡因）不能减弱利莫那班的辨别刺激。所有测试化合物均减弱摇头。这些结果表明，与利莫那班诱导的摇头相比，在接受 Δ9-THC 治疗的猴子中，利莫那班的辨别刺激作用是大麻素戒断更具药理学选择性的测量。这些结果表明，大麻素和非大麻素（α2-肾上腺素能）激动剂可能对大麻依赖的治疗有用，因为它们减弱了 Δ9-THC 戒断的主观体验。
