Apparent affinity estimates of rimonabant in combination with anandamide and chemical analogs of anandamide in rhesus monkeys discriminating Delta9-tetrahydrocannabinol.
Apparent affinity estimates of rimonabant in combination with anandamide and chemical analogs of anandamide in rhesus monkeys discriminating Delta9-tetrahydrocannabinol.
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DOI：
10.1007/s00213-008-1230-8
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发表时间：
2009-04
影响因子：
3.4
通讯作者：
McMahon LR
中科院分区：
文献类型：
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作者：
McMahon LR
Anandamide和Δ9-tetrahydrocannabinol （Δ9-THC）有时会产生不同的区别性刺激效应，因此，它们的作用机制似乎有所不同。为了了解大麻的广泛使用和大麻素的治疗潜力，需要确定负责行为影响的机制。采用药物鉴别法比较Δ9-THC、阿南达明和阿南达明两种结构类似物对恒河猴的作用机制。猴子区分出Δ9-THC （0.1 mg/kg静脉注射）。Δ9-THC, anandamide， methanandamide和花生四烯基环丙酰胺（ACPA）单独静脉注射，并与至少一剂利莫那班联合使用。使用Schild分析和单剂量表观亲和估计来估计利莫那班作为每种大麻素拮抗剂的效力；将这些值进行比较，以检验相同的受体是否介导了区别刺激效应。Δ9-THC， ACPA， methanandamide和anandamide在Δ9-THC杠杆上产生了大于96%的反应。Δ9-THC的ED50值为0.024 mg/kg， ACPA为0.14 mg/kg，甲胺为0.28 mg/kg， anandamide为1.7 mg/kg。Δ9-THC的作用时间为4 ~ 6 h，比ACPA、甲胺和阿南达胺的作用时间更长（即均小于50 min）。利莫那班可明显拮抗各激动剂的特异性刺激作用，其表观亲和值（pA2和pKB值）为6.24 ~ 6.83。利莫那班不仅可以对Δ9-THC，还可以对阿南达胺、甲南达胺和ACPA的行为效应产生可克服的拮抗作用，并且相互作用表现为简单、竞争性和可逆的。这些大麻素激动剂作用于相同的受体产生区别刺激效应。
Anandamide and Δ9-tetrahydrocannabinol (Δ9-THC) sometimes produce different discriminative stimulus effects and, therefore, appear to differ in their mechanism of action. In order to understand the widespread use of cannabis and the therapeutic potential of cannabinoids, mechanisms responsible for behavioral effects need to be identified. Drug discrimination was used to compare the mechanism of action of Δ9-THC, anandamide, and two structural analogs of anandamide in rhesus monkeys. Monkeys discriminated Δ9-THC (0.1 mg/kg i.v.) from vehicle. Δ9-THC, anandamide, methanandamide, and arachidonylcyclopropylamide (ACPA) were administered i.v. alone and in combination with at least one dose of rimonabant. Schild analysis and single-dose apparent affinity estimates were used to estimate the potency of rimonabant as an antagonist of each cannabinoid; these values were compared to examine whether the same receptors mediated discriminative stimulus effects. Δ9-THC, ACPA, methanandamide, and anandamide produced greater than 96% of responses on the Δ9-THC lever. The ED50 values were 0.024 mg/kg for Δ9-THC, 0.14 mg/kg for ACPA, 0.28 mg/kg for methanandamide, and 1.7 mg/kg for anandamide. The duration of action of Δ9-THC was 4–6 h and longer than the duration of action ACPA, methanandamide, and anandamide (i.e., each less than 50 min). Rimonabant surmountably antagonized the discriminative stimulus effects of each agonist, and the apparent affinity estimates (pA2 and pKB values) were 6.24–6.83. Rimonabant can produce surmountable antagonism of the behavioral effects of not only Δ9-THC but also anandamide, methanandamide, and ACPA, and the interactions appear simple, competitive, and reversible. These cannabinoid agonists act at the same receptors to produce discriminative stimulus effects.