Department of Psychology, Temple University, 265-67 Weiss Hall, 1701 North 13th Street, Philadelphia, PA 19122, USA.
Psychopharmacology (Berl). 2010 Jan;208(1):87-98. doi: 10.1007/s00213-009-1708-z. Epub 2009 Nov 10.
The aim of the study was to characterize in vivo the aminoalkylindoles WIN55,212-2 (WIN) and AM678 (naphthalen-1-yl(1-pentyl-1H-indol-3-yl)methanone) as cannabinoid receptor (CB(1)R) ligands using drug discrimination. Tests also involved delta(9)-tetrahydrocannabinol (THC) and R-(+)-methanandamide (mAEA), a metabolically stable analog of the endogenous ligand anandamide, as well as the CB(1)R selective antagonist/inverse agonist rimonabant; tests with ethanol assessed pharmacological specificity. We used two different drug discriminations (mAEA and THC) allowing us to explore potential differences in CB(1)R activation which could be attributed to variations in their respective CB(1)R signaling mechanisms.
There were two concurrently trained groups of rats. One group discriminated between i.p. injected vehicle and 10 mg/kg mAEA. The other group was trained to discriminate between vehicle and 1.8 mg/kg THC.
Dose generalization curves for AM678, WIN55,212-2, THC, and mAEA suggested the following rank order of potency: AM678 > WIN55,212-2 > or = THC > mAEA in both drug discrimination groups. Challenge by 1 mg/kg rimonabant resulted in shifts to the right of the generalization curves for the two aminoalkylindoles (4.4-fold for AM678 and 11.3-fold for WIN in the mAEA group, whereas for the THC group, the corresponding values were 13 and 2.6, respectively), suggesting surmountable antagonism. Ethanol did not generalize in either of the two groups, suggesting pharmacological specificity.
Data are congruent with the general observation that there is substantial overlap in the discriminative stimulus effects of CB(1)R ligands across different chemical classes. However, the quantitative differences in the interactions between the two aminoalkylindoles and rimonabant in the two discrimination groups suggest subtle variations in the ligand-receptor activation(s).
本研究旨在通过药物辨别实验，对 WIN55,212-2（WIN）和 AM678（萘-1-基（1-戊基-1H-吲哚-3-基）甲酮）这两种氨基烷基吲哚类化合物作为大麻素受体（CB（1）R）配体进行体内特征分析。实验还涉及到了 delta（9）-四氢大麻酚（THC）和 R-（+）-甲氧基乙酰胺（mAEA），后者是内源性配体大麻酰胺的代谢稳定类似物，以及 CB（1）R 选择性拮抗剂/反向激动剂利莫那班；乙醇实验评估了药物的药理特异性。我们使用了两种不同的药物辨别实验（mAEA 和 THC），这使我们能够探究 CB（1）R 激活的潜在差异，这些差异可能归因于它们各自的 CB（1）R 信号机制的变化。
有两组同时接受训练的大鼠。一组大鼠辨别腹腔注射的载体和 10mg/kg mAEA。另一组大鼠被训练辨别载体和 1.8mg/kg THC。
AM678、WIN55,212-2、THC 和 mAEA 的剂量概括曲线表明，在这两种药物辨别组中，以下化合物的效力顺序为：AM678＞WIN55,212-2≥THC＞mAEA。1mg/kg 利莫那班的挑战导致两种氨基烷基吲哚的概括曲线向右移位（在 mAEA 组中，AM678 为 4.4 倍，WIN 为 11.3 倍，而在 THC 组中，相应的值分别为 13 和 2.6），提示可克服的拮抗作用。在这两个组中，乙醇都没有概括，提示药物具有药理特异性。
数据与普遍观察结果一致，即不同化学类别的 CB（1）R 配体的辨别刺激效应有很大的重叠。然而，在这两个辨别组中，两种氨基烷基吲哚类化合物和利莫那班之间的相互作用的定量差异表明，配体-受体激活存在细微变化。
