Discriminative stimulus functions of methanandamide and a†9-THC in rats: tests with aminoalkylindoles (WIN55,212-2 and AM678) and ethanol
Discriminative stimulus functions of methanandamide and a†9-THC in rats: tests with aminoalkylindoles (WIN55,212-2 and AM678) and ethanol
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DOI：
10.1007/s00213-009-1708-z
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发表时间：
2010-01-01
影响因子：
3.4
通讯作者：
Makriyannis, Alexandros
中科院分区：
文献类型：
--
作者：
Jarbe, Torbjoern U. C.;Li, Chen;Makriyannis, Alexandros
本研究的目的是在体内表征氨基烷基吲哚WIN 55，212-2（WIN）和AM 678（萘-1-基（1-戊基-1H-吲哚-3-基）甲酮）作为大麻素受体（CB 1 R）配体使用药物歧视。测试还涉及匕首（9）-四氢大麻酚（THC）和R-（+）-甲烟酰胺（mAEA），内源性配体anandamide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;乙醇测试评估药理学特异性。我们使用了两种不同的药物歧视（mAEA和THC），使我们能够探索CB 1 R激活的潜在差异，这可能是由于其各自的CB 1 R信号传导机制的变化。一组区分腹膜内注射溶剂和10 mg/kg mAEA。在两个药物辨别组中，AM 678、WIN 55、212-2、THC和mAEA的剂量概括曲线表明效力的以下等级顺序：AM 678> WIN 55、212-2 a份/千日元aEuro份/千日元aTHC> mAEA。用1 mg/kg利莫那班激发导致两种氨基烷基吲哚的泛化曲线向右移动（mAEA组中AM 678为4.4倍，WIN为11.3倍，而THC组的相应值分别为13和2.6），表明可克服的拮抗作用。乙醇没有概括在两组中的任何一个，这表明药理学specificity.Data是一致的一般观察，有大量的重叠在不同的化学类的CB 1 R配体的歧视性刺激作用。然而，在两个辨别组中两种氨基烷基吲哚和利莫那班之间的相互作用的定量差异表明配体-受体活化的细微变化。
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 (CB1R) ligands using drug discrimination. Tests also involved a dagger(9)-tetrahydrocannabinol (THC) and R-(+)-methanandamide (mAEA), a metabolically stable analog of the endogenous ligand anandamide, as well as the CB1R 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 CB1R activation which could be attributed to variations in their respective CB1R 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 a parts per thousand yenaEuro parts per thousand 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 CB1R 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).