The effects of beta-arrestin1 deletion on acute cannabinoid activity, brain cannabinoid receptors and tolerance to cannabinoids in mice
The effects of beta-arrestin1 deletion on acute cannabinoid activity, brain cannabinoid receptors and tolerance to cannabinoids in mice
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DOI：
10.3109/10799893.2014.1003659
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发表时间：
2015-02-01
影响因子：
2.8
通讯作者：
Vaghela, Manan S.
中科院分区：
文献类型：
--
作者：
Breivogel, Chris S.;Vaghela, Manan S.
内容：以前的研究表明β-arrestin 2在调节大脑大麻素效应和大麻素CB 1受体中的作用，但β-arrestin 1是否有作用尚未研究。目的：研究β-arrestin 1在大麻素活性中的作用。材料与方法：在单次和重复给药后，测定β-arrestin 1-/-小鼠及其野生型（+/+）对应物的两种配体δ（9）-四氢大麻酚（THC）和CP 55940的抗伤害感受和降温作用。体外试验检测了缺失对CB 1受体密度、激动剂结合和G蛋白活化的影响。结果如下：β-arrestin 1的缺失减弱了CP 55940在小鼠中的抗伤害感受（缩尾潜伏期）和温度抑制试验中的作用。然而，删除β-arrestin 1对THC的作用没有影响。拮抗剂放射性配体（[H-3] SR 141716 A）饱和结合表明，β-arrestin 1 +/+和-/-小鼠之间在脑膜中大麻素CB 1受体的密度或亲和力方面无差异。β-arrestin 1 +/+小鼠脑细胞膜中的CP 55940激动剂结合显示出高亲和力和中等亲和力位点，但β-arrestin 1-/-膜显示出低亲和力的额外位点。与+/+小鼠相比，CP 55940对β-arrestin 1-/-小鼠全脑膜[S-35] GTP γ S结合产生更大的刺激。对慢性THC或CP 55940给药的耐受性的发展率似乎不受基因型的影响。讨论：β-arrestin 1似乎介导了CP 55940的作用，但不影响THC的活性。结论：β-arrestin 1调节大麻素CB 1受体的敏感性在一个激动剂选择性的方式，但可能不是耐受大麻素激动剂的主要介质。
Context: Previous studies have indicated a role for beta-arrestin2 in the regulation of brain cannabinoid effects and cannabinoid CB1 receptors, but whether beta-arrestin1 has a role has not been investigated. Objective: To determine the role of beta-arrestin1 in cannabinoid activity. Materials and methods: Beta-arrestin1 -/- mice and their wild-type (+/+) counterparts were assayed for antinociceptive and temperature-decreasing effects of two ligands, Delta(9) -tetrahydro-cannabinol (THC) and CP55940, after both single and repeated administration. In vitro assays examined the effects of deletion on CB1 receptor density, agonist-binding and G-protein activation. Results: Deletion of beta-arrestin1 diminished the effects of CP55940 in both antinociception (latency to tail withdrawal) and temperature-depression assays in mice. However, deleting beta-arrestin1 had no effect on the actions of THC in either assay. Antagonist radioligand ([H-3]SR141716A) saturation binding indicated no difference between beta-arrestin1 +/+ and -/- mice in the density or affinity for cannabinoid CB1 receptors in brain membranes. CP55940 agonist binding in brain membranes from beta-arrestin1 +/+ mice exhibited high-and intermediate-affinity sites, but beta-arrestin1 -/- membranes exhibited an additional site with low affinity. CP55940 produced greater stimulation of [S-35] GTP gamma S binding to membranes from whole brain of beta-arrestin1 -/- than +/+ mice. The rates of the development of tolerance to chronic THC or CP55940 administration did not appear to be affected by genotype. Discussion: Beta-arrestin1 appeared to mediate the actions of CP55940, but did not affect the activity of THC. Conclusion: Beta-arrestin1 regulates cannabinoid CB1 receptor sensitivity in an agonist-selective manner, but may not be the primary mediator of tolerance to cannabinoid agonists.