Lack of hippocampal CB1 receptor desensitization by Δ9-tetrahydrocannabinol in aged mice and by low doses of JZL 184
Lack of hippocampal CB1 receptor desensitization by Δ9-tetrahydrocannabinol in aged mice and by low doses of JZL 184
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DOI：
10.1007/s00210-016-1226-6
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发表时间：
2016-06-01
影响因子：
3.6
通讯作者：
Schlicker, Eberhard
中科院分区：
文献类型：
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作者：
Feliszek, Monika;Bindila, Laura;Schlicker, Eberhard
大麻素CB 1受体的激活可能提供新的治疗策略，但CB 1受体激动剂的效率可能会受到长期给药后耐受性发展的损害。我们比较了重复给予Delta（9）-四氢大麻酚（THC）10 mg/kg对青春期和老年小鼠运动性以及基础和CB 1受体刺激的S-35-GTP γ S结合的影响。此外，我们还测定了JZL 184（可抑制2-花生四烯酰甘油（2-AG）降解酶单酰基甘油脂肪酶（MAGL））对年轻成年小鼠S-35-GTP γ S结合和2-AG水平的影响。在旷场中测试小鼠运动性。在海马膜中研究S-35-GTP γ S结合。THC和CP 55，940分别在行为和生物化学研究中用作大麻素激动剂。通过液相色谱-多反应监测定量2-AG水平。THC（10 mg/kg）诱导的运动功能减退在未治疗的青少年小鼠中比THC预处理的青少年小鼠中更强，但在老年小鼠的两个治疗组中相似。基础和刺激的S-35-GTP γ S结合减少THC预处理的青少年的膜，但不受影响的膜从老年小鼠。用JZL 184（4、10和40 mg/kg）处理年轻成年小鼠14天不影响基础结合。仅在用JZL 184（40 mg/kg）处理的小鼠中，刺激结合倾向于降低25%。JZL 184在40和10 mg/kg时可增加海马2-AG水平，但在4 mg/kg时不受影响。总之，CB 1受体耐受性不发生在用THC预处理的老年小鼠和用低剂量的MAGL抑制剂JZL 184处理的年轻成年小鼠中。
Activation of cannabinoid CB1 receptors may offer new therapeutic strategies, but the efficiency of CB1 receptor agonists may be impaired by tolerance development upon prolonged administration. We compared the influence of repeated administration of Delta(9)-tetrahydrocannabinol (THC) 10 mg/kg on the motility and on basal and CB1 receptor-stimulated S-35-GTP gamma S binding of adolescent and aged mice. Moreover, we determined the influence of JZL 184 (which inhibits the 2-arachidonoylglycerol, 2-AG, degrading enzyme monoacylglycerol lipase, MAGL) on S-35-GTP gamma S binding and 2-AG levels of young adult mice. Mouse motility was tested in the open field. S-35-GTP gamma S binding was studied in hippocampal membranes. THC and CP 55,940 were used as cannabinoid agonists in the behavioural and biochemical studies, respectively. 2-AG levels were quantified by liquid chromatography-multiple reaction monitoring. The THC (10 mg/kg)-induced hypomotility was stronger in untreated than in THC-pretreated adolescent mice but similar in both treatment groups of aged mice. Basal and stimulated S-35-GTP gamma S binding was decreased in membranes from THC-pretreated adolescent but not affected in membranes from aged mice. Treatment of young adult mice with JZL 184 (4, 10 and 40 mg/kg) for 14 days did not affect basal binding. Stimulated binding tended to be decreased by 25 % only in mice treated with JZL 184 (40 mg/kg). Hippocampal 2-AG level was increased by JZL 184 at 40 and 10 but not affected at 4 mg/kg. In conclusion, CB1 receptor tolerance does not occur in aged mice pretreated with THC and in young adult mice treated with a low dose of the MAGL inhibitor JZL 184.