The effects of Δ9-tetrahydrocannabinol physical dependence on brain cannabinoid receptors
The effects of Δ9-tetrahydrocannabinol physical dependence on brain cannabinoid receptors
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DOI：
10.1016/s0014-2999(02)02854-6
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发表时间：
2003-01-17
影响因子：
5
通讯作者：
Martin, BR
中科院分区：
文献类型：
--
作者：
Breivogel, CS;Scates, SM;Martin, BR
研究了慢性Delta(9)-四氢大麻酚对大麻素受体水平和受体-G蛋白偶联的影响。雄性SD大鼠连续灌胃低、高剂量Delta(9)-四氢大麻酚或赋形剂4天。治疗后，处死大鼠进行大麻素CB1受体结合分析，或用大麻素CB1受体拮抗剂N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2，4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide(SR141716A)激发。接受Delta(9)-四氢大麻酚治疗的大鼠表现出拮抗剂沉淀的戒断症状。高剂量组大鼠各脑区(小脑、皮质、海马区和基底节)的[H-3](-)-cis-3-[2-hydroxy-4-(1，1-dimethylheptyl)phenyl]-trans-4-(3-hydroxyphenyl)cyclohexanol(WIN55212-2)B-max值下降30-70%，表明受体下调。WIN552122刺激[S-35]鸟苷-5‘-O-3-硫代三聚磷酸(GTP-GammaS)结合的大部分区域出现下降，表明大麻素CB1受体脱敏。另外，小脑膜受体结合分析显示，激动剂的降幅明显大于拮抗剂的B-max值，这表明治疗后偶联受体的比例较低。对5种激动剂的浓度-效应分析表明，治疗导致低效激动剂的疗效下降更大。(C)2002 Elsevier Science B.V.保留所有权利。
The effects of chronic Delta(9)-tetrahydrocannabinol on cannabinoid receptor levels and receptor-G-protein coupling were investigated. Male Sprague-Dawley rats were infused continuously with low or high dose regimens of Delta(9)-tetrahydrocannabinol or vehicle for 4 days. Following treatment, rats were sacrificed for cannabinoid CB1 receptor binding analysis or challenged with the cannabinoid CB1 receptor antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A). The rats receiving Delta(9)-tetrahydrocannabinol exhibited antagonist-precipitated withdrawal signs. Each brain region (cerebellum, cortex, hippocampus and basal ganglia) from high-dose rats showed 30-70% decreases in [H-3] (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxyphenyl)cyclohexanol (WIN55212-2) B-max values, indicating receptor down-regulation. Most regions showed decreased WIN552122-stimulated [S-35]guanosine-5'-O-3-thiotripliosphate (GTPgammaS) binding, indicating desensitization of cannabinoid CB1 receptors. Additional receptor binding assays in cerebellar membranes showed a significantly greater decrease in agonist than in antagonist B-max values, indicating a lower fraction of coupled receptors after treatment. Concentration-effect analysis of five agonists revealed that the treatment resulted in greater decreases in the efficacy of low-efficacy agonists. (C) 2002 Elsevier Science B.V. All rights reserved.