Sex, THC, and hormones: Effects on density and sensitivity of CB1 cannabinoid receptors in rats
Sex, THC, and hormones: Effects on density and sensitivity of CB1 cannabinoid receptors in rats
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DOI：
10.1016/j.drugalcdep.2018.09.018
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发表时间：
2019-01-01
影响因子：
4.2
通讯作者：
Wiley, Jenny L.
中科院分区：
文献类型：
--
作者：
Farquhar, Charlotte E.;Breivogel, Christopher S.;Wiley, Jenny L.
背景资料：最近，美国国立卫生研究院要求在临床前研究中将性别视为一个生物学变量，这一要求将注意力集中在行为的性别差异上。为了探讨Delta（9）-四氢大麻酚（THC）效应性别差异的潜在机制，我们检查了性激素和性腺激素对小脑、海马、前额叶皮质和纹状体CB 1受体的影响。方法：成年Sprague-Dawley大鼠接受性腺切除术（GDX）或假GDX。GDX女性和男性的一半分别接受雌二醇或睾酮替代（GDX + H）。所有大鼠在脑收集前注射载体或30 mg/kg THC，每天两次，持续1周。CP 55，940刺激的[S-35]GTP γ S和[H-3] SR 141716 A饱和结合assessment.Results：除了增强的受体激活的雌性大鼠相比，雄性，溶剂处理的大鼠表现出最小的性别差异CB 1受体密度或G-蛋白偶联。THC重复治疗导致显着的CB 1受体脱敏和下调，在所有的大脑区域中的性别与一个更大的变化幅度在females.Conclusions：这些结果表明，脑CB 1受体的密度和G-蛋白偶联的性别差异可能发挥有限的作用，在急性THC的影响不介导的海马的性别差异。相反，重复THC后的性别差异很常见，与相应的男性组相比，女性（完整，GDX和GDX + H）在所有四个脑区中显示出更大的下调或脱敏。这一结果与一项发现相一致，即在开始使用大麻后，女性往往比男性更快地发展到耐受性和依赖性。
Background: The recent NIH mandate to consider sex as a biological variable in preclinical research has focused attention on delineation of sex differences in behavior. To investigate mechanisms underlying sex differences in Delta(9)-tetrahydrocannabinol (THC) effects, we examined the effects of sex and gonadal hormones on CB1 receptors in cerebellum, hippocampus, prefrontal cortex, and striatum.Methods: Adult Sprague-Dawley rats underwent gonadectomy (GDX) or sham-GDX. Half of the GDX females and males received estradiol or testosterone replacement (GDX + H), respectively. All rats were injected with vehicle or 30 mg/kg THC twice daily for 1 week before brain collection. CP55,940-stimulated [S-35]GTP gamma S and [H-3] SR141716A saturation binding assays were performed.Results: With exception of enhanced receptor activation in the hippocampi of female rats compared to males, vehicle-treated rats exhibited minimal sex differences in CB1 receptor densities or G-protein coupling. Repeated treatment with THC resulted in pronounced CB1 receptor desensitization and downregulation in both sexes in all brain regions with a greater magnitude of change in females.Conclusions: These results suggest that sex differences in the density and G-protein coupling of brain CB1 receptors may play a limited role in sex differences in acute THC effects not mediated by the hippocampus. In contrast, sex differences after repeated THC were common, with females (intact, GDX, and GDX + H) showing greater downregulation or desensitization in all four brain regions compared to the respective male groups. This result is consistent with a finding that women tend to progress to tolerance and dependence quicker than men after initiation of cannabis use.