Sex differences in Δ(9)-tetrahydrocannabinol metabolism and in vivo pharmacology following acute and repeated dosing in adolescent rats.
Sex differences in Δ(9)-tetrahydrocannabinol metabolism and in vivo pharmacology following acute and repeated dosing in adolescent rats.
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DOI：
10.1016/j.neulet.2014.05.057
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发表时间：
2014-07-25
影响因子：
2.5
通讯作者：
Burston JJ
中科院分区：
文献类型：
--
作者：
Wiley JL;Burston JJ
大麻素药理作用的年龄和性别差异的潜在机制相对未被探索。本研究的目的是确定Δ9-四氢大麻酚（THC）代谢的性别差异（类似于先前在成年大鼠中观察到的差异）是否也发生在青春期大鼠中，并可能导致其体内药理学的年龄和性别差异。雄性和雌性青春期大鼠急性或重复暴露于THC 10天。随后，处死一些大鼠，测量THC及其代谢物之一11-羟基-Δ9-THC（11-OH-THC）的血液和脑水平。其他大鼠在一系列对大麻素敏感的体内试验中进行了评估。11-OH-THC在雌性成年和青春期大鼠的大脑中的浓度超过了在雄性同种中观察到的浓度，特别是在重复THC给药后。相比之下，大脑中THC的水平在性别之间没有差异。在体内，急性四氢大麻酚产生剂量相关的体温过低，僵住症和抑制运动的青春期大鼠的性别，与耐受性发展后，重复给药。除了一个小的例外，在体内试验中THC的作用的性别差异并不明显。与以前的研究结果一起，目前的结果表明，药代动力学的性别差异不能完全解释大麻素对行为影响的性别差异（以及缺乏性别差异）模式。激素和/或药效学因素也可能发挥作用。
Mechanisms that may underlie age and sex differences in the pharmacological effects of cannabinoids are relatively unexplored. The purpose of the present study was to determine whether sex differences in metabolism of Δ9-tetrahydrocannabinol (THC), similar to those observed previously in adult rats, also occurred in adolescent rats and might contribute to age and sex differences in its in vivo pharmacology. Male and female adolescent rats were exposed to THC acutely or repeatedly for 10 days. Subsequently, some of the rats were sacrificed and blood and brain levels of THC and one of its metabolites, 11-hydrox-Δ9-THC (11-OH-THC), were measured. Other rats were evaluated in a battery of in vivo tests that are sensitive to cannabinoids. Concentrations of 11-OH-THC in the brains of female adult and adolescent rats exceeded those observed in male conspecifics, particularly after repeated THC administration. In contrast, brain levels of THC did not differ between the sexes. In vivo, acute THC produced dose-related hypothermia, catalepsy and suppression of locomotion in adolescent rats of both sexes, with tolerance developing after repeated administration. With a minor exception, sex differences in THC’s effects in the in vivo assays were not apparent. Together with previous findings, the present results suggest that sex differences in pharmacokinetics cannot fully explain the patterns of sex differences (and lack of sex differences) in cannabinoid effects across behaviors. Hormonal and/or pharmacodynamic factors are also likely to play a role.
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