Pharmacokinetic factors in sex differences in Δ9-tetrahydrocannabinol-induced behavioral effects in rats
Pharmacokinetic factors in sex differences in Δ9-tetrahydrocannabinol-induced behavioral effects in rats
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DOI：
10.1016/j.bbr.2004.01.029
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发表时间：
2004-09-23
影响因子：
2.7
通讯作者：
Craft, RM
中科院分区：
文献类型：
--
作者：
Tseng, AH;Harding, JW;Craft, RM
大麻素已被证明对雌性大鼠的行为影响大于雄性大鼠。一项研究还证明了Delta（9）-四氢大麻酚（Delta（9）-THC）代谢的性别差异。本研究的目的是确定Delta（9）-THC处置或代谢的性别差异是否可以解释Delta（9）-THC诱导的行为效应的性别差异。腹腔内（i. p.）给予[H-3]-Delta（9）-THC并在注射后多次比较雄性与雌性大鼠血清和脑组织中[H-3]-Delta（9）-THC和代谢物的存在。雄性和雌性动物的Delta（9）-THC及其代谢物的血清水平相似。在脑组织中。[H-3]-Delta（9）-THC水平在男性和女性中也相似。相比之下，女性脑组织中Delta（9）-THC代谢物（包括主要活性代谢物11-羟基-Delta（9）-THC）的水平高于男性。为了进一步研究雌性产生更多活性代谢物是否解释了在雌性中观察到的更大Delta（9）-THC诱导的行为效应，在用生理盐水或细胞色素P450抑制剂SKF 525 A预处理后的雄性和雌性大鼠中比较了i. p. Delta（9）-THC诱导的抗伤害感受（50 ℃温水尾部戒断试验）和僵住症（棒试验）。SKF 525 A在两种性别中均不影响缩尾试验或棒试验中的基础反应。SKF 525 A仅在雌性中显著减弱Delta（9）-THC诱导的抗伤害感受。在SKF 525 A对Delta（9）-THC诱导的僵住症的影响中观察到类似的性别差异。这些结果表明，与雄性大鼠相比，雌性大鼠产生的更高水平的活性Delta（9）-THC代谢物有助于Delta（9）-THC在雌性大鼠中产生更大的行为效应。(C)2004 Elsevier B. V.保留所有权利。
Cannabinoids have been shown to produce greater behavioral effects in female than in male rats. Sex differences in the metabolism of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) have also been demonstrated in one study. The goal of this study was to determine if sex differences in Delta(9)-THC disposition or metabolism could explain sex differences in Delta(9)-THC-induced behavioral effects. [H-3]-Delta(9)-THC was administered intraperitoneally (i.p.) to rats and the presence of [H-3]-Delta(9)-THC and metabolites in serum and brain tissue were compared at multiple times post-injection in male versus female rats. Serum levels of Delta(9)-THC and its metabolites were similar in males and females. In brain tissue. [H-3]-Delta(9)-THC levels also were similar in males and females. In contrast, levels of Delta(9)-THC metabolites in brain tissue, including 11-hydroxy-Delta(9)-THC, the major active metabolite, were higher in females than in males. To further investigate if greater production of active metabolites by females explained the greater Delta(9)-THC-induced behavioral effects observed in females, i.p. Delta(9)-THC-induced antinociception (50 degreesC warm water tail withdrawal assay) and catalepsy (bar test) were compared in male and female rats following pretreatment with saline or SKF525A, a cytochrome P450 inhibitor. SKF525A did not affect basal responding in the tail withdrawal assay or bar test in either sex. SKF525A significantly attenuated Delta(9)-THC-induced antinociception only in females. A similar sex difference was observed in the effects of SKF525A on Delta(9)-THC-induced catalepsy. These results suggest that the greater levels of active Delta(9)-THC metabolites produced by females contribute to greater behavioral effects of Delta(9)-THC in female compared to male rats. (C) 2004 Elsevier B.V. All rights reserved.