目的:性别差异在理解阿片类药物成瘾的脆弱性中起着至关重要的作用。然而,在从青春期过渡到成年期的过程中,对这种影响的临床前研究有限。本研究比较了雄性和雌性啮齿动物对芬太尼治疗的反应行为以及纹状体和内侧前额叶皮层的靶向分子相关性。
方法:30只青少年C57BL/6J小鼠接受了1周的芬太尼治疗,剂量递增。除了评估运动活动和焦虑相关参数外,我们还评估了纳洛酮诱导的芬太尼急性戒断跳跃.我们采用实时定量PCR(qPCR)来评估多巴胺能受体(Drd1,Drd2,Drd4和Drd5)和μ阿片受体Oprm1的整体基因表达。在相关基因的CpG岛上评估包括5-甲基胞嘧啶(5mC)和5-羟甲基胞嘧啶(5hmC)的表观遗传碱基修饰的水平。
结果:慢性芬太尼治疗后,女性的运动能力高于男性,他们表现出纳洛酮诱导的更高的芬太尼戒断跳跃行为。雌性在纹状体中也呈现较低的Drd4基因表达和DNA甲基化(5mC+5hmC)。我们发现运动活动和芬太尼戒断跳跃与纹状体中Drd4甲基化和基因表达呈负相关,分别。
结论:研究结果表明,雌性小鼠在从青春期到成年期的过程中表现出对芬太尼治疗作用的敏感性增强。这种效应可能与Drd4基因相关的分子改变有关。
OBJECTIVE: Sex differences play a crucial role in understanding vulnerability to opioid addiction, yet there have been limited preclinical investigations of this effect during the transition from adolescence to adulthood. The present study compared the behaviors of male and female rodents in response to fentanyl treatment and targeted molecular correlates in the striatum and medial prefrontal cortex.
METHODS: Thirty adolescent C57BL/6J mice underwent a 1-week fentanyl treatment with an escalating dose. In addition to evaluating locomotor activity and anxiety-related parameters, we also assessed naloxone-induced fentanyl acute withdrawal jumps. We employed real-time quantitative PCR (qPCR) to assess overall gene expression of dopaminergic receptors (Drd1, Drd2, Drd4 and Drd5) and the μ-opioid receptor Oprm1. The levels of epigenetic base modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were assessed on CpG islands of relevant genes.
RESULTS: Females had higher locomotor activity than males after chronic fentanyl treatment, and they exhibited higher fentanyl withdrawal jumping behavior induced by naloxone. Females also presented lower Drd4 gene expression and DNA methylation (5mC + 5hmC) in the striatum. We found that locomotor activity and fentanyl withdrawal jumps were negatively correlated with Drd4 methylation and gene expression in the striatum, respectively.
CONCLUSIONS: The findings suggested that female mice displayed heightened sensitivity to the effects of fentanyl treatment during the transition from adolescence to adulthood. This effect may be associated with molecular alterations related to the Drd4 gene.