Kestering-Ferreira Érika, Heberle Bernardo Aguzzoli, Sindermann Lumertz Francisco, Gobira Pedro Henrique, Orso Rodrigo, Grassi-Oliveira Rodrigo, Viola Thiago Wendt
School of Medicine, Brain Institute of Rio Grande do Sul, Developmental Cognitive Neuroscience Lab, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.
Department of Neuroscience, College of Medicine, University of Kentucky, KY, USA.
Neurosci Lett. 2024 Aug 10;837:137898. doi: 10.1016/j.neulet.2024.137898. Epub 2024 Jul 14.
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.
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.
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.
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.
性别差异在理解阿片类药物成瘾易感性方面起着关键作用，但从青春期到成年期过渡阶段对此效应的临床前研究有限。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质中的靶向分子相关性。
30只青春期C57BL/6J小鼠接受为期1周的芬太尼递增剂量治疗。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）在内的表观遗传碱基修饰水平。
慢性芬太尼治疗后，雌性小鼠的运动活动高于雄性，并且它们表现出更高的纳洛酮诱导的芬太尼戒断跳跃行为。雌性小鼠纹状体中的Drd4基因表达和DNA甲基化（5mC + 5hmC）也较低。我们发现运动活动和芬太尼戒断跳跃分别与纹状体中Drd4甲基化和基因表达呈负相关。
研究结果表明，雌性小鼠在从青春期到成年期的过渡阶段对芬太尼治疗的影响表现出更高的敏感性。这种效应可能与Drd4基因相关的分子改变有关。
