Cg Modrak, Cs Wilkinson, Ad Claypool, Aj Moore, L Wu, LA Knackstedt, M Schwendt
Psychology Department, University of Florida, Gainesville, FL, USA.
Center for Addiction Research and Education, University of Florida, Gainesville, FL, USA.
Addict Neurosci. 2025 Jun;15. doi: 10.1016/j.addicn.2025.100205. Epub 2025 Mar 20.
Methamphetamine use disorder (MUD) is frequently comorbid with other disorders, such as post-traumatic stress disorder (PTSD). Here, we used a rat model of PTSD+MUD to evaluate the influence of sex and stress on methamphetamine-seeking and on the activation of frontocortical regions during reinstatement of meth-seeking. Male and female Sprague-Dawley rats were exposed to predator scent stress (PSS) or a control odor for 10 min, followed by anxiety testing one week later. Rats were re-exposed to the odor context three weeks after the exposure and then self-administered methamphetamine for 18 days. Rats underwent extinction training followed by a cue-primed reinstatement test. We found evidence for sex-specific fear and anxiety-like behaviors in PSS-exposed rats, with females exhibiting anxiety-like behavior in the elevated plus maze and males exhibiting increased acoustic startle response. There were no effects of PSS on methamphetamine intake, but males exhibited greater intake and cued reinstatement. PSS-exposed females reinstated methamphetamine-seeking, but control-exposed females did not, in parallel with higher reinstatement-induced infralimbic cortex c-Fos expression. PSS males exhibited reduced prelimbic and infralimbic c-Fos relative to control-exposed males despite similar reinstatement behavior. To identify relationships between fear and anxiety-like behavior, cortical activation, and meth-seeking, a principal components analysis was used. The analysis revealed that discrete behaviors exhibited during PSS exposure (locomotion and digging), together with select markers of anxiety (reduced startle response), predict methamphetamine intake and seeking. Altogether, these findings suggest that a specific set of stress-reactive and anxiety-like behaviors contribute to long-term resilience to drug-taking and seeking in a sex-specific manner.
甲基苯丙胺使用障碍（MUD）常与其他疾病共病，如创伤后应激障碍（PTSD）。在此，我们使用PTSD+MUD大鼠模型来评估性别和应激对甲基苯丙胺寻求行为以及在甲基苯丙胺寻求行为恢复过程中前额叶皮质区域激活的影响。将雄性和雌性斯普拉格-道利大鼠暴露于捕食者气味应激（PSS）或对照气味中10分钟，一周后进行焦虑测试。在暴露三周后，大鼠再次暴露于气味环境中，然后自我给药甲基苯丙胺18天。大鼠接受消退训练，随后进行线索引发的恢复测试。我们发现暴露于PSS的大鼠存在性别特异性的恐惧和焦虑样行为，雌性在高架十字迷宫中表现出焦虑样行为，而雄性表现出增强的听觉惊吓反应。PSS对甲基苯丙胺摄入量没有影响，但雄性表现出更高的摄入量和线索引发的恢复。暴露于PSS的雌性恢复了甲基苯丙胺寻求行为，但暴露于对照的雌性没有，同时恢复诱导的边缘下皮质c-Fos表达更高。尽管恢复行为相似，但与暴露于对照的雄性相比，暴露于PSS的雄性前额叶和边缘下皮质c-Fos表达降低。为了确定恐惧和焦虑样行为、皮质激活与甲基苯丙胺寻求行为之间的关系，我们使用了主成分分析。分析表明，在PSS暴露期间表现出的离散行为（运动和挖掘），以及焦虑的特定标志物（惊吓反应降低），可预测甲基苯丙胺的摄入量和寻求行为。总之，这些发现表明，一组特定的应激反应性和焦虑样行为以性别特异性方式有助于长期抵抗药物摄入和寻求行为。
