Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Department of Psychology, Franklin and Marshall College, Lancaster, PA, USA.
Neuropsychopharmacology. 2021 Sep;46(10):1724-1733. doi: 10.1038/s41386-021-01035-0. Epub 2021 May 26.
Increasing evidence suggests that females are more vulnerable to the harmful effects of drugs of abuse, including opioids. Additionally, rates of heroin-related deaths substantially increased in females from 1999 to 2017 [1], underscoring the need to evaluate sex differences in heroin vulnerability. Moreover, the neurobiological substrates underlying sexually dimorphic responding to heroin are not fully defined. Thus, we evaluated male and female Long Evans rats on acquisition, dose-responsiveness, and seeking for heroin self-administration (SA) as well as using a long access model to assess escalation of intake at low and high doses of heroin, 0.025 and 0.1 mg/kg/inf, respectively. We paired this with ex vivo fast-scan cyclic voltammetry (FSCV) in the medial nucleus accumbens (NAc) shell and quantification of mu-opioid receptor (MOR) protein in the ventral tegmental area (VTA) and NAc. While males and females had similar heroin SA acquisition rates, females displayed increased responding and intake across doses, seeking for heroin, and escalation on long access. However, we found that males and females had similar expression levels of MORs in the VTA and NAc, regardless of heroin exposure. FSCV results revealed that heroin exposure did not change single-pulse elicited dopamine release, but caused an increase in dopamine transporter activity in both males and females compared to their naïve counterparts. Phasic-like stimulations elicited robust increases in dopamine release in heroin-exposed females compared to heroin-naïve females, with no differences seen in males. Together, our results suggest that differential adaptations of dopamine terminals may underlie the increased heroin SA behaviors seen in females.
越来越多的证据表明，女性比男性更容易受到滥用药物（包括阿片类药物）的有害影响。此外，1999 年至 2017 年期间，女性与海洛因相关的死亡人数大幅增加[1]，这突显出需要评估女性对海洛因易感性的性别差异。此外，海洛因易感性的性别差异的神经生物学基础尚未完全确定。因此，我们对雄性和雌性长耳大仓鼠进行了评估，包括海洛因的获得、剂量反应和寻求行为，以及使用长时程接触模型评估在低剂量（0.025mg/kg/inf）和高剂量（0.1mg/kg/inf）海洛因下的摄入增加情况。我们将这些结果与伏隔核壳部（NAc）中的中脑边缘多巴胺系统（medial nucleus accumbens shell，mNAc）中的快速扫描循环伏安法（fast-scan cyclic voltammetry，FSCV）以及腹侧被盖区（ventral tegmental area，VTA）和 NAc 中的 μ-阿片受体（mu-opioid receptor，MOR）蛋白的定量相结合。虽然雄性和雌性的海洛因获得率相似，但雌性在不同剂量、寻求海洛因和长时间接触时的反应和摄入都增加了。然而，我们发现无论是否接触海洛因，雄性和雌性的 VTA 和 NAc 中的 MOR 表达水平相似。FSCV 结果表明，海洛因暴露不会改变单一脉冲引发的多巴胺释放，但与未接触海洛因的对照相比，会导致多巴胺转运体活性增加。与海洛因未接触的雌性相比，海洛因暴露会引起类似脉冲样刺激引起的多巴胺释放显著增加，而雄性则没有差异。综上所述，多巴胺末梢的差异适应可能是女性海洛因 SA 行为增加的基础。
