De Sa Nogueira David, Corwin Chuhyon, Rakholia Yogesh, Punnuru Varnitha, Nampally Meghana, Kohtz Amy S, Aston-Jones Gary
Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, NJ, USA.
University of Mississippi Medical Center, Jackson, MS, USA.
Addict Neurosci. 2024 Dec;13. doi: 10.1016/j.addicn.2024.100178. Epub 2024 Oct 9.
The orexin system plays a major role in drug reward. Orexin-1 receptor (OxR1) blockade reduces fentanyl demand in males. However, there are a number of sex differences in the orexin system, and it is unclear how OxR1 antagonism would decrease fentanyl demand in females. Furthermore, the relationships between the estrous cycle and fentanyl intake are yet to be delineated. Here, we conducted a behavioral economics (BE) procedure in female rats to assess the effects of the OxR1 antagonist SB-334867 on fentanyl demand before and after short-(ShA), long- (LgA) or intermittent-access (IntA) self-administration of fentanyl; we also tested the effect of SB-334867 on cued reinstatement of fentanyl seeking. Finally, we measured the impact of the estrous cycle on fentanyl demand, intake and seeking. Results showed that in females SB-334867 did not consistently modulate demand for fentanyl before or after chronic access periods. However, SB-334867 at 30mg/kg reduced the number of active lever presses during cued-reinstatement of fentanyl seeking. We also found that fentanyl self-administration disrupted estrous cyclicity, in particular proestrus epochs, an effect that depended on short versus chronic access. Furthermore, extended access to fentanyl shifted the role of progesterone from facilitation of fentanyl demand during short periods, to attenuation of fentanyl demand after long term exposure. These results indicate that an orexin-based therapy in women for treating opioid use disorder must consider prior drug history as well as cycle phase.
食欲素系统在药物奖赏中起主要作用。食欲素-1受体（OxR1）阻断可降低雄性对芬太尼的需求。然而，食欲素系统存在许多性别差异，目前尚不清楚OxR1拮抗作用如何降低雌性对芬太尼的需求。此外，发情周期与芬太尼摄入之间的关系尚待阐明。在此，我们对雌性大鼠进行了行为经济学（BE）实验，以评估OxR1拮抗剂SB-334867在短期（ShA）、长期（LgA）或间歇性获取（IntA）芬太尼自我给药前后对芬太尼需求的影响；我们还测试了SB-334867对芬太尼寻求的线索恢复的影响。最后，我们测量了发情周期对芬太尼需求、摄入和寻求的影响。结果表明，在雌性大鼠中，SB-334867在慢性给药期前后并未持续调节对芬太尼的需求。然而，30mg/kg的SB-334867减少了芬太尼寻求线索恢复期间主动压杆的次数。我们还发现，芬太尼自我给药扰乱了发情周期，尤其是发情前期，这种影响取决于短期与长期给药。此外，长期接触芬太尼会使孕酮的作用从短期促进芬太尼需求转变为长期暴露后减弱芬太尼需求。这些结果表明，基于食欲素的女性阿片类药物使用障碍治疗必须考虑既往用药史以及周期阶段。
