Kohtz Amy S, Davies Hannah, Lin Belle, Aston-Jones Gary
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Brain Health Institute, Rutgers University, Piscataway, NJ 08854, USA.
Addict Neurosci. 2025 Jun;15. doi: 10.1016/j.addicn.2025.100197. Epub 2025 Jan 15.
There are substantial sex differences in substance use disorders (SUDs), and a key feature of SUD is pathologically high economic demand for drug. The hypothalamic neuropeptide oxytocin (OXT) is heavily implicated in the modern treatment of SUDs. Using a within-session threshold behavioral economics (BE) procedure, we quantified demand elasticity (a, inverse motivation) and free consumption (Q) in male and female rats to investigate the effect of OXT on cocaine demand. Results showed that OXT decreased motivation for cocaine; an effect greater during the high-demand phase (diestrus, low progesterone, P) vs low demand phases (proestrus, high P). We confirmed our prior findings that P attenuates cocaine demand in female rats and that chronic cocaine self-administration disrupts estrus cyclicity. Following each injection, OXT at either 0.1mg/kg or 0.3mg/kg restored estrous cycling in intact females with prior cocaine experience for one week and remained effective with up to 4 weeks of injections. Fos reactivity in OXT+ neurons was greater when rats were in proestrus compared to diestrus and significantly correlated to motivation and circulating levels of P. Finally, using ovariectomized females with P replacement, we show that P's demand attenuating effects are reversed by atosiban (1.0 mg/kg, IP), an OXT antagonist. These data show an interaction between oxytocin and progesterone in female rats that may underlie differences in cocaine demand between sexes. Additionally, we show critical periods for using OXT as a treatment to reduce cocaine demand in females. Our results indicate novel therapeutic treatments for SUDs must be tailored to hormonal states.
物质使用障碍（SUDs）存在显著的性别差异，而SUD的一个关键特征是对毒品的病理性高经济需求。下丘脑神经肽催产素（OXT）在SUD的现代治疗中具有重要作用。我们采用会话内阈值行为经济学（BE）程序，对雄性和雌性大鼠的需求弹性（a，反向动机）和自由消费量（Q）进行量化，以研究OXT对可卡因需求的影响。结果表明，OXT降低了对可卡因的动机；在高需求阶段（动情后期，低孕酮，P）比低需求阶段（动情前期，高P）的影响更大。我们证实了之前的发现，即P减弱了雌性大鼠对可卡因的需求，并且长期可卡因自我给药会扰乱发情周期。每次注射后，0.1mg/kg或0.3mg/kg的OXT可使有可卡因使用经历的完整雌性大鼠在一周内恢复发情周期，并且在注射长达4周时仍保持有效。与动情后期相比，大鼠在动情前期时OXT+神经元中的Fos反应性更高，并且与动机和循环中的P水平显著相关。最后，使用接受P替代的去卵巢雌性大鼠，我们发现托烷司琼（1.0mg/kg，腹腔注射），一种OXT拮抗剂，可逆转P的需求减弱作用。这些数据表明雌性大鼠中催产素和孕酮之间存在相互作用，这可能是两性之间可卡因需求差异的基础。此外，我们展示了使用OXT作为减少雌性大鼠可卡因需求治疗方法的关键时期。我们的结果表明，针对SUD的新型治疗方法必须根据激素状态进行调整。
