Brain Health Institute, Rutgers University, Piscataway, NJ, 08854, USA.
Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ, 08854, USA.
Neuropsychopharmacology. 2022 Jul;47(8):1484-1492. doi: 10.1038/s41386-022-01304-6. Epub 2022 Mar 25.
There are substantial sex differences in drug abuse, and a key feature of cocaine addiction is pathologically high motivation for drug. We investigated the role of ovarian hormones on cocaine demand in female rats using a within-session threshold behavioral economics (BE) procedure, which allows us to compare motivation for drug across hormonal states and sex while controlling for differences in dose and intake. This approach quantifies demand elasticity (α) and free consumption (Q, consumption at null effort) to determine motivation for cocaine. Overall, female rats showed greater motivation for cocaine compared to males. However, this difference was cycle phase-dependent - motivation for cocaine when females were in proestrus was lower compared to the same animals across cycle phases, and overall similar to that of males. Hormonal cycle phase accounted for 70% of the within-subject variance in demand elasticity, obscuring other individual differences in female demand. High serum progesterone (P4; e.g., in proestrus) predicted decreased cocaine motivation (high demand elasticity), whereas serum estradiol (E2) correlated to greater intake at null effort (Q). However, individual differences were revealed across OVX females, who displayed a range of demand elasticity, as seen in males. E2 replacement in OVX females increased motivation for cocaine, whereas P4 replacement decreased motivation. We also found that as few as 4 weeks of cocaine self-administration accelerated estropause in female rats as young as 12 weeks old. By 13 weeks of self-administration, proestrus epochs were no longer observed, and cocaine demand was potentiated by persistent estrus in all females. Thus, P4 signaling is a key modulator of cocaine demand in females that may underlie previously observed sex differences in addiction phenotypes.
滥用药物存在显著的性别差异，而可卡因成瘾的一个关键特征是对药物的病理性高动机。我们使用单次疗程阈行为经济学（BE）程序研究了卵巢激素对雌性大鼠可卡因需求的作用，该程序允许我们在控制剂量和摄入量差异的同时，比较不同激素状态和性别的药物需求。这种方法量化了需求弹性（α）和自由消费（Q，零努力时的消费），以确定可卡因的动机。总体而言，雌性大鼠比雄性大鼠表现出更高的可卡因动机。然而，这种差异与周期阶段有关 - 发情期雌性大鼠的可卡因动机低于整个周期阶段的相同动物，总体上与雄性相似。激素周期阶段占需求弹性的 70%的个体差异，掩盖了雌性需求的其他个体差异。高血清孕激素（P4；例如，发情期）预测可卡因动机降低（高需求弹性），而血清雌二醇（E2）与零努力时的更大摄入量（Q）相关。然而，OVX 雌性个体之间存在个体差异，其表现出与雄性相似的需求弹性范围。E2 替代物增加了 OVX 雌性对可卡因的动机，而 P4 替代物则降低了动机。我们还发现，即使是在 12 周龄的年轻大鼠中，只需 4 周的可卡因自我给药就可以加速雌性大鼠的绝经期。在自我给药 13 周后，发情期阶段不再观察到，所有雌性动物的持续发情都增强了可卡因的需求。因此，P4 信号是雌性可卡因需求的关键调节剂，可能是以前观察到的成瘾表型性别差异的基础。
