Hinds Nicole M, Wojtas Ireneusz D, Gallagher Corinne A, Corbett Claire M, Manvich Daniel F
Graduate School of Biomedical Sciences, Rowan University School of Osteopathic Medicine, Stratford, NJ, USA.
Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, Stratford, NJ, USA.
bioRxiv. 2023 Jun 6:2023.06.02.543393. doi: 10.1101/2023.06.02.543393.
The increasing misuse of both prescription and illicit opioids has culminated in a national healthcare crisis in the United States. Oxycodone is among the most widely prescribed and misused opioid pain relievers and has been associated with a high risk for transition to compulsive opioid use. Here, we sought to examine potential sex differences and estrous cycle-dependent effects on the reinforcing efficacy of oxycodone, as well as on stress-induced or cue-induced oxycodone-seeking behavior, using intravenous (IV) oxycodone self-administration and reinstatement procedures. In experiment 1, adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone according to a fixed-ratio 1 schedule of reinforcement in daily 2-hr sessions, and a dose-response function was subsequently determined (0.003-0.03 mg/kg/inf). In experiment 2, a separate group of adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone for 8 sessions, followed by 0.01 mg/kg/inf oxycodone for 10 sessions. Responding was then extinguished, followed by sequential footshock-induced and cue-induced reinstatement tests. In the dose-response experiment, oxycodone produced a typical inverted U-shape function with 0.01 mg/kg/inf representing the maximally effective dose in both sexes. No sex differences were detected in the reinforcing efficacy of oxycodone. In the second experiment, the reinforcing effects of 0.01-0.03 mg//kg/inf oxycodone were significantly attenuated in females during proestrus/estrus as compared to metestrus/diestrus phases of the estrous cycle. Neither males nor females displayed significant footshock-induced reinstatement of oxycodone seeking, but both sexes exhibited significant cue-induced reinstatement of oxycodone seeking at magnitudes that did not differ either by sex or by estrous cycle phase. These results confirm and extend previous work suggesting that sex does not robustly influence the primary reinforcing effects of oxycodone nor the reinstatement of oxycodone-seeking behavior. However, our findings reveal for the first time that the reinforcing efficacy of IV oxycodone varies across the estrous cycle in female rats.
处方类和非法阿片类药物的滥用现象日益严重，最终在美国引发了一场全国性的医疗危机。羟考酮是最广泛开具处方和滥用的阿片类镇痛药之一，与成瘾性阿片类药物使用的高风险相关。在此，我们试图通过静脉注射（IV）羟考酮自我给药和恢复程序，研究潜在的性别差异以及发情周期依赖性对羟考酮强化效果的影响，以及对压力诱导或线索诱导的羟考酮觅药行为的影响。在实验1中，成年雄性和雌性Long-Evans大鼠按照固定比率1强化程序，在每日2小时的实验中接受训练，自我给药0.03 mg/kg/次的羟考酮，随后确定剂量反应函数（0.003 - 0.03 mg/kg/次）。在实验2中，另一组成年雄性和雌性Long-Evans大鼠接受训练，自我给药0.03 mg/kg/次的羟考酮8次，然后自我给药0.01 mg/kg/次的羟考酮10次。之后停止反应，接着进行顺序性的足底电击诱导和线索诱导的恢复测试。在剂量反应实验中，羟考酮产生了典型的倒U形函数，0.01 mg/kg/次代表两性的最大有效剂量。在羟考酮的强化效果方面未检测到性别差异。在第二个实验中，与发情周期的间情期/动情后期相比，在发情前期/发情期雌性大鼠中，0.01 - 0.03 mg//kg/次羟考酮的强化效果显著减弱。雄性和雌性大鼠均未表现出显著的足底电击诱导的羟考酮觅药行为恢复，但两性均表现出显著的线索诱导的羟考酮觅药行为恢复，且恢复程度在性别或发情周期阶段上均无差异。这些结果证实并扩展了先前的研究工作，表明性别对羟考酮的主要强化效果以及羟考酮觅药行为的恢复没有显著影响。然而，我们的研究结果首次揭示，静脉注射羟考酮的强化效果在雌性大鼠的发情周期中有所不同。
