Towers Eleanor Blair, Hsu Kyle A, Qillawala Emaan I, Fraser Shaniece D, Lynch Wendy J
Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia.
Medical Scientist Training Program, University of Virginia, Charlottesville, Virginia.
Biol Psychiatry Glob Open Sci. 2024 Aug 13;4(6):100373. doi: 10.1016/j.bpsgos.2024.100373. eCollection 2024 Nov.
Women develop addiction and drug-related health consequences after fewer years of drug use than men; this accelerated time course, or telescoping effect, has been observed clinically for multiple drugs, including opioids. Preclinical studies indicate that this is a biologically based phenomenon; however, these studies have focused exclusively on cocaine, and none have considered health effects.
In this study, we used a rat (Sprague Dawley) model to determine sex differences in the time course for the development of an opioid addiction-like phenotype, as defined by the development of physical dependence (withdrawal-induced weight loss) and an increase in motivation for fentanyl (under a progressive-ratio schedule). Effects were determined following either 10 days (optimized, experiment 1) or 3 days (threshold, experiment 2) of extended-access fentanyl self-administration (24 hours/day, fixed ratio 1, 2- to 5-minute trials/hour) or following short-access fentanyl self-administration (subthreshold, experiment 3; fixed ratio 1, up to 40 infusions/day). Opioid-related adverse health effects were also determined (experiment 4).
Motivation for fentanyl was similarly increased in males and females following 10 days of extended-access self-administration (experiment 1), was transiently increased in females, but not males, following 3 days of extended-access self-administration (experiment 2) and was not increased in either sex following short-access self-administration (experiment 3). Females developed fentanyl-associated adverse health effects more readily than males (experiment 4), with particularly robust differences during extended-access self-administration and withdrawal.
As with findings in humans, female rats developed opioid addiction-like features and adverse health consequences more readily than male rats. These data provide support for a biologically based telescoping effect in females for opioids, particularly for opioid-related adverse health consequences.
女性在吸毒年限少于男性的情况下就会出现成瘾及与药物相关的健康后果；这种加速的病程，即时间压缩效应，在临床上已在包括阿片类药物在内的多种药物中观察到。临床前研究表明这是一种基于生物学的现象；然而，这些研究仅聚焦于可卡因，且均未考虑对健康的影响。
在本研究中，我们使用大鼠（斯普拉格-道利大鼠）模型来确定阿片类药物成瘾样表型发展过程中的性别差异，该表型由身体依赖性（戒断引起的体重减轻）的发展以及对芬太尼的动机增加（采用累进比率程序）来定义。在进行10天（优化，实验1）或3天（阈值，实验2）的延长接触式芬太尼自我给药（每天24小时，固定比率1，每小时2至5分钟试验）或短接触式芬太尼自我给药（阈下，实验3；固定比率1，每天最多40次输注）后确定效果。还确定了与阿片类药物相关的不良健康影响（实验4）。
在进行10天的延长接触式自我给药后，雄性和雌性大鼠对芬太尼的动机同样增加（实验1）；在进行3天的延长接触式自我给药后，雌性大鼠对芬太尼的动机短暂增加，而雄性大鼠则未增加（实验2）；在进行短接触式自我给药后，两性对芬太尼的动机均未增加（实验3）。雌性大鼠比雄性大鼠更容易出现与芬太尼相关的不良健康影响（实验4），在延长接触式自我给药和戒断期间差异尤为明显。
与人类研究结果一样，雌性大鼠比雄性大鼠更容易出现阿片类药物成瘾样特征和不良健康后果。这些数据为雌性大鼠中阿片类药物存在基于生物学的时间压缩效应提供了支持，特别是对于与阿片类药物相关的不良健康后果。
