Sex Differences in the Development of an Opioid Addiction–Like Phenotype: A Focus on the Telescoping Effect

Eleanor Blair Towers , Kyle A. Hsu , Emaan I. Qillawala , Shaniece D. Fraser , Wendy J. Lynch
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Abstract

Background

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.

Methods

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).

Results

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.

Conclusions

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.

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类阿片成瘾表型发展过程中的性别差异:聚焦伸缩效应
背景与男性相比,女性吸食毒品的年数较少,但却会成瘾并产生与毒品相关的健康后果;临床上已经观察到包括阿片类药物在内的多种药物会出现这种加速的时间过程或伸缩效应。在这项研究中,我们使用大鼠(Sprague Dawley)模型来确定阿片类药物成瘾样表型发展时间过程中的性别差异,该表型的定义是生理依赖性的发展(戒断引起的体重减轻)和芬太尼动机的增加(在渐进比率时间表下)。实验结果是在 10 天(优化,实验 1)或 3 天(阈值,实验 2)延长芬太尼自我给药(24 小时/天,固定比率 1,2 到 5 分钟/小时)或短期芬太尼自我给药(阈值以下,实验 3;固定比率 1,最多 40 次/天)后得出的。结果男性和女性在延长自我给药时间 10 天后对芬太尼的渴求度同样增加(实验 1),女性在延长自我给药时间 3 天后对芬太尼的渴求度短暂增加,而男性则没有(实验 2),男性和女性在短时间自我给药后对芬太尼的渴求度都没有增加(实验 3)。结论 与人类的研究结果一样,雌性大鼠比雄性大鼠更容易出现类似阿片类药物成瘾的特征和不良健康后果(实验 4)。这些数据支持雌性大鼠对阿片类药物产生基于生物学的伸缩效应,尤其是与阿片类药物相关的不良健康后果。
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来源期刊
Biological psychiatry global open science
Biological psychiatry global open science Psychiatry and Mental Health
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91 days
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