Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, USA.
Psychopharmacology (Berl). 2021 Aug;238(8):2213-2224. doi: 10.1007/s00213-021-05846-3. Epub 2021 Apr 27.
Women meet criteria for substance use disorder after fewer years of drug use than men; this accelerated time course, or telescoping effect, has been observed for multiple drugs, including cocaine. Preclinical findings similarly indicate an enhanced vulnerability in females to developing an addiction-like phenotype; however, it is not yet known if this phenotype develops faster in females versus males.
The goal of this study was to determine using a rat model whether two key features of addiction in humans, an enhanced motivation for cocaine and compulsive use, emerge sooner during withdrawal from extended access cocaine self-administration in females versus males.
Motivation for cocaine, as assessed under a progressive-ratio reinforcement schedule, was determined prior to and following extended access cocaine self-administration (24 h/day, 96 infusions/day, 10 days) and after 7, 14, or 60 days of withdrawal. Compulsive use, or use despite punishment, was evaluated once progressive-ratio responding stabilized by adding histamine, an aversive stimulus, to the cocaine solutions.
Motivation for cocaine increased from baseline sooner during withdrawal in females than males (at 7 versus 14 days); motivation was also highest in the 60-day group. Histamine decreased progressive-ratio responding for cocaine in both sexes, although effects were greatest in males in the 7-day withdrawal group; males reached the female-level of resistance to histamine punishment by 14 days of withdrawal.
Female rats developed addition-like features sooner during withdrawal than male rats indicating that the telescoping effect observed in humans is biologically based. Additionally, like drug-seeking/craving, motivation for cocaine and measures of compulsive use incubate over withdrawal.
女性在使用药物的年限少于男性时就符合物质使用障碍的标准；这种加速的时间进程或缩短效应已在多种药物中观察到，包括可卡因。临床前研究结果同样表明，女性在发展类似成瘾的表型方面存在更高的易感性；然而，目前尚不清楚这种表型在女性中的发展速度是否快于男性。
本研究的目的是使用大鼠模型确定，在延长可卡因自我给药后戒断期间，女性是否比男性更快地出现人类成瘾的两个关键特征，即对可卡因的增强动机和强迫使用。
在延长接触可卡因自我给药（24 小时/天，96 次/天，10 天）之前和之后，以及在 7、14 或 60 天戒断后，使用递增比率强化方案评估可卡因的动机。通过向可卡因溶液中添加组胺（一种厌恶刺激）来评估强迫使用，或在出现强迫使用时评估使用，此时递增比率反应已经稳定。
与男性相比，女性在戒断期间更快地出现对可卡因的增强动机（在 7 天而非 14 天）；在 60 天组中，动机也最高。组胺降低了两性对可卡因的递增比率反应，但在 7 天戒断组中，男性的作用最大；男性在 14 天的戒断期就达到了对组胺惩罚的女性水平的抵抗力。
雌性大鼠在戒断期间比雄性大鼠更快地出现类似成瘾的特征，这表明人类中观察到的缩短效应是基于生物学的。此外，与觅药/渴望一样，对可卡因的动机和强迫使用的测量在戒断期间逐渐出现。
