Department of Neuroscience, Medical University of South Carolina, 173 Ashley Avenue, BSB 403-MSC 510, Charleston, SC, 29425, USA.
School of Pharmacy, University of Camerino, Camerino, Italy.
Psychopharmacology (Berl). 2022 Nov;239(11):3605-3620. doi: 10.1007/s00213-022-06235-0. Epub 2022 Sep 16.
The ongoing rise in opioid use disorder (OUD) has made it imperative to better model the individual variation within the human population that contributes to OUD vulnerability. Using animal models that capture such variation can be a useful tool. Individual variation in novelty-induced locomotion is predictive of substance use disorder (SUD) propensity. In this model, rats are characterized as high-responders (HR) or low-responders (LR) using a median split based on distance travelled during a locomotor test, and HR rats are generally found to exhibit a more SUD vulnerable behavioral phenotype.
The HR/LR model has commonly been used to assess behaviors in male rats using psychostimulants, with limited knowledge of the predictive efficacy of this model in females or the use of an opioid as the reward. In the current study, we assessed several behaviors across the different phases of drug addiction (heroin taking, refraining, and seeking) in over 500 male and female heterogeneous stock rats run at two geographically separate locations. Rats were characterized as HRs or LRs within each sex for analysis.
Overall, females exhibit a more OUD vulnerable phenotype relative to males. Additionally, the HR/LR model was predictive of OUD-like behaviors in male, but not female rats. Furthermore, phenotypes did not differ in anxiety-related behaviors, reacquisition of heroin-taking, or punished heroin-taking behavior in either sex.
These results emphasize the importance of assessing females in models of individual variation in SUD and highlight limitations in using the HR/LR model to assess OUD propensity.
阿片类药物使用障碍（OUD）的持续上升使得更好地模拟导致 OUD 易感性的人类个体内的个体差异变得至关重要。使用能够捕捉到这种差异的动物模型可以是一种有用的工具。新奇诱导的运动个体差异可预测物质使用障碍（SUD）倾向。在该模型中，根据运动测试中行进的距离，使用中位数分割将大鼠分为高反应者（HR）或低反应者（LR），通常发现 HR 大鼠表现出更易患 SUD 的行为表型。
HR/LR 模型通常用于使用精神兴奋剂评估雄性大鼠的行为，而对该模型在雌性中的预测效力或使用阿片类药物作为奖励知之甚少。在当前研究中，我们在两个地理位置不同的地点评估了超过 500 只异质 stock 大鼠在药物成瘾的不同阶段（海洛因摄入、戒断和觅药）的几种行为。在每个性别中，将大鼠分为 HRs 或 LRs 进行分析。
总体而言，雌性相对于雄性表现出更易患 OUD 的表型。此外，HR/LR 模型可预测雄性大鼠但不能预测雌性大鼠的 OUD 样行为。此外，在两性的焦虑相关行为、海洛因摄入的重新获得或惩罚性海洛因摄入行为中，表型没有差异。
这些结果强调了在 SUD 的个体差异模型中评估雌性的重要性，并突出了使用 HR/LR 模型评估 OUD 倾向的局限性。
