Sharp Burt M, Leng Shuangying, Huang Jun, Jones Caroline, Williams Robert W, Chen Hao
Department of Genetics, Genomics and Informatics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States.
Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, Tennessee, United States.
PLoS One. 2025 Mar 10;20(3):e0314777. doi: 10.1371/journal.pone.0314777. eCollection 2025.
Oxycodone abuse frequently begins with prescription oral oxycodone, yet vulnerability factors (e.g. sex, genetics) determining abuse are largely undefined. We evaluated genetic vulnerability in a rat model of oral oxycodone self-administration (SA): increasing oxycodone concentration/session (0.025-0.1mg/ml; 1-, 4-, and 16-h) followed by extinction and reinstatement. Active licks and oxycodone intake were greater in females than males during 4-h and 16-h sessions (p < 0.001). Both sexes increased intake between 4-h and 16-h sessions (p < 2e-16), but a subset of strains augmented intake at 16-h (p = 0.0005). Heritability (h2) of active licks during 4-h sessions at increasing oxycodone dose ranged from 0.30 to 0.53. Under a progressive ratio (PR) schedule, breakpoints were strain-dependent (p < 2e-16). Cued reinstatement was greater in females (p < 0.001). Naive rats were assessed using elevated plus maze (EPM), open field (OF), and novel object interaction (NOI) tests. We correlated these behaviors with 28 parameters of oxycodone SA. Anxiety-defining EPM traits were most associated with SA in both sexes, whereas OF and NOI traits were more associated with SA in males. Sex and heredity are major determinants of motivation to take and seek oxycodone; intake augments dramatically during extended access in specific strains; and anxiety correlates with multiple SA parameters across strains.
羟考酮滥用通常始于口服处方羟考酮，但决定滥用的易感性因素（如性别、基因）在很大程度上尚不清楚。我们在口服羟考酮自我给药（SA）的大鼠模型中评估了基因易感性：逐渐增加每次给药的羟考酮浓度（0.025 - 0.1mg/ml；1小时、4小时和16小时），随后进行消退和恢复实验。在4小时和16小时的给药过程中，雌性大鼠的主动舔舐次数和羟考酮摄入量均高于雄性（p < 0.001）。两性在4小时和16小时给药过程中的摄入量均有所增加（p < 2e - 16），但有一部分品系在16小时时摄入量增加（p = 0.0005）。在增加羟考酮剂量的4小时给药过程中，主动舔舐的遗传力（h2）范围为0.30至0.53。在累进比率（PR）时间表下，断点具有品系依赖性（p < 2e - 16）。线索恢复实验中，雌性大鼠的反应更强（p < 0.001）。对未接触过羟考酮的大鼠使用高架十字迷宫（EPM）、旷场（OF）和新物体交互（NOI）测试进行评估。我们将这些行为与羟考酮SA的28个参数进行了关联分析。定义焦虑的EPM特征在两性中与SA的相关性最强，而OF和NOI特征在雄性中与SA的相关性更强。性别和遗传是服用和寻求羟考酮动机的主要决定因素；在特定品系的延长给药过程中，摄入量会显著增加；并且焦虑与各品系的多个SA参数相关。
