Allen Mia I, Siebert Erin R, Wakeford Alison G P, Jenkins Kendra, Khan Jessica, Howell Leonard L, Sanchez Mar M, Nader Michael A
Department of Translational Neuroscience and the Center for Addiction Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Emory National Primate Research Center, Emory University, Atlanta, GA, USA.
Neuropsychopharmacology. 2025 Jul 5. doi: 10.1038/s41386-025-02161-9.
A phenomenon involving cocaine use disorders is the "incubation of drug craving" - the drive for the drug increases the longer the abstinence period. The present longitudinal study provided a unique opportunity to test whether an increase in the reinforcing effects of cocaine developed after prolonged abstinence and if early life stress was a risk factor. Fourteen (N = 6 female, 8 male) adult rhesus monkeys, some (N = 7) that were maltreated as infants by their mothers (MALT), had previously self-administered cocaine under a fixed-ratio (FR) schedule of reinforcement as adolescents, but had not been studied for >3 years. In Experiment 1, cocaine self-administration dose-response curves were redetermined in adulthood when responding was maintained under the identical FR 20 schedule used during adolescence. In Experiment 2, the reinforcing strength of cocaine was evaluated (n = 12) under a progressive-ratio (PR) schedule of reinforcement. While there were no statistical differences between male and female monkeys on FR responding in adolescents, when redetermined as adults, MALT monkeys showed higher peak response rates relative to adolescence. No such differences were noted in Control monkeys. Under the PR schedule, peak reinforcing strength was not different between groups or sexes. However, higher total adolescent cocaine intake was significantly associated with higher cocaine breakpoints in adulthood. These findings show that after adolescent cocaine self-administration and a long abstinence period, sensitivity to cocaine reinforcement increased, particularly in monkeys who experienced early life stress. Although early life stress (MALT) did not significantly impact measures of cocaine's reinforcing strength, higher adolescent cocaine intake did.
一种与可卡因使用障碍有关的现象是“药物渴望的潜伏期”——戒毒时间越长，对药物的渴望就越强烈。本纵向研究提供了一个独特的机会，来测试长时间戒毒后可卡因强化作用是否增强，以及早期生活压力是否为一个风险因素。14只（N = 6只雌性，8只雄性）成年恒河猴，其中一些（N = 7只）在幼年时受到母亲虐待（MALT组），它们在青少年时期曾按照固定比率（FR）强化程序自行服用可卡因，但已有3年多未进行研究。在实验1中，当按照青少年时期相同的FR 20强化程序维持反应时，重新测定成年期可卡因自我给药的剂量反应曲线。在实验2中，按照渐进比率（PR）强化程序评估可卡因的强化强度（n = 12）。虽然青少年时期雄性和雌性猴子在FR反应上没有统计学差异，但成年后重新测定时，MALT组猴子相对于青少年时期表现出更高的峰值反应率。对照组猴子未观察到此类差异。在PR程序下，各组和各性别之间的峰值强化强度没有差异。然而，青少年时期较高的可卡因总摄入量与成年后较高的可卡因断点显著相关。这些发现表明，青少年时期自行服用可卡因并经过长时间戒毒后，对可卡因强化的敏感性增加，尤其是在经历过早期生活压力的猴子中。虽然早期生活压力（MALT组）并未显著影响可卡因强化强度的测量指标，但青少年时期较高的可卡因摄入量却有影响。
