University of Texas Southwestern Medical Center, Department of Psychiatry, United States.
University of Texas Southwestern Medical Center, Department of Psychiatry, United States.
Pharmacol Biochem Behav. 2017 Aug;159:12-17. doi: 10.1016/j.pbb.2017.06.017. Epub 2017 Jun 29.
Prior studies have shown that drug-seeking behaviors increase, rather than dissipate, over weeks to months after withdrawal from drug self-administration. This phenomenon - termed incubation - suggests that drug-craving responses elicited by conditioned environmental or discrete cues may intensify over pronged abstinence. While most of this work is conducted in rats with intravenous drug self-administration models, there is less evidence for incubation in mice that have greater utility for molecular genetic analysis and perturbation. We tested whether incubation of cocaine-seeking behavior is evident in C57BL/6J mice following 3weeks (5days/week) of cocaine self-administration in 2h self-administration sessions. We compared cocaine-seeking (drug-paired lever) responses 1, 7, or 28days after withdrawal from cocaine self-administration, and over similar times following sucrose pellet self-administration. We found that the initial re-exposure to the self-administration test chambers elicited increased reward-seeking behavior in both sucrose and cocaine self-administering mice, with maximal responses found at 7days compared to 1 or 28days after self-administration with either reinforcer. However, following extinction training, reinstatement of cocaine seeking reinforced by response-contingent presentation of reward-associated cues (tone/light) was significantly higher after 28days compared to 1 or 7days following cocaine self-administration. In contrast, cue-induced reinstatement of sucrose-paired lever pressing did not increase over this time frame, demonstrating a drug-specific incubation effect not seen with a natural reward. Thus, C57BL/6J mice display incubation of cue-induced reinstatement of cocaine seeking similar to findings with rats, but only show a transient incubation of context-induced cocaine seeking.
先前的研究表明，在药物自我给药戒断后的数周到数月内，觅药行为会增加，而不是减少。这种现象被称为潜伏期——表明由条件环境或离散线索引起的药物渴望反应可能会在长时间的禁欲中加剧。虽然大多数这类工作都是在静脉内药物自我给药模型的大鼠中进行的，但在具有更大分子遗传分析和干扰能力的小鼠中，潜伏期的证据较少。我们测试了在可卡因自我给药 3 周（每周 5 天）后，C57BL/6J 小鼠是否会出现可卡因觅药行为的潜伏期。我们比较了可卡因觅药（药物配对杠杆）反应在戒断可卡因自我给药后 1、7 或 28 天，以及在类似的时间后，蔗糖丸自我给药。我们发现，在重新暴露于自我给药测试室时，两种蔗糖和可卡因自我给药的小鼠都表现出了更强的奖赏寻求行为，与 1 天或 28 天后相比，7 天时的反应最大。然而，在消退训练后，用与奖励相关的线索（音调和灯光）连续呈现作为强化刺激来重新引发可卡因寻求的复吸反应，在可卡因自我给药 28 天后明显高于 1 天或 7 天后。相比之下，在这段时间内，与蔗糖配对的杠杆按压引起的线索诱导复吸并没有增加，表明与自然奖励不同，出现了一种特定于药物的潜伏期效应。因此，C57BL/6J 小鼠表现出与大鼠相似的可卡因寻求的线索诱导复吸潜伏期，但仅表现出短暂的环境诱导可卡因寻求的潜伏期。
