Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland.
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland.
Biol Psychiatry. 2019 Jun 1;85(11):915-924. doi: 10.1016/j.biopsych.2019.01.015. Epub 2019 Jan 29.
Studies using continuous-access drug self-administration showed that cocaine seeking increases during abstinence (incubation of cocaine craving). Recently, studies using intermittent-access self-administration showed increased motivation to self-administer and seek cocaine. We examined whether intermittent cocaine self-administration would potentiate incubation of craving in male and female rats and examined the estrous cycle's role in this incubation.
In experiment 1, male and female rats self-administered cocaine either continuously (8 hours/day) or intermittently (5 minutes ON, 25 minutes OFF × 16) for 12 days, followed by relapse tests after 2 or 29 days. In experiments 2 and 3, female rats self-administered cocaine intermittently for six, 12, or 18 sessions. In experiment 4, female rats self-administered cocaine continuously followed by relapse tests after 2 or 29 days. In experiments 3 and 4, the estrous cycle was measured using a vaginal smear test.
Incubation of cocaine craving was observed in both sexes after either intermittent or continuous drug self-administration. Independent of access condition and abstinence day, cocaine seeking was higher in female rats than in male rats. In both sexes, cocaine seeking on both abstinence days was higher after intermittent drug access than after continuous drug access. In female rats, incubation of craving after either intermittent or continuous drug access was significantly higher during estrus than during non-estrus; for intermittent drug access, this effect was independent of the training duration.
In both sexes, intermittent cocaine access caused time-independent increases in drug seeking during abstinence. In female rats, the time-dependent increase in drug seeking (incubation) is critically dependent on the estrous cycle phase.
使用连续获取药物自我给药的研究表明，在禁欲期间（可卡因渴望的潜伏期）可卡因寻求会增加。最近，使用间歇获取自我给药的研究表明，寻求可卡因的动机增加。我们研究了间歇可卡因自我给药是否会增强雄性和雌性大鼠的渴望潜伏期，并研究了发情周期在这种潜伏期中的作用。
在实验 1 中，雄性和雌性大鼠连续（每天 8 小时）或间歇（5 分钟开，25 分钟关×16）自我给药 12 天，然后在 2 天或 29 天后进行复发测试。在实验 2 和 3 中，雌性大鼠间歇自我给药 6、12 或 18 次。在实验 4 中，雌性大鼠连续自我给药，然后在 2 天或 29 天后进行复发测试。在实验 3 和 4 中，使用阴道涂片试验测量发情周期。
无论是间歇还是连续药物自我给药，雄性和雌性大鼠都观察到可卡因渴望的潜伏期。无论访问条件和禁欲天数如何，雌性大鼠的可卡因寻求都高于雄性大鼠。在两性中，间歇药物获取后的禁欲天数的可卡因寻求都高于连续药物获取后的禁欲天数。在雌性大鼠中，无论是间歇还是连续药物给药，潜伏期后的可卡因渴望潜伏期在发情期都明显高于非发情期；对于间歇药物获取，这种效果独立于训练持续时间。
在两性中，间歇可卡因的获取会导致禁欲期间药物寻求的非时间依赖性增加。在雌性大鼠中，可卡因寻求的时间依赖性增加（潜伏期）严重依赖于发情周期阶段。
