Department of Biomedical Sciences, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
Addict Biol. 2020 Sep;25(5):e12809. doi: 10.1111/adb.12809. Epub 2019 Aug 1.
Studies in humans suggest that women progress more rapidly from initial cocaine use to addiction. Similarly, female rats can show more incentive motivation for cocaine than male rats do. Most preclinical studies on this issue have used self-administration procedures that provide continuous cocaine access during each session ("long-access" or LgA and "short-access"). However, intermittent access (IntA) cocaine self-administration better models the intermittency of human cocaine use. Here, we compared cocaine use in female and male rats that received ten, daily 6-hour LgA or IntA sessions. Cocaine intake was greatest under LgA, and female LgA rats escalated their intake. Only IntA rats (both sexes) developed locomotor sensitization to self-administered cocaine, and sensitization was greatest in females. Five and 25 days after the last self-administration session, we quantified responding for cocaine (0.083-0.75 mg/kg/infusion) under a progressive ratio (PR) schedule, a measure of motivation for drug. Across conditions, females earned more cocaine infusions than males under the PR schedule. Across sexes, IntA rats earned more infusions than LgA rats, even though IntA rats had previously taken much less cocaine. Cumulative cocaine intake significantly predicted responding for cocaine under the PR schedule in male LgA rats only. In IntA rats, the extent of locomotor sensitization significantly predicted responding under the PR schedule. Thus, LgA might be appropriate to study sex differences in cocaine intake, whereas IntA might be best suited to study sex differences in sensitization-related neuroadaptations involved in cocaine addiction. This has implications for modelling distinct features of cocaine addiction in preclinical studies.
研究表明，女性从最初使用可卡因到成瘾的进展速度比男性更快。同样，雌性大鼠对可卡因的激励动机比雄性大鼠更强。在这个问题上，大多数临床前研究都使用了自我给药程序，即在每个疗程中提供连续的可卡因（“长时程”或 LgA 和“短时程”）。然而，间歇性可卡因自我给药（IntA）更好地模拟了人类可卡因使用的间歇性。在这里，我们比较了接受 10 次每日 6 小时 LgA 或 IntA 疗程的雌性和雄性大鼠的可卡因使用情况。在 LgA 下，可卡因摄入量最大，雌性 LgA 大鼠的摄入量增加。只有 IntA 大鼠（雌雄两性）对自我给予的可卡因产生了运动敏化作用，而敏化作用在雌性大鼠中最大。在最后一次自我给药疗程后 5 天和 25 天，我们在一个逐步比率（PR）方案下量化了对可卡因（0.083-0.75 mg/kg/infusion）的反应，这是衡量对药物的动机的一种措施。在所有条件下，雌性大鼠在 PR 方案下获得的可卡因输注量多于雄性大鼠。在所有性别中，IntA 大鼠获得的可卡因输注量多于 LgA 大鼠，尽管 IntA 大鼠之前摄入的可卡因要少得多。雄性 LgA 大鼠只有在累积可卡因摄入量显著预测 PR 方案下可卡因反应的情况下，可卡因摄入量才显著预测 PR 方案下的可卡因反应。在 IntA 大鼠中，运动敏化的程度显著预测了 PR 方案下的反应。因此，LgA 可能适合研究可卡因摄入量的性别差异，而 IntA 可能最适合研究可卡因成瘾中与敏化相关的神经适应性的性别差异。这对临床前研究中模拟可卡因成瘾的不同特征具有重要意义。
