Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, USA.
Addict Biol. 2022 May;27(3):e13165. doi: 10.1111/adb.13165.
This study investigated the potential therapeutic effects of the FDA-approved drug metformin on cue-induced reinstatement of cocaine seeking. Metformin (dimethyl-biguanide) is a first-line treatment for type II diabetes that, among other mechanisms, is involved in the activation of adenosine monophosphate activated protein kinase (AMPK). Cocaine self-administration and extinction is associated with decreased levels of phosphorylated AMPK within the nucleus accumbens core (NAcore). Previously, it was shown that increasing AMPK activity in the NAcore decreased cue-induced reinstatement of cocaine seeking. Decreasing AMPK activity produced the opposite effect. The goal of the present study was to determine if metformin in the NAcore reduces cue-induced cocaine seeking in adult male and female Sprague Dawley rats. Rats were trained to self-administer cocaine followed by extinction prior to cue-induced reinstatement trials. Metformin microinjected in the NAcore attenuated cue-induced reinstatement in male and female rats. Importantly, metformin's effects on cocaine seeking were not due to a general depression of spontaneous locomotor activity. In female rats, metformin's effects did generalize to a reduction in cue-induced reinstatement of sucrose seeking. These data support a potential role for metformin as a pharmacotherapy for cocaine use disorder but warrant caution given the potential for metformin's effects to generalize to a natural reward in female rats.
本研究探讨了已获美国食品和药物管理局批准的药物二甲双胍对可卡因觅药行为的线索诱导复吸的潜在治疗效果。二甲双胍（双胍盐酸盐）是治疗 II 型糖尿病的一线药物，其通过多种机制激活单磷酸腺苷激活的蛋白激酶（AMPK）。可卡因的自我给药和消退与伏隔核核心（NAcore）内磷酸化 AMPK 水平降低有关。先前的研究表明，增加 NAcore 中的 AMPK 活性可减少可卡因线索诱导的觅药行为。降低 AMPK 活性则会产生相反的效果。本研究的目的是确定 NAcore 中的二甲双胍是否能减少成年雄性和雌性 Sprague Dawley 大鼠的可卡因线索诱导觅药行为。大鼠接受可卡因自我给药训练，然后进行消退训练，再进行线索诱导复吸试验。NAcore 中的二甲双胍可减弱雄性和雌性大鼠的可卡因线索诱导复吸。重要的是，二甲双胍对可卡因觅药行为的影响并非由于自发运动活动的普遍抑制。在雌性大鼠中，二甲双胍的作用可推广到减少可卡因线索诱导的蔗糖觅药行为。这些数据支持二甲双胍作为可卡因使用障碍的一种药物治疗的潜在作用，但鉴于其对雌性大鼠自然奖励的作用可能会泛化，因此需要谨慎对待。
