Urena Esteban S, Diezel Cody C, Serna Mauricio, Hala'ufia Grace, Majuta Lisa, Barber Kara R, Vanderah Todd W, Riegel Arthur C
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, USA.
Neuroscience Graduate Interdisciplinary Program, University of Arizona, Tucson, Arizona, USA.
Addict Biol. 2024 Aug;29(8):e13428. doi: 10.1111/adb.13428.
The increasing rates of drug misuse highlight the urgency of identifying improved therapeutics for treatment. Most drug-seeking behaviours that can be modelled in rodents utilize the repeated intravenous self-administration (SA) of drugs. Recent studies examining the mesolimbic pathway suggest that K7/KCNQ channels may contribute to the transition from recreational to chronic drug use. However, to date, all such studies used noncontingent, experimenter-delivered drug model systems, and the extent to which this effect generalizes to rats trained to self-administer drugs is not known. Here, we tested the ability of retigabine (ezogabine), a K7 channel opener, to regulate instrumental behaviour in male Sprague Dawley rats. We first validated the ability of retigabine to target experimenter-delivered cocaine in a conditioned place preference (CPP) assay and found that retigabine reduced the acquisition of place preference. Next, we trained rats for cocaine-SA under a fixed-ratio or progressive-ratio reinforcement schedule and found that retigabine pretreatment attenuated the SA of low to moderate doses of cocaine. This was not observed in parallel experiments, with rats self-administering sucrose, a natural reward. Compared with sucrose-SA, cocaine-SA was associated with reductions in the expression of the K7.5 subunit in the nucleus accumbens, without alterations in K7.2 and K7.3. Therefore, these studies reveal a reward-specific reduction in SA behaviour and support the notion that K7 is a potential therapeutic target for human psychiatric diseases with dysfunctional reward circuitry.
药物滥用率的不断上升凸显了确定改进治疗方法以进行治疗的紧迫性。大多数可在啮齿动物中模拟的觅药行为都利用了药物的重复静脉自我给药（SA）。最近对中脑边缘通路的研究表明，K7/KCNQ通道可能有助于从娱乐性用药向慢性用药的转变。然而，迄今为止，所有此类研究都使用了非偶然性的、由实验者给予药物的模型系统，而这种效应在训练有素的自我给药大鼠中普遍存在的程度尚不清楚。在这里，我们测试了K7通道开放剂瑞替加滨（依佐加滨）调节雄性Sprague Dawley大鼠工具性行为的能力。我们首先在条件性位置偏爱（CPP）试验中验证了瑞替加滨针对实验者给予的可卡因的能力，发现瑞替加滨减少了位置偏爱的获得。接下来，我们在固定比率或累进比率强化方案下训练大鼠进行可卡因自我给药，发现瑞替加滨预处理减弱了低至中等剂量可卡因的自我给药。在平行实验中，大鼠自我给药蔗糖（一种天然奖励）时未观察到这种情况。与蔗糖自我给药相比，可卡因自我给药与伏隔核中K7.5亚基表达的降低有关，而K7.2和K7.3没有改变。因此，这些研究揭示了自我给药行为中特定奖励的减少，并支持K7是具有功能失调奖励回路的人类精神疾病潜在治疗靶点的观点。
