K v 7 Channel Opener Retigabine Reduces Self-Administration of Cocaine but Not Sucrose in Rats.
K v 7 Channel Opener Retigabine Reduces Self-Administration of Cocaine but Not Sucrose in Rats.
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K v 7 通道开放剂瑞替加滨可减少大鼠自行服用可卡因，但不会减少蔗糖。
DOI：
10.1101/2023.05.18.541208
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Riegel,ArthurC
中科院分区：
文献类型：
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作者：
Urena,EstebanS;Diezel,CodyC;Serna,Mauricio;Hala'ufia,Grace;Majuta,Lisa;Barber,KaraR;Vanderah,ToddW;Riegel,ArthurC
药物滥用率的增加突出了确定改进的治疗方法的紧迫性。大多数可以在啮齿类动物中建模的药物寻求行为利用药物的重复静脉内自我给药（SA）。最近的研究表明，中脑边缘通路Kv 7/KCNQ通道可能有助于从娱乐到慢性药物使用的过渡。然而，到目前为止，所有这些研究都使用了非偶然的、实验者递送的药物模型系统，并且这种效应在多大程度上适用于训练自我给药的大鼠尚不清楚。在这里，我们测试了瑞替加滨（依佐加滨），一种Kv 7通道开放剂，调节雄性Sprague道利大鼠的工具行为的能力。我们首先验证了瑞替加滨在条件性位置偏好（CPP）试验中靶向实验者递送的可卡因的能力，并发现瑞替加滨减少了位置偏好的获得。接下来，我们在固定比例或渐进比例强化计划下训练大鼠可卡因-SA，发现瑞替加滨预处理减弱了低至中等剂量可卡因的SA。这在平行实验中没有观察到，大鼠自我给予蔗糖，一种自然的奖励。与蔗糖-SA相比，可卡因-SA与延髓核中Kv7.5亚基表达的减少相关，而Kv7.2和Kv7.3没有改变。因此，这些研究揭示了SA行为的奖励特异性减少，并支持Kv 7是具有功能失调的奖励回路的人类精神疾病的潜在治疗靶点的观点。
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 Kv7/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 Kv7 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 Kv7.5 subunit in the nucleus accumbens, without alterations in Kv7.2 and Kv7.3. Therefore, these studies reveal a reward‐specific reduction in SA behaviour and support the notion that Kv7 is a potential therapeutic target for human psychiatric diseases with dysfunctional reward circuitry.