PDF(Pubmed)
Abstract：
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.
摘要：
药物滥用率的上升凸显了确定改进的治疗方法的紧迫性。可以在啮齿动物中模拟的大多数寻求药物的行为都利用了反复的静脉内自我给药（SA）。最近对中胚层途径的研究表明，Kv7/KCNQ通道可能有助于从娱乐性药物向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性，实验者交付的药物模型系统，这种效应在接受自我给药训练的大鼠中的推广程度尚不清楚。这里,我们测试了瑞替加滨（ezogagabine）的能力，Kv7通道开启器，调节雄性SpragueDawley大鼠的工具行为。我们首先在条件位置偏好（CPP）测定中验证了瑞替加滨靶向实验者递送的可卡因的能力，并发现瑞替加滨降低了对位置偏好的获得。接下来,我们在固定比例或渐进比例强化计划下对大鼠进行可卡因-SA训练,发现瑞替加滨预处理可使低剂量至中等剂量可卡因的SA减弱.这在平行实验中没有观察到，大鼠自行施用蔗糖，自然的奖励。与蔗糖-SA相比，可卡因-SA与伏隔核中Kv7.5亚基表达的减少有关，在Kv7.2和Kv7.3中没有更改。因此,这些研究揭示了SA行为的奖赏特异性降低,并支持Kv7是具有功能失调的人类精神疾病的潜在治疗靶点的观点.
