Iptakalim attenuates self-administration and acquired goal-tracking behavior controlled by nicotine.
Iptakalim attenuates self-administration and acquired goal-tracking behavior controlled by nicotine.
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DOI：
10.1016/j.neuropharm.2013.07.019
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发表时间：
2013-12
影响因子：
4.7
通讯作者：
Bevins RA
中科院分区：
文献类型：
--
作者：
Charntikov S;Swalve N;Pittenger S;Fink K;Schepers S;Hadlock GC;Fleckenstein AE;Hu G;Li M;Bevins RA
埃他卡林是一种ATP敏感性钾通道开放剂，也是一种含α4β2的烟碱乙酰胆碱受体（nAChR）拮抗剂。预处理埃他卡林减少尼古丁诱导的多巴胺（DA）和谷氨酸释放在延髓核。这种神经药理学特征表明，埃他卡林可用于治疗尼古丁依赖。因此，我们研究了埃他卡林在两个临床前模型中的作用。首先，通过在区分目标跟踪任务中训练大鼠来评价埃他卡林对尼古丁的内感受性刺激效应的影响，该任务包括混合尼古丁（0.4 mg/kg，SC）和生理盐水会话。蔗糖间歇性地呈现在一个响应独立的方式，只有尼古丁会话。在干预试验日，用埃他卡林（10、30、60 mg/kg，IP）预处理大鼠。结果显示，埃他卡林以剂量依赖性方式减弱尼古丁刺激控制的尼古丁诱发反应。在一项单独的研究中，通过训练大鼠按压以自我给予尼古丁（0.03 mg/kg/输注），研究了埃他卡林对尼古丁强化作用的影响。结果显示，用埃他卡林（1、3、6 mg/kg，IV）预处理降低了尼古丁摄入量（即，较少的主动杆响应）。行为效应既不是由于埃他卡林的非特异性运动效应，也不是由于埃他卡林抑制DA转运体（DAT）或血清素转运体（SERT）功能的能力。总之，这些发现支持了这样一种观点，即埃他卡林可能是一种有效的药物疗法，用于增加戒烟，更好地了解其作用可能有助于药物开发。
Iptakalim is an ATP-sensitive potassium channel opener, as well as an α4β2-containing nicotinic acetylcholine receptor (nAChR) antagonist. Pretreatment with iptakalim diminishes nicotine-induced dopamine (DA) and glutamate release in the nucleus accumbens. This neuropharmacological profile suggests that iptakalim may be useful for treatment of nicotine dependence. Thus, we examined the effects of iptakalim in two preclinical models. First, the impact of iptakalim on the interoceptive stimulus effect of nicotine was evaluated by training rats in a discriminated goal-tracking task that included intermixed nicotine (0.4 mg/kg, SC) and saline sessions. Sucrose was intermittently presented in a response-independent manner only on nicotine sessions. On intervening test days, rats were pretreated with iptakalim (10, 30, 60 mg/kg, IP). Results revealed that iptakalim attenuated nicotine-evoked responding controlled by the nicotine stimulus in a dose-dependent manner. In a separate study, the impact of iptakalim on the reinforcing effects of nicotine was investigated by training rats to lever-press to self-administer nicotine (0.03 mg/kg/infusion). Results revealed that pretreatment with iptakalim (1, 3, 6 mg/kg, IV) decreased nicotine intake (i.e., less active lever responding). Neither behavioral effect was due to a non-specific motor effect of iptakalim, nor to an ability of iptakalim to inhibit DA transporter (DAT) or serotonin transporter (SERT) function. Together, these finding support the notion that iptakalim may be an effective pharmacotherapy for increasing smoking cessation and better understanding its action could contribute medication development.
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