Reversing Cocaine-Induced Adaptations and Reducing Relapse: An Opportunity for Repurposing Riluzole.
Reversing Cocaine-Induced Adaptations and Reducing Relapse: An Opportunity for Repurposing Riluzole.
复制标题
逆转可卡因引起的适应并减少复发：重新利用利鲁唑的机会。
DOI：
10.1038/npp.2017.300
复制
发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Ziminski JJ
中科院分区：
文献类型：
--
作者：
Ziminski JJ
吸毒复发率高通常是由接触毒品相关线索或滥用药物引发的，它们是成功治疗吸毒成瘾的主要障碍（O’Brien，2005）。尽管迄今为止进行了多年的深入研究，但仍缺乏治疗复发的有效药物。发现潜在有效减少复发的药物背后的核心原则是识别能够逆转药物引起的大脑变化的药理学化合物，特别是那些与动机和奖励有关的区域，例如内侧前额叶皮层（mPFC）和伏核。过去 10-15 年的大量临床前研究表明，反复接触可卡因会导致 mPFC 和伏隔核的内在神经元兴奋性、谷氨酸突触可塑性和谷氨酸摄取异常（Kalivas 和 Kalivas，2016；Kourrich 等，2015）。因此，非常需要一种抗复发化合物来使这些类型的广泛的药物引起的变化重新正常化。此外，具有已知安全记录、已经通过临床试验并上市的化合物将大大增强其需求。在本期《神经精神药理学》中，Sepulveda-Orengo 等人 (2017) 研究了利鲁唑（一种目前用于治疗肌萎缩侧索硬化症的化合物）是否可以使这些类型的适应重新正常化，并防止线索诱导和可卡因引发的可卡因寻求的恢复。作者利用该化合物，因为它具有多靶点定向作用：(1) 通过抑制电压门控 Na+ 通道来阻断动作电位 (AP) 启动（Cheah 等人，2010）；(2) 增加谷氨酸转运蛋白的表达和活性（Brothers 等人，2013）； (3)通过Ca+2通道抑制来抑制突触谷氨酸释放(Cheah等人，2010)。最初，作者在消退学习过程中（每次消退期之前）和恢复测试之前重复施用利鲁唑，这减弱了提示和可卡因引发的可卡因寻求的恢复。这种效果不是由于该化合物的任何运动失活作用，因为重复施用利鲁唑并没有减弱提示诱导的蔗糖寻求的恢复，也没有减弱一般的可卡因寻求的恢复。 运动活动。接下来，Sepulveda-Orengo 等人于 2017 年利用脑切片电生理学检查了利鲁唑是否会逆转可卡因自我给药消退后 mPFC 前边缘 (PL) 和边缘下 (IL) 区域锥体细胞的内在兴奋性适应。这种内在的兴奋性适应调节神经元引发 AP 的能力，从而与其他神经元进行通信。 PL 和 IL 区域在可卡因寻找中具有不同的作用，其中 PL 的功能是驱动响应，而 IL 则介导响应抑制（Gourley 和 Taylor，2016；Peters 等，2008）。作者发现，在注入电流后，PL 和 IL 神经元的兴奋性在放电能力水平上分别增强和减弱。这些内在兴奋性变化的背后是 AP 超极化后快成分的变化，这有助于 AP 的复极化阶段。此外，还观察到伏隔核中谷氨酸转运蛋白“GLT-1”的表达减少。该分子通过去除谷氨酸来严格控制细胞外谷氨酸水平，并且重新正常化可卡因诱导的该分子的减少已被证明可以减少可卡因寻求（Kalivas 和 Kalivas，2016）。有趣的是，利鲁唑逆转了这两种兴奋性适应……
High rates of relapse to drug taking are often triggered by exposure to drug-associated cues or drugs of abuse, and they present a major obstacle for the successful treatment of drug addiction (O’Brien, 2005). Despite years of intensive research efforts to date, there is a paucity of effective medications to treat relapse. A core principle behind discovering potentially effective drugs to reduce relapse has been to identify pharmacological compounds that reverse drug-induced changes in the brain, in particular those areas implicated in motivation and reward, such as the medial prefrontal cortex (mPFC) and nucleus accumbens. A plethora of pre-clinical studies from the last 10–15 years have revealed that repeated cocaine exposure produces abnormalities in intrinsic neuronal excitability, glutamatergic synaptic plasticity, and glutamate uptake, in the mPFC and accumbens (Kalivas and Kalivas, 2016; Kourrich et al, 2015). Thus, it would be highly desirable for an anti-relapse compound to renormalize these types of widespread drug-induced changes. Moreover, a compound with a known safety record that has already passed clinical trials and existing on the market would greatly enhance its desirability. In this issue of Neuropsychopharmacology, Sepulveda-Orengo et al, 2017 investigated whether Riluzole, a compound that is currently in use for treating amyotrophic lateral sclerosis (Traynor et al, 2006), could renormalize these types of adaptations and prevent the reinstatement of cue-induced and cocaine-primed cocaine-seeking. The authors took advantage of this compound because of its multi-target directed action to (1) block action potential (AP) initiation via inhibiting voltage-gated Na+ channels (Cheah et al, 2010);(2) increase expression and activity of glutamate transporters (Brothers et al, 2013); and (3) inhibit synaptic glutamate release via Ca+ 2 channel inhibition (Cheah et al, 2010). Initially, the authors repeatedly administered Riluzole during extinction learning (before each extinction session) and before the reinstatement test, which attenuated reinstatement of cue-and cocaine-primed cocaine seeking.This effect was not due to any locomotor inactivating effects of the compound, as repeated Riluzole administration did not attenuate the reinstatement of cue-induced sucrose seeking nor general locomotor activity. Next, using brain slice electrophysiology, Sepulveda-Orengo et al, 2017 examined whether Riluzole would reverse the intrinsic excitability adaptations in pyramidal cells from the prelimbic (PL) and infralimbic (IL) regions of the mPFC following extinction from cocaine self-administration. Such intrinsic excitability adaptations modulate the ability of a neuron to elicit an AP and thus communicate with other neurons. The PL and IL areas have distinct roles in cocaine seeking, in which the PL functions to drive responding while the IL mediates response inhibition (Gourley and Taylor, 2016; Peters et al, 2008). The authors found that PL and IL neuronal excitability was enhanced and attenuated, respectively, at the level of firing capacity following electrical current injections. Underlying these changes in intrinsic excitability were alterations in the fast after hyperpolarization component of the AP, which contributes to the repolarization phase of the AP. Furthermore, decreased expression of the glutamate transporter ‘GLT-1’in the nucleus accumbens was also observed. This molecule critically controls extracellular glutamate levels by removing glutamate, and renormalizing cocaine-induced decreases of this molecule has been shown to decrease cocaine-seeking (Kalivas and Kalivas, 2016). Interestingly, Riluzole reversed both the excitability adaptations …