A line before liquor: a novel model of cocaine and alcohol co-abuse reveals changes in glutamate homeostasis.
A line before liquor: a novel model of cocaine and alcohol co-abuse reveals changes in glutamate homeostasis.
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酒前一行：可卡因和酒精共同滥用的新模型揭示了谷氨酸稳态的变化。
DOI：
10.1038/s41386-019-0470-0
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Olive,MFoster
中科院分区：
文献类型：
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作者：
Leyrer-Jackson,JonnaM;Olive,MFoster
目前，大约 1.9% 的 12 岁及以上美国人口正在吸食可卡因，大约 0.9% 的美国人口目前符合可卡因使用障碍的诊断标准 [1]。诊断为可卡因依赖的个体与酒精依赖具有很高的共病性，超过一半的可卡因依赖个体报告同时使用酒精和可卡因[2]。酒精通常与可卡因一起使用，部分是为了抵消可卡因引起的戒断症状，相反，可卡因通常用于抵消酒精的镇静和运动损害作用[3]。同样，在遭受共同滥用的个体中，可卡因和酒精的复吸率更高[4]，认知功能障碍和各种健康问题的发生率也更高[5]。虽然确定多物质滥用背后的神经适应以及治疗此类疾病的药物开发依赖于啮齿动物模型，但多物质滥用啮齿动物模型的成功开发仍然是一个尚未解决的关键问题。许多研究广泛研究了单独使用可卡因和酒精的神经适应性，但未能解决多物质滥用可能引起的变化，以及重要的是可卡因和酒精共同滥用的共病。到目前为止，啮齿类动物研究滥用物质的神经适应性效应已经检查了中皮质边缘回路内的谷氨酸传递，因为它在介导药物寻求的复发/恢复中发挥作用。目前的大量文献得出结论，从内侧前额叶皮层到伏核的谷氨酸能传出投射的改变对药物寻求有显着贡献[6]。此外，在接触滥用药物后，谷氨酸调节机制的突触后改变，包括谷氨酸转运蛋白 GLT-1 的下调和谷氨酸/半胱氨酸交换器 xCT 的下调，已被反复证实。此外，恢复伏隔核内谷氨酸能张力的药物已显示出抑制药物寻求恢复的有希望的能力[7]。然而，对该电路进行修改的程度可能会根据药物类型、暴露时间和停药情况而有所不同。虽然谷氨酸能回路的变化为患有可卡因和酒精滥用疾病的患者提供了治疗选择的见解，但目前的研究未能解决多物质滥用和两者共病引起的可能变化。在他们最近的文章中，Stennett 等人[8]使用了连续自我施用可卡因和酒精的大鼠模型。该模型旨在探索可卡因和酒精共同使用的神经适应，这可能与单独使用这两种物质引起的神经适应不同。此外，Stennett 等人[8]确定头孢曲松是否
Approximately, 1.9% of the US population age 12 and older are current users of cocaine, and approximately 0.9% of the US population currently meet diganostic criteria for cocaine use disorder [1]. Individuals diagnosed with cocaine dependence show high comorbidity with alcohol dependence, and more than half of cocaine-dependent individuals report using both alcohol and cocaine simultaneously [2]. Alcohol is often used in conjunction with cocaine, in part, to counteract cocaine-induced withdrawal symptoms, and conversely, cocaine is often used to counteract the sedating and motor impairing effects of alcohol [3]. As well, cocaine and alcohol relapse are higher in individuals suffering from co-abuse [4], as are the incidences of cognitive dysfunction and various health issues [5]. While identifying the neuroadaptations underlying polysubstance abuse and the development of medications to treat such disorders rely on rodent models, the successful development of rodent models of polysubstance abuse remains a key unaddressed issue. Many studies have extensively studied the neuroadaptations of cocaine and alcohol use alone, yet have failed to address possible changes induced by polysubstance abuse and importantly the comorbidity of cocaine and alcohol co-abuse.Thus far, rodent studies examining the neuroadaptive effects of abused substances have examined glutamatergic transmission within the mesocorticolimbic circuitry, due to its role in mediating the relapse/reinstatement of drug seeking. A breadth of current literature has concluded that altered glutamatergic efferent projections from the medial prefrontal cortex into the nucleus accumbens significantly contributes to drug seeking [6]. In addition, postsynaptic alterations in glutamate regulation mechanisms, including downregulation of the glutamate transporter, GLT-1, and downregulation of the glutamate/cysteine exchanger, xCT, have been repeatedly shown following exposure to drugs of abuse. Further, pharmacological agents which restore glutamatergic tone within the nucleus accumbens have shown promising ability to inhibit reinstatement of drug seeking [7]. However, the degree to which modifications are made to this circuit can vary based on drug type, exposure time, and withdrawal. While changes within glutamatergic circuits have provided insight into treatment options for patients suffering from both cocaine and alcohol abuse disorders, current studies fail to address possible changes induced from polysubstance abuse and the comorbidity of the two. In their recent article, Stennett et al.[8] have used a rat model of sequential cocaine and alcohol self-administration. This model has been designed to explore neuroadaptations underlying co-use of cocaine and alcohol, which may be different than the neuroadaptations induced by either of these substances alone. In addition, Stennett et al.[8] determined whether ceftriaxone, a