Changes in endocannabinoid and N-acylethanolamine levels in rat brain structures following cocaine self-administration and extinction training
Changes in endocannabinoid and N-acylethanolamine levels in rat brain structures following cocaine self-administration and extinction training
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DOI：
10.1016/j.pnpbp.2013.12.002
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发表时间：
2014-04-03
影响因子：
5.6
通讯作者：
Filip, Malgorzata
中科院分区：
文献类型：
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作者：
Bystrowska, Beata;Smaga, Irena;Filip, Malgorzata
临床前研究表明，滥用药物会改变啮齿动物大脑中基于脂质的信号分子的水平，包括内源性大麻素（eCBs）和n -酰基乙醇胺（NAEs）。此外，一些靶向eCBs和/或NAEs的药物涉及与刺激大脑多巴胺系统相关的奖励和/或寻求行为。在本研究中，采用LC-MS/MS方法分析了可卡因自我给药期间大鼠脑内eCBs （anandamide （AEA）和2-花生四烯醇甘油（2-AG））和NAEs （oil - yl乙醇酰胺（OEA）和棕榈酰乙醇酰胺（PEA））的水平，并根据“双联”对照程序进行了灭绝训练。重复（14天）可卡因（0.5 mg/kg/输注）自我给药和联合给药导致小脑中AEA水平显著降低（约52%），而额叶皮质、海马和小脑中2-AG水平升高，海马和背纹状体中2-AG水平降低。此外，我们检测到两个可卡因处理组边缘区域的OEA和PEA水平增加（b> 150%），并且仅在可卡因成瘾组中背纹状体的OEA组织水平增加，背纹状体（两个可卡因组）和伏隔核（仅可卡因成瘾组）的PEA组织水平增加。与生理盐水对照组相比，消失训练（10天）导致额叶皮质、海马和伏隔核中的AEA水平以及海马、背纹状体和小脑中的2-AG水平显著降低。自我服用可卡因的大鼠大脑边缘和皮层下区域的减少更为明显。在灭绝之后，先前注射可卡因的大鼠的NAEs水平发生了区域特异性变化；在前额叶皮层和海马体中检测到OEA和PEA水平的显著增加（约100%），而纹状体区域与盐水对照动物相比有所下降。我们的发现支持了之前的药理学证据，即eCB系统和NAEs参与了积极强化行为的强化和消失，这些脂质衍生分子可能代表了开发药物成瘾新疗法的有希望的靶点。(C) 2014爱思唯尔公司版权所有。
Preclinical investigations have demonstrated that drugs of abuse alter the levels of lipid-based signalling molecules, including endocannabinoids (eCBs) and N-acylethanolamines (NAEs), in the rodent brain. In addition, several drugs targeting eCBs and/or NAEs are implicated in reward and/or seeking behaviours related to the stimulation of dopamine systems in the brain.In our study, the brain levels of eCBs (anandamide (AEA) and 2-arachidonoylglycerol (2-AG)) and NAEs (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)) were analyzed via an LC-MS/MS method in selected brain structures of rats during cocaine self-administration and after extinction training according to the "yoked" control procedure.Repeated (14 days) cocaine (0.5 mg/kg/infusion) self-administration and yoked drug delivery resulted in a significant decrease (ca. 52%) in AEA levels in the cerebellum, whereas levels of 2-AG increased in the frontal cortex, the hippocampus and the cerebellum and decreased in the hippocampus and the dorsal striatum. In addition, we detected increases (> 150%) in the levels of OEA and PEA in the limbic areas in both cocaine treated groups, as well as an increase in the tissue levels of OEA in the dorsal striatum in only the yoked cocaine group and increases in the tissue levels of PEA in the dorsal striatum (both cocaine groups) and the nucleus accumbens (yoked cocaine group only). Compared to the yoked saline control group, extinction training (10 days) resulted in a potent reduction in AEA levels in the frontal cortex, the hippocampus and the nucleus accumbens and in 2-AG levels in the hippocampus, the dorsal striatum and the cerebellum. The decreases in the limbic and subcortical areas were more apparent for rats that self-administered cocaine. Following extinction, there was a region-specific change in the levels of NAEs in rats previously injected with cocaine; a potent increase (ca. 100%) in the levels of OEA and PEA was detected in the prefrontal cortex and the hippocampus, whilst a drop was noted in the striatal areas versus yoked saline yoked animals.Our findings support the previous pharmacological evidence that the eCB system and NAEs are involved in reinforcement and extinction of positively reinforced behaviours and that these lipid-derived molecules may represent promising targets for the development of new treatments for drug addiction. (C) 2014 Elsevier Inc. All rights reserved.