食欲素/下丘脑泌素-1受体拮抗作用可选择性降低高动机大鼠的乙醇自我给药及复吸行为。

Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats.

作者信息

Moorman David E, James Morgan H, Kilroy Elisabeth A, Aston-Jones Gary

机构信息

Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Psychological and Brain Sciences & Neuroscience and Behavior Graduate Program, University of Massachusetts Amherst, Amherst, MA 01003, USA.

Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA; Brain Health Institute, Rutgers University/Rutgers Biomedical and Health Sciences, Piscataway, NJ 08854, USA; The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia.

出版信息

Brain Res. 2017 Jan 1;1654(Pt A):34-42. doi: 10.1016/j.brainres.2016.10.018. Epub 2016 Oct 19.

Abstract

The orexin/hypocretin (ORX) system regulates motivation for natural rewards and drugs of abuse such as alcohol. ORX receptor antagonists, most commonly OX1R antagonists including SB-334867 (SB), decrease alcohol drinking, self-administration and reinstatement in both genetically-bred alcohol-preferring and outbred strains of rats. Importantly, levels of alcohol seeking and drinking in outbred rats are variable, as they are in humans. We have shown that OX1R antagonism selectively decreases homecage alcohol drinking in high-, but not low-alcohol-preferring rats. It is unknown, however, whether this effect is selective to homecage drinking or whether it also applies to alcohol seeking paradigms such as self-administration and reinstatement following extinction, in which motivation is high in the absence of alcohol. Here we trained Sprague Dawley rats to self-administer 20% ethanol paired with a light-tone cue on an FR3 regimen. Rats were then extinguished and subjected to cue-induced reinstatement. Rats were segregated into high- and low-ethanol-responding groups (HR and LR) based on self-administration levels. During self-administration and cue-induced reinstatement, rats were given SB or vehicle prior to ethanol seeking. In both conditions, OX1R antagonism decreased responding selectively in HR, but not LR rats. There were no non-specific effects of SB treatment on arousal or general behavior. These data indicate that ORX signaling at the OX1R receptor specifically regulates high levels of motivation for alcohol, even in the absence of direct alcohol reinforcement. This implicates the ORX system in the pathological motivation underlying alcohol abuse and alcoholism and demonstrates that the OX1R may be an important target for treating alcohol abuse.

摘要

食欲素/下丘脑泌素(ORX)系统调节对自然奖赏以及酒精等成瘾性药物的动机。ORX受体拮抗剂,最常见的是包括SB - 334867(SB)在内的OX1R拮抗剂,可减少基因培育的嗜酒大鼠和远交系大鼠的酒精摄入量、自我给药量及复吸率。重要的是,远交系大鼠的酒精寻求和摄入量存在个体差异,就像人类一样。我们已经表明,OX1R拮抗作用可选择性降低高嗜酒但非低嗜酒大鼠在笼内的酒精摄入量。然而,尚不清楚这种作用是否仅针对笼内饮酒,还是也适用于自我给药和戒断后复吸等酒精寻求范式,在这些范式中,即使没有酒精时动机也很高。在这里,我们训练斯普拉格 - 道利大鼠在固定比率为3的强化程序下自我给药20%乙醇,并伴有轻音提示。然后使大鼠戒断,并进行线索诱导的复吸实验。根据自我给药水平将大鼠分为高乙醇反应组和低乙醇反应组(HR和LR)。在自我给药和线索诱导的复吸过程中,在大鼠寻求乙醇之前给予SB或赋形剂。在两种情况下,OX1R拮抗作用均选择性降低了HR组大鼠的反应,但对LR组大鼠没有影响。SB处理对觉醒或一般行为没有非特异性影响。这些数据表明,即使在没有直接酒精强化的情况下,OX1R受体处的ORX信号传导也特异性调节对酒精的高水平动机。这表明ORX系统参与了酒精滥用和酒精中毒的病理动机,并证明OX1R可能是治疗酒精滥用的重要靶点。

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