The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats
The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats
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DOI：
10.1007/s00213-007-0905-x
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发表时间：
2007-12-01
影响因子：
3.4
通讯作者：
Le, A. D.
中科院分区：
文献类型：
--
作者：
Marinelli, Peter W.;Funk, Douglas;Le, A. D.
育亨宾是一种α-2肾上腺素受体拮抗剂，在人类和实验动物中引起应激和焦虑样反应。在大鼠中，育亨宾增加操作性酒精自我管理和恢复酒精寻求。在这项研究中，我们评估是否这些影响育亨宾全身注射的促肾上腺皮质激素释放因子1（CRF 1）受体拮抗剂antalarmin衰减。1，我们训练大鼠杠杆按酒精溶液（12%w/v，1小时/天）在几个星期内;在训练期间，响应要求从固定比例-1（FR-1）增加到固定比例-3（FR-3）强化计划。然后，我们测试了antalarmin（10或20 mg/kg）对育亨宾（1.25 mg/kg）诱导的操作性酒精自我给药（FR-3强化方案）增加的影响。随后，我们评估了antalarmin对育亨宾诱导的先前自我给药大鼠血浆皮质酮水平升高的影响。在Exp. 2，我们训练大鼠自我给药酒精，如在实验。结果育亨宾可增加操作性酒精自我给药，并使酒精强化的杠杆反应消失13天后，再恢复酒精寻求。育亨宾的这些作用可被安他拉明减弱。在没有育亨宾的情况下注射安他拉明对操作性酒精自我给药或消退反应没有影响。安他拉明没有影响育亨宾诱导的皮质酮释放酒精experiencedrats.Conclusions这些结果表明，下丘脑外的CRF 1受体参与育亨宾对操作性酒精自我管理和酒精寻求复发的影响，并支持CRF 1受体拮抗剂应考虑在酒精成瘾治疗的概念。
Rationale and objectives Yohimbine is an alpha-2 adrenoreceptor antagonist that provokes stress- and anxiety-like responses in both humans and laboratory animals. In rats, yohimbine increases operant alcohol self-administration and reinstates alcohol seeking. In this study, we assess whether these effects of yohimbine are attenuated by systemic injections of the corticotrotropin-releasing factor 1 (CRF1) receptor antagonist antalarmin.Materials and methods In Exp. 1, we trained rats to lever press for alcohol solutions (12% w/v, 1 h/day) over several weeks; during training, the response requirement was increased from a fixed-ratio-1 (FR-1) to a fixed-ratio-3 (FR-3) reinforcement schedule. We then tested the effect of antalarmin (10 or 20 mg/kg) on yohimbine (1.25 mg/kg)-induced increases in operant alcohol self-administration (FR-3 reinforcement schedule). Subsequently, we assessed the effect of antalarmin on yohimbine-induced increases in plasma corticosterone levels in the previously self-administering rats. In Exp. 2, we trained the rats to self-administer alcohol as in Exp. 1, and after extinction of the alcohol-reinforced lever responding over 13 days, we tested antalarmin's effect on yohimbine-induced reinstatement of alcohol seeking.Results Yohimbine increased operant alcohol self-administration and reinstated alcohol seeking after extinction. These effects of yohimbine were attenuated by antalarmin. Antalarmin injections in the absence of yohimbine had no effect on either operant alcohol self-administration or extinction responding. Antalarmin had no effect on yohimbine-induced corticosterone release in alcohol-experienced rats.Conclusions These results suggest that extrahypothalamic CRF1 receptors are involved in the effect of yohimbine on operant alcohol self-administration and on relapse to alcohol seeking and support the notion that CRF1 receptor antagonists should be considered in alcohol addiction treatment.