Poznanski Piotr, Lesniak Anna, Korostynski Michal, Szklarczyk Klaudia, Lazarczyk Marzena, Religa Piotr, Bujalska-Zadrozny Magdalena, Sadowski Bogdan, Sacharczuk Mariusz
Laboratory of Neurogenomics and Department of Animal Behaviour, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, Postepu 36A Str., 05-552 Magdalenka, Poland.
Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland.
Neuropharmacology. 2017 May 15;118:90-101. doi: 10.1016/j.neuropharm.2017.03.016. Epub 2017 Mar 18.
The opioid system modulates the central reinforcing effects of ethanol and participates in the etiology of addiction. However, the pharmacotherapy of ethanol dependence targeted on the opioid system is little effective and varies due to individual patients' sensitivity. In the present study, we used two mouse lines with high (HA) and low (LA) activity of the endogenous opioid system to analyze the effect of opioid receptor blockade on ethanol drinking behavior. We found that LA and HA lines characterized by divergent magnitudes of swim stress-induced analgesia also differ in ethanol intake and preference. Downregulation of the opioid system in LA mice was associated with increased ethanol consumption. Treatment with a non-selective opioid receptor antagonist (naloxone) had no effect on ethanol intake in this line. Surprisingly, in HA mice, the blockage of opioid receptors led to excessive ethanol consumption. Moreover, naloxone selectively induced high levels of anxiety- and depressive-like behaviors in HA mice which was attenuated by ethanol. With the use of specific opioid receptor antagonists we showed that the naloxone-induced increase in ethanol drinking in HA mice is mediated mainly by δ and to a lower extent by μ opioid receptors. The effect of δ-opioid receptor antagonism was abolished in HA mice carrying a C320T transition in the δ-opioid receptor gene (EU446125.1), which impairs this receptor's function. Our results indicate that high activity of the opioid system plays a protective role against ethanol dependence. Therefore, its blockage with opioid receptor antagonists may lead to a profound increase in ethanol consumption.
阿片系统调节乙醇的中枢强化作用，并参与成瘾的病因学。然而，针对阿片系统的乙醇依赖药物治疗效果不佳，且因个体患者的敏感性而异。在本研究中，我们使用了两种内源性阿片系统活性高（HA）和低（LA）的小鼠品系，以分析阿片受体阻断对乙醇饮用行为的影响。我们发现，以游泳应激诱导镇痛程度不同为特征的LA和HA品系在乙醇摄入量和偏好方面也存在差异。LA小鼠中阿片系统的下调与乙醇消耗量增加有关。用非选择性阿片受体拮抗剂（纳洛酮）治疗对该品系的乙醇摄入量没有影响。令人惊讶的是，在HA小鼠中，阿片受体的阻断导致乙醇消耗量过多。此外，纳洛酮在HA小鼠中选择性地诱导高水平的焦虑样和抑郁样行为，而乙醇可减轻这种行为。通过使用特异性阿片受体拮抗剂，我们表明纳洛酮诱导的HA小鼠乙醇饮用量增加主要由δ阿片受体介导，μ阿片受体介导的程度较低。在δ阿片受体基因（EU446125.1）中携带C320T突变的HA小鼠中，δ阿片受体拮抗作用的效果被消除，该突变损害了该受体的功能。我们的结果表明，阿片系统的高活性对乙醇依赖起保护作用。因此，用阿片受体拮抗剂阻断它可能会导致乙醇消耗量大幅增加。
