Sleep, Chronobiology and Addiction Group, School of Biosciences and Medicine, Department of Biochemistry and Physiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
Neuropsychopharmacology. 2014 Mar;39(4):855-65. doi: 10.1038/npp.2013.285. Epub 2013 Oct 15.
The main challenge in treating opioid addicts is to maintain abstinence due to the affective consequences associated with withdrawal which may trigger relapse. Emerging evidence suggests a role of the neurohypophysial peptide oxytocin (OT) in the modulation of mood disorders as well as drug addiction. However, its involvement in the emotional consequences of drug abstinence remains unclear. We investigated the effect of 7-day opioid abstinence on the oxytocinergic system and assessed the effect of the OT analogue carbetocin (CBT) on the emotional consequences of opioid abstinence, as well as relapse. Male C57BL/6J mice were treated with a chronic escalating-dose morphine regimen (20-100 mg/kg/day, i.p.). Seven days withdrawal from this administration paradigm induced a decrease of hypothalamic OT levels and a concomitant increase of oxytocin receptor (OTR) binding in the lateral septum and amygdala. Although no physical withdrawal symptoms or alterations in the plasma corticosterone levels were observed after 7 days of abstinence, mice exhibited increased anxiety-like and depressive-like behaviors and impaired sociability. CBT (6.4 mg/kg, i.p.) attenuated the observed negative emotional consequences of opioid withdrawal. Furthermore, in the conditioned place preference paradigm with 10 mg/kg morphine conditioning, CBT (6.4 mg/kg, i.p.) was able to prevent the stress-induced reinstatement to morphine-seeking following extinction. Overall, our results suggest that alterations of the oxytocinergic system contribute to the mechanisms underlying anxiety, depression, and social deficits observed during opioid abstinence. This study also highlights the oxytocinergic system as a target for developing pharmacotherapy for the treatment of emotional impairment associated with abstinence and thereby prevention of relapse.
治疗阿片类成瘾者的主要挑战是由于戒断相关的情感后果而保持戒断，这可能会引发复发。新出现的证据表明神经垂体肽催产素（OT）在调节情绪障碍以及药物成瘾方面具有重要作用。然而，其在药物戒断的情感后果中的参与仍不清楚。我们研究了 7 天阿片类药物戒断对催产素能系统的影响，并评估了 OT 类似物卡贝缩宫素（CBT）对阿片类药物戒断的情感后果以及复发的影响。雄性 C57BL/6J 小鼠接受慢性递增剂量吗啡方案（20-100mg/kg/天，ip）治疗。从这种给药方案中戒断 7 天会导致下丘脑 OT 水平降低，同时 lateral septum 和杏仁核中的催产素受体（OTR）结合增加。尽管在戒断 7 天后没有观察到身体戒断症状或血浆皮质酮水平的改变，但小鼠表现出焦虑样和抑郁样行为增加以及社交能力受损。CBT（6.4mg/kg，ip）减轻了观察到的阿片类药物戒断的负面情绪后果。此外，在 10mg/kg 吗啡条件作用的条件性位置偏好范式中，CBT（6.4mg/kg，ip）能够防止在消退后应激诱导的对吗啡寻求的复燃。总体而言，我们的研究结果表明，催产素能系统的改变有助于解释阿片类药物戒断期间观察到的焦虑、抑郁和社交缺陷的机制。这项研究还强调了催产素能系统作为开发治疗与戒断相关的情感障碍的药理学治疗方法的靶标，从而预防复发。
