Georgiou Polymnia, Zanos Panos, Garcia-Carmona Juan-Antonio, Hourani Susanna, Kitchen Ian, Kieffer Brigitte L, Laorden Maria-Luisa, Bailey Alexis
Sleep, Chronobiology & Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH Surrey, UK.
Department of Pharmacology, School of Medicine, University of Murcia, Spain.
Eur Neuropsychopharmacol. 2015 Dec;25(12):2459-64. doi: 10.1016/j.euroneuro.2015.09.015. Epub 2015 Oct 9.
Relapse to illicit drug-seeking following abstinence is a major challenge for the treatment of addiction as no effective pharmacotherapy is available. We have recently shown that activating the central oxytocinergic system prevents emotional impairment and stress-induced reinstatement associated with opioid withdrawal. Here, we investigated whether the oxytocin analogue carbetocin (CBT) is able to reverse morphine-primed reinstatement of conditioned-place preference (CPP) in mice. The mechanism underlining the behavioural effect of CBT was investigated by assessing the involvement of the striatal noradrenergic and dopaminergic systems in CBT reversal of priming- and stress-induced reinstatement of opioid CPP. In addition, given recent evidence suggesting the presence of oxytocin receptor (OTR)-μ-opioid receptor (MOPr) interactions in the brain, we further explored these interactions by carrying out OTR autoradiographic binding in brain of mice lacking MOPr. CBT administration prevented priming-induced reinstatement of morphine CPP. While an acute effect of CBT in enhancing dopamine turnover was observed following stress- and priming-induced reinstatement, CBT significantly decreased striatal noradrenaline turnover only following priming-induced reinstatement. Moreover, a significant brain region- specific increase in OTR binding was observed in MOPr knockout mice, indicating the presence of a possible OTR-MOPr interaction, which may be involved in the modulation of relapse. These results support the oxytocinergic system as a promising target for the prevention of relapse to opioid use and highlight the differential involvement of monoaminergic systems on the effects of OTR stimulation in preventing stress- and priming-induced reinstatement of opioid CPP behaviour.
戒毒后复吸寻求非法药物是成瘾治疗的一项重大挑战，因为目前尚无有效的药物疗法。我们最近发现，激活中枢催产素能系统可预防与阿片类药物戒断相关的情绪障碍和应激诱导的复吸。在此，我们研究了催产素类似物卡贝缩宫素（CBT）是否能够逆转小鼠中吗啡引发的条件性位置偏爱（CPP）复吸。通过评估纹状体去甲肾上腺素能和多巴胺能系统在CBT逆转阿片类CPP引发和应激诱导的复吸中的作用，研究了CBT行为效应的潜在机制。此外，鉴于最近有证据表明大脑中存在催产素受体（OTR）-μ-阿片受体（MOPr）相互作用，我们通过在缺乏MOPr的小鼠大脑中进行OTR放射自显影结合，进一步探索了这些相互作用。给予CBT可预防吗啡CPP引发的复吸。虽然在应激和引发诱导的复吸后观察到CBT对增强多巴胺周转有急性作用，但CBT仅在引发诱导的复吸后显著降低纹状体去甲肾上腺素周转。此外，在MOPr基因敲除小鼠中观察到OTR结合在大脑区域有显著特异性增加，表明可能存在OTR-MOPr相互作用，这可能参与复吸的调节。这些结果支持将催产素能系统作为预防阿片类药物复吸的一个有前景的靶点，并突出了单胺能系统在OTR刺激预防阿片类CPP行为的应激和引发诱导复吸效应中的不同作用。
