Sleep, Chronobiology & Addiction Group, Department of Biochemistry & Physiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH, Surrey, UK.
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, B-1070, Belgium.
Pharmacol Biochem Behav. 2014 Apr;119:72-9. doi: 10.1016/j.pbb.2013.05.009. Epub 2013 May 13.
There is mounting evidence that the neuropeptide oxytocin is a possible candidate for the treatment of drug addiction. Oxytocin was shown to reduce methamphetamine self-administration, conditioned place-preference, hyperactivity and reinstatement in rodents, highlighting its potential for the management of methamphetamine addiction. Thus, we hypothesised that the central endogenous oxytocinergic system is dysregulated following chronic methamphetamine administration. We tested this hypothesis by examining the effect of chronic methamphetamine administration on oxytocin receptor density in mice brains with the use of quantitative receptor autoradiographic binding. Saline (4ml/kg/day, i.p.) or methamphetamine (1mg/kg/day, i.p.) was administered daily for 10 days to male, CD1 mice. Quantitative autoradiographic mapping of oxytocin receptors was carried out with the use of [(125)I]-vasotocin in brain sections of these animals. Chronic methamphetamine administration induced a region specific upregulation of oxytocin receptor density in the amygdala and hypothalamus, but not in the nucleus accumbens and caudate putamen. As there is evidence suggesting an involvement of central adenosine A2A receptors on central endogenous oxytocinergic function, we investigated whether these methamphetamine-induced oxytocinergic neuroadaptations are mediated via an A2A receptor-dependent mechanism. To test this hypothesis, autoradiographic oxytocin receptor binding was carried out in brain sections of male CD1 mice lacking A2A receptors which were chronically treated with methamphetamine (1mg/kg/day, i.p. for 10 days) or saline. Similar to wild-type animals, chronic methamphetamine administration induced a region-specific upregulation of oxytocin receptor binding in the amygdala and hypothalamus of A2A receptor knockout mice and no genotype effect was observed. These results indicate that chronic methamphetamine use can induce profound neuroadaptations of the oxytocinergic receptor system in brain regions associated with stress, emotionality and social bonding and that these neuroadaptations are independent on the presence of A2A receptors. These results may at least partly explain some of the behavioural consequences of chronic methamphetamine use.
越来越多的证据表明，神经肽催产素可能是治疗药物成瘾的候选药物。催产素被证明可以减少老鼠的甲基苯丙胺自我给药、条件性位置偏好、过度活跃和复吸，突出了其管理甲基苯丙胺成瘾的潜力。因此，我们假设慢性甲基苯丙胺给药后中枢内源性催产素能系统失调。我们通过使用定量受体放射自显影结合来检查慢性甲基苯丙胺给药对小鼠大脑中催产素受体密度的影响，从而检验了这一假设。雄性 CD1 小鼠每天接受生理盐水（4ml/kg/天，腹腔注射）或甲基苯丙胺（1mg/kg/天，腹腔注射）治疗 10 天。用 [(125)I]-血管加压素对这些动物的大脑切片进行催产素受体的定量放射自显影定位。慢性甲基苯丙胺给药诱导杏仁核和下丘脑催产素受体密度的区域特异性上调，但纹状体和尾状核无变化。有证据表明，中枢腺苷 A2A 受体参与中枢内源性催产素能功能，我们研究了这些中枢内源性催产素能神经适应性变化是否通过 A2A 受体依赖性机制介导。为了检验这一假设，我们对缺乏 A2A 受体的雄性 CD1 小鼠进行了脑切片的放射自显影催产素受体结合实验，这些小鼠接受了慢性甲基苯丙胺（1mg/kg/天，腹腔注射 10 天）或生理盐水治疗。与野生型动物相似，慢性甲基苯丙胺给药诱导 A2A 受体敲除小鼠的杏仁核和下丘脑催产素受体结合的区域特异性上调，且未观察到基因型效应。这些结果表明，慢性甲基苯丙胺使用可诱导与应激、情感和社交联系相关的大脑区域中催产素能受体系统的深刻神经适应性变化，并且这些神经适应性变化独立于 A2A 受体的存在。这些结果至少可以部分解释慢性甲基苯丙胺使用的一些行为后果。
