背景:胰淀素受体由降钙素受体(CTR)和三种受体活性修饰蛋白(RAMPs)之一组成。在处理奖励的区域中识别胰淀素受体,即背外侧被盖区(LDTg),腹侧被盖区(VTA),和伏隔核(NAc),将他们归因于奖励监管机构。的确,胰淀素受体激动剂鲑鱼降钙素(sCT)对胰淀素受体的急性激活减弱了啮齿动物中酒精诱导的行为。
目的:长期服用sCT对酒精相关行为的影响以及这些过程的分子机制尚未阐明。为了填补这一知识空白,我们研究了亚慢性sCT治疗对小鼠对酒精运动刺激反应的影响及其分子途径.
方法:我们通过小鼠运动活动实验评估了亚慢性sCT治疗的行为效应。我们使用蛋白质印迹来鉴定CTR水平的变化,并使用离体生化分析来检测单胺及其代谢物的变化。
结果:在停止sCT治疗5天后,与载体相比,在用sCT预处理的小鼠中,酒精不会诱导运动刺激,而不改变同一组动物的运动活动实验的次要行为参数或奖励相关区域中CTR的蛋白质水平。此外,重复的sCT治疗改变了不同脑区的单胺能神经传递,包括VTA中5-羟色胺的增加和多巴胺的减少。最后,我们确定了重复sCT和急性酒精给药对小鼠酒精诱导的运动的不同影响,sCT最初减弱,后来增加了这种酒精反应。进一步发现,该治疗组合不影响在该运动活动实验中测量的次要行为参数。
结论:这些数据表明,亚慢性sCT治疗不同程度地改变了酒精引起运动刺激的能力,可能是通过涉及各种神经递质系统的分子机制,而不是CTR水平本身。
BACKGROUND: Amylin receptors consist of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins (RAMPs). The identification of amylin receptors in areas processing reward, namely laterodorsal tegmental area (LDTg), ventral tegmental area (VTA), and nucleus accumbens (NAc), has attributed them a role as reward regulators. Indeed, acute activation of amylin receptors by the amylin receptor agonist salmon calcitonin (sCT) attenuates alcohol-induced behaviours in rodents.
OBJECTIVE: The effects of long-term administration of sCT on alcohol-related behaviours and the molecular mechanisms underlying these processes are not yet elucidated. To fill this knowledge gap, we investigated the effects of sub-chronic sCT treatment on the locomotor stimulatory responses to alcohol in mice and the molecular pathways involved.
METHODS: We assessed the behavioural effects of sub-chronic sCT treatment by means of locomotor activity experiments in mice. We used western blot to identify changes of the CTR levels and ex vivo biochemical analysis to detect changes in monoamines and their metabolites.
RESULTS: After discontinuation for 5 days of sCT treatment, alcohol did not induce locomotor stimulation in mice pre-treated with sCT when compared with vehicle, without altering secondary behavioural parameters of the locomotor activity experiment or the protein levels of the CTR in reward-related areas in the same set of animals. Moreover, repeated sCT treatment altered monoaminergic neurotransmission in various brain areas, including increased serotonin and decreased dopamine turnover in the VTA. Lastly, we identified a differential effect of repeated sCT and acute alcohol administration on alcohol-induced locomotion in mice, where sCT initially attenuated and later increased this alcohol response. It was further found that this treatment combination did not affect secondary behavioural parameters measured in this locomotor activity experiments.
CONCLUSIONS: These data suggest that sub-chronic sCT treatment differentially alters the ability of alcohol to cause locomotor stimulation, possibly through molecular mechanisms involving various neurotransmitter systems and not the CTR levels per se.