Aliczki Mano, Varga Zoltan Kristof, Balogh Zoltan, Haller Jozsef
Department of Behavioural Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, P.O. Box 67, 1450, Hungary,
Psychopharmacology (Berl). 2015 Jun;232(12):2157-67. doi: 10.1007/s00213-014-3846-1. Epub 2014 Dec 31.
Endocannabinoids are strong modulators of emotionality and present a novel target for psychotropic drug development. Increasing evidence suggests that endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) affect behavior differentially. While the roles of anandamide have been investigated extensively, studies regarding the specific roles of 2-AG became possible only recently, and its involvement in social behaviors has not yet been studied.
We studied the impact of 2-AG signaling on aggression as a first attempt to characterize the role of this endocannabinoid in social behaviors.
2-AG signaling was enhanced by the monoacylglycerol lipase inhibitor JZL184 (8, and 16 mg/kg) in mice later submitted to the resident/intruder paradigm.
JZL184 near completely abolished aggressiveness in residents and increased victimization (i.e., attacks by the opponent). Interestingly, the level of defensiveness remained unaltered, despite the large increase in bites received. The CB1 receptor blocker AM251 (0.5 mg/kg) did not influence the effects of JZL184. In intruders, JZL184 near completely suppressed bites and offensive behavior in a fashion similar to residents, but it also increased agitation and defensiveness during, and the corticosterone response to, aggressive encounters. Experiments involving the corticosterone synthesis inhibitor metyrapone (30 mg/kg) suggest that the suppression of biting and offensive behavior is directly influenced by JZL184, whereas increased agitation and defensiveness (seen in intruders only) are a secondary development of the stress-endocrine effects of JZL184.
2-AG signaling emerges as a surprisingly strong negative modulator of aggressiveness, which warrants further studies into its general role in social behavior and the target receptors involved.
内源性大麻素是情绪的强效调节剂，是精神药物开发的一个新靶点。越来越多的证据表明，内源性大麻素花生四烯乙醇胺和2-花生四烯酸甘油酯（2-AG）对行为的影响存在差异。虽然花生四烯乙醇胺的作用已得到广泛研究，但关于2-AG具体作用的研究直到最近才得以开展，其在社会行为中的作用尚未得到研究。
我们研究了2-AG信号传导对攻击性的影响，这是表征这种内源性大麻素在社会行为中作用的首次尝试。
通过单酰基甘油脂肪酶抑制剂JZL184（8和16mg/kg）增强2-AG信号传导，随后将小鼠置于定居者/入侵者范式中。
JZL184几乎完全消除了定居者的攻击性，并增加了受害程度（即来自对手的攻击）。有趣的是，尽管被咬次数大幅增加，但防御水平并未改变。CB1受体阻滞剂AM251（0.5mg/kg）不影响JZL184的作用。在入侵者中，JZL184几乎完全抑制了撕咬和攻击行为，其方式与定居者相似，但它也增加了在攻击性遭遇期间的激动和防御性，以及皮质酮对攻击性遭遇的反应。涉及皮质酮合成抑制剂美替拉酮（30mg/kg）的实验表明，撕咬和攻击行为的抑制直接受JZL184影响，而激动和防御性增加（仅在入侵者中出现）是JZL184应激内分泌效应的继发表现。
2-AG信号传导是一种出人意料的强效攻击性负调节剂，这值得进一步研究其在社会行为中的总体作用以及相关的靶受体。
