Modi Meera E, Inoue Kiyoshi, Barrett Catherine E, Kittelberger Kara A, Smith Daniel G, Landgraf Rainer, Young Larry J
1] Center Translational Social Neuroscience, Silvio O Conte Center for Oxytocin and Social Cognition, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA [2] Neuroscience Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, USA.
Center Translational Social Neuroscience, Silvio O Conte Center for Oxytocin and Social Cognition, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
Neuropsychopharmacology. 2015 Jul;40(8):1856-65. doi: 10.1038/npp.2015.35. Epub 2015 Feb 5.
The central melanocortin (MC) system has been widely studied for its effects on food intake and sexual behavior. However, the MC system, and more specifically the MC4 receptor (MC4R), also interacts with neurochemical systems that regulate socioemotional behaviors, including oxytocin (OT) and dopamine. In monogamous prairie voles, OT and dopamine interact to promote partner preference formation, a laboratory measure of an enduring social bond between mates. Here we investigated the effects of MC receptor activation on partner preference formation in prairie voles, as well as the interaction between the MC and OT systems during this process. Peripheral administration of the brain penetrant MC3/4R receptor peptide agonist, Melanotan II (MTII), and the highly selective, small-molecule MC4R agonist, Pf-446687, enhanced partner preference formation in the prairie vole, but not in the non-monogamous meadow vole. MTII-induced partner preferences were enduring, as they were present 1 week after drug manipulation. The prosocial effects of MCR agonists may be mediated, in part, through modulation of OT, as coadministration of an OT receptor antagonist prevented MTII-induced partner preferences. MTII also selectively activated hypothalamic OT neurons and potentiated central OT release. As OT has been shown to enhance some aspects of social cognition in humans, our data suggest that the MC4R may be a viable therapeutic target for enhancing social function in psychiatric disorders, including autism spectrum disorders and schizophrenia, potentially through activation of the OT system.
中枢黑皮质素（MC）系统因其对食物摄入和性行为的影响而受到广泛研究。然而，MC系统，更具体地说是MC4受体（MC4R），也与调节社会情感行为的神经化学系统相互作用，包括催产素（OT）和多巴胺。在实行一夫一妻制的草原田鼠中，OT和多巴胺相互作用以促进伴侣偏好的形成，这是一种衡量配偶之间持久社会纽带的实验室指标。在此，我们研究了MC受体激活对草原田鼠伴侣偏好形成的影响，以及在此过程中MC系统与OT系统之间的相互作用。脑渗透性MC3/4R受体肽激动剂黑素皮质素II（MTII）和高选择性小分子MC4R激动剂Pf - 446687的外周给药增强了草原田鼠的伴侣偏好形成，但对非一夫一妻制的草甸田鼠没有影响。MTII诱导的伴侣偏好具有持久性，因为在药物处理后1周仍存在。MCR激动剂的亲社会作用可能部分通过调节OT介导，因为OT受体拮抗剂的共同给药可阻止MTII诱导的伴侣偏好。MTII还选择性激活下丘脑OT神经元并增强中枢OT释放。由于OT已被证明可增强人类社会认知的某些方面，我们的数据表明，MC4R可能是增强精神疾病（包括自闭症谱系障碍和精神分裂症）社会功能的一个可行治疗靶点，可能是通过激活OT系统来实现。
