Millón Carmelo, Flores-Burgess Antonio, Narváez Manuel, Borroto-Escuela Dasiel O, Santín Luis, Gago Belen, Narváez José Angel, Fuxe Kjell, Díaz-Cabiale Zaida
Universidad de Málaga, Instituto de Investigación Biomédica de Málaga, Facultad de Medicina, Departamento de Fisiología, Campus de Teatinos s/n, 29071, Málaga, Spain.
Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
Brain Struct Funct. 2016 Dec;221(9):4491-4504. doi: 10.1007/s00429-015-1180-y. Epub 2016 Jan 20.
Galanin N-terminal fragment (1-15) [GAL(1-15)] is associated with depression-related and anxiogenic-like effects in rats. In this study, we analyzed the ability of GAL(1-15) to modulate 5-HT1A receptors (5-HT1AR), a key receptor in depression. GAL(1-15) enhanced the antidepressant effects induced by the 5-HT1AR agonist 8-OH-DPAT in the forced swimming test. These effects were stronger than the ones induced by Galanin (GAL). This action involved interactions at receptor level since GAL(1-15) affected the binding characteristics and the mRNA levels of 5-HT1AR in the dorsal hippocampus and dorsal raphe. The involvement of the GALR2 was demonstrated with the GALR2 antagonist M871. Proximity ligation assay experiments indicated that 5-HT1AR are in close proximity with GALR1 and GALR2 in both regions and in raphe RN33B cells. The current results indicate that GAL(1-15) enhances the antidepressant effects induced by 8-OH-DPAT acting on 5-HT1AR operating as postjunctional or as autoreceptors. These results may give the basis for the development of drugs targeting potential GALR1-GALR2-5-HT1AR heteroreceptor complexes linked to the raphe-hippocampal 5-HT neurons for the treatment of depression.
甘丙肽N端片段（1-15）[GAL(1-15)]与大鼠的抑郁相关及焦虑样效应有关。在本研究中，我们分析了GAL(1-15)调节5-羟色胺1A受体（5-HT1AR）的能力，5-HT1AR是抑郁症中的一种关键受体。在强迫游泳试验中，GAL(1-15)增强了5-HT1AR激动剂8-羟基二丙胺（8-OH-DPAT）诱导的抗抑郁作用。这些效应比甘丙肽（GAL）诱导的效应更强。此作用涉及受体水平的相互作用，因为GAL(1-15)影响了背侧海马体和中缝背核中5-HT1AR的结合特性和mRNA水平。用GALR2拮抗剂M871证明了GALR2的参与。邻近连接分析实验表明，在这两个区域以及中缝RN33B细胞中，5-HT1AR与GALR1和GALR2紧密相邻。目前的结果表明，GAL(1-15)增强了8-OH-DPAT作用于作为突触后受体或自身受体的5-HT1AR所诱导的抗抑郁作用。这些结果可能为开发靶向与中缝-海马5-羟色胺能神经元相关的潜在GALR1-GALR2-5-HT1AR异源受体复合物的药物以治疗抑郁症提供依据。
