A need for new antidepressants is necessary since traditional antidepressants have several flaws. Neuropeptide Y(NPY) Y1 receptor (NPYY1R) and galanin (GAL) receptor 2 (GALR2) interact in several regions of the limbic system, including the hippocampus. The current study assesses the antidepressant effects induced by GALR2 and NPYY1R coactivation, together with the evaluation of cell proliferation through 5‐Bromo‐2'‐deoxyuridine expression within the dentate gyrus of the ventral hippocampus (vDG). We employed in situ proximity ligation assay to manifest GALR2/NPYY1R heteroreceptor complexes. Additionally, the expression pattern of GALR2 and the activation of the extracellular‐regulated kinases (ERK) pathway after GALR2 and NPYY1R costimulation in cell cultures were examined. GALR2 and NPYY1R coactivation resulted in sustained antidepressant behaviors in the FST after 24 h, linked to increased cell proliferation in the vDG. Moreover, an increased density of GALR2/NPYY1R heteroreceptor complexes was observed in vDG, on doublecortin‐expressing neuroblasts. Recruitment of the GALR2 expression to the plasma membrane was observed upon the coactivation of GALR2 and NPYY1R in cell cultures, presumably associated to the enhanced effects on the activation of ERK pathway. GALR2 may promote the GALR2/NPYY1R heteroreceptor complexes formation in the ventral hippocampus. It may induce a transformation of cell proliferation toward a neuronal lineage by enhancement of ERK pathway. Thus, it may give the mechanism for the antidepressant behavior observed. These results may provide the basis for the development of heterobivalent agonist pharmacophores, targeting GALR2/NPYY1R heteromers, especially in the neuronal precursor cells of the dentate gyrus in the ventral hippocampus for the novel treatment of depression.

中文翻译：

---

甘丙肽和神经肽Y相互作用引起与腹侧海马齿状回神经元前体细胞相关的抗抑郁活性

由于传统的抗抑郁药有几个缺陷，因此需要新的抗抑郁药。神经肽 Y(NPY) Y1 受体 (NPYY1R) 和甘丙肽 (GAL) 受体 2 (GALR2) 在边缘系统的几个区域相互作用，包括海马。目前的研究评估了 GALR2 和 NPYY1R 共激活诱导的抗抑郁作用，以及通过腹侧海马齿状回 (vDG) 中 5-Bromo-2'-脱氧尿苷表达评估细胞增殖。我们采用原位邻近连接试验来证明 GALR2/NPYY1R 异源受体复合物。此外，还检查了细胞培养物中 GALR2 和 NPYY1R 共刺激后 GALR2 的表达模式和细胞外调节激酶 (ERK) 通路的激活。GALR2 和 NPYY1R 共激活导致 24 小时后 FST 中持续的抗抑郁行为，这与 vDG 中细胞增殖的增加有关。此外，在表达双皮质素的神经母细胞上，在 vDG 中观察到 GALR2/NPYY1R 异源受体复合物的密度增加。在细胞培养物中 GALR2 和 NPYY1R 共激活后观察到 GALR2 表达向质膜的募集，这可能与对 ERK 通路激活的增强作用有关。GALR2 可能促进腹侧海马中 GALR2/NPYY1R 异质受体复合物的形成。它可以通过增强 ERK 通路诱导细胞增殖向神经元谱系的转化。因此，它可以给出观察到的抗抑郁行为的机制。