Dysregulation of adult hippocampal neurogenesis is linked to major depressive disorder(MDD), with more than 300 million people diagnosed and worsened by the COVID‐19pandemic. Accumulating evidence for neuropeptideY (NPY) and galanin (GAL) interactionwas shown in various limbic system regions at molecular‐, cellular‐, and behavioral‐specific levels. The purpose of the current work was to evaluate the proliferating role ofGAL2 receptor (GALR2) and Y1R agonists interaction upon intranasal infusion in theventral hippocampus. We studied their hippocampal proliferating actions using theproliferating cell nuclear antigen (PCNA) on neuroblasts or stem cells and the expressionof the brain‐derived neurothrophic factor (BDNF). Moreover, we studied the formation ofY1R–GALR2 heteroreceptor complexes and analyzed morphological changes inhippocampal neuronal cells. Finally, the functional outcome of the NPY and GALinteraction on the ventral hippocampus was evaluated in the forced swimming test. Wedemonstrated that the intranasal infusion of GALR2 and the Y1R agonists promotesneuroblasts proliferation in the dentate gyrus of the ventral hippocampus and the induction of the neurotrophic factor BDNF. These effects were mediated by theincreased formation of Y1R–GALR2 heteroreceptor complexes, which may mediate theneurites outgrowth observed on neuronal hippocampal cells. Importantly, BDNF actionwas found necessary for the antidepressant‐like effects after GALR2 and the Y1Ragonists intranasal administration. Our data may suggest the translational development ofnew heterobivalent agonist pharmacophores acting on Y1R–GALR2 heterocomplexes inthe ventral hippocampus for the novel therapy of MDD or depressive‐affecting diseases.
