BackgroundDespite our poor understanding of the pathophysiology of depression, a growing body of evidence indicates the role of both glutamate and gamma-aminobutyric acid (GABA) signaling behind the effects of rapid-acting antidepressants (RAADs). GPR39 is a zinc-sensing receptor whose activation leads to a prolonged antidepressant-like response in mice. Both GPR39 and zinc can modulate glutamatergic and GABAergic neurotransmission, however, exact molecular mechanisms are still elusive. In this study, we aimed to research the role of glutamatergic and GABAergic system activation in TC-G 1008 antidepressant-like effects and the disruptions in this effect caused by a low-zinc diet.MethodsIn the first part of our study, we investigated the role of joint administration of the GPR39 agonist (TC-G 1008) and ligands of the glutamatergic or GABAergic systems, in antidepressant-like response. To evaluate animal behaviour we used the forced swim test in mice. In the second part of the study, we assessed the effectiveness of TC-G 1008-induced antidepressant-like response in conditions of decreased dietary zinc intake and its molecular underpinning by conducting a Western Blot analysis of selected proteins involved in glutamatergic and GABAergic neurotransmission.ResultsThe TC-G 1008-induced effect was blocked by the administration of NMDA or picrotoxin. The joint administration of TC-G 1008 along with muscimol or SCH50911 showed a trend toward decreased immobility time. Zinc-deficient diet resulted in dysregulation of GluN1, PSD95, and KCC2 protein expression.ConclusionsOur findings indicate the important role of glutamate/GABA signaling in the antidepressant-like effect of TC-G 1008 and imply that GPR39 regulates the balance between excitatory and inhibitory activity in the brain. Thus, we suggest the zinc-sensing receptor be considered an interesting new target for the development of novel antidepressants.Supplementary InformationThe online version contains supplementary material available at 10.1007/s43440-023-00478-0.