Interaction between zinc, the GPR39 zinc receptor and the serotonergic system in depression

•Mild and severe zinc deficiency is a risk factor in developing depressive symptoms.•Zn2+ modulates the activity of the 5-HT1A receptor.•Monoamine-based antidepressants fail to display a therapeutic effect in GPR39 Kos.•GPR39 agonist TC-G 1008 causes antidepressant-like effects.•There is an interaction between zinc, GPR39 and serotonergic system in depression. Zinc signalling has a crucial impact on the proper functioning of the brain. Disturbances within the zincergic system may lead to neuropsychological disorders, including major depression. Studying this disease and designing effective treatment is hampered by its heterogeneous etiology and the diversified nature of the symptoms. Over the years, studies have shown that zinc deficiency and disturbances in the expression profile of the zinc receptor – GPR39 – might be a useful neurobiological indicator of a pathological state. Zinc levels and the zinc receptor are altered by classic antidepressant treatment, which indicates possible reciprocity between the monoaminergic system and zinc signalling. Disruptions in this specific interplay might be a cause of a pathological depressive state, and restoring balance and cooperation between those systems might be key to a successful form of pharmacotherapy. In this review, we aim to describe interactions between the serotonergic and zincergic systems and to highlight their significance in the pathophysiology and treatment of depression.