Interaction of the serotonergic system and GPR39 zinc receptor in antidepressant-like response in mice

Background Zinc and 5-HT1A receptors have both been implicated in modulating CREB/BDNF/TrkB pathway when exerting their antidepressant-like effects. That pathway is an important regulator of neuroplasticity, shown to be sensitive to serotonergic and zinc-dependent signalling. This study aimed to determine whether co-administration of GPR39 and 5-HT1A receptor agonists produces antidepressant-like responses in mice and whether these effects are associated with changes in proteins of the CREB/BDNF/TrkB pathway and selected serotonergic markers. Methods Male CD1 mice received inactive doses of TC-G 1008 (GPR39 agonist, 5 mg/kg) and 8-OH-DPAT (5-HT1A agonist, 1 mg/kg). Antidepressant-like effects following acute, subacute and chronic treatment were assessed using the forced swim test (FST). Western blot analysis examined the levels of CREB-BDNF-TrkB pathway proteins in the prefrontal cortex and hippocampus. In GPR39 knock-out (KO) mice, chronic 8-OH-DPAT treatment was further evaluated in FST alongside measurements of CREB-BDNF-TrkB, 5-HT1A, 5-HT7 and SERT protein levels in aforementioned structures. Results Combined treatment with TC-G 1008 and 8-OH-DPAT reduced immobility in the FST across all treatments durations. Neither treatment nor GPR39 expression affected CREB-BDNF-TrkB protein levels. However, chronic co-treatment increased hippocampal SERT levels in wild-type mice, while producing opposite effects on 5-HT7 protein levels in the prefrontal cortex of GPR39 KO mice. Conclusions The rapid antidepressant-like effects of combined TC-G 1008 and 8-OH-DPAT treatment appear independent of the CREB-BDNF-TrkB pathway. Differences in SERT and 5-HT7 protein levels between wild-type and GPR39 KO mice suggest that GPR39 modulates serotonergic system responsiveness to antidepressant treatment.