Work

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

Year: 2026

Type: article

Abstract: 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.

Source: Pharmacological Reports

DOI: 10.1007/s43440-026-00896-w

Authors: Dominika Siodłak, Urszula Doboszewska, Katarzyna Mlyniec

Institutions: Jagiellonian University, Oklahoma Medical Research Foundation, AGH University of Krakow

Language: English

Topic: Treatment of Major Depression

Subfield: Pharmacology (medical)

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,290