Antidepressant-like activity of JZ-1201 in male rodents: a novel selective 5-HT/NE reuptake inhibitor and 5-HT1A receptor partial agonist,

JZ-1201, targeting SERT, NET, and 5-HT 1A receptors, attenuates depressive-like behaviors. • The antidepressant effect of JZ-1201 is partially mediated by activation of the 5-HT 1A receptor. • JZ-1201 enhances PACAP-related neuroplasticity in the hippocampus. Depression has become a significant public health issue, highlighting the need for novel antidepressants. Based on the monoaminergic mechanisms of classical antidepressant drugs and the therapeutic potential of 5-HT 1A receptor activation, we designed a novel compound, JZ-1201, which acts as a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor and 5-HT 1A receptor partial agonist. This study aimed to evaluate its antidepressant-like effects and explore the underlying mechanisms involving 5-HT 1A receptor activation and enhanced neuroplasticity. The results demonstrated that JZ-1201 exhibited high affinity for the serotonin transporter (SERT) and norepinephrine transporter (NET), and 5-HT 1A receptors, inhibited 5-HT and NE reuptake. It enhanced the 5-hydroxytryptophan (5-HTP)-induced head-twitch response (HTR) and inhibited forskolin-stimulated cAMP formation. In male ICR mice, acute administration of JZ-1201 reduced immobility time in the tail suspension test (TST) and forced swim test (FST), an effect that was attenuated by the selective 5-HT 1A receptor antagonist WAY-100635. Chronic administration of JZ-1201 significantly ameliorated depressive-like behaviors in male Wistar rats subjected to chronic unpredictable mild stress (CUMS). In CUMS rats, JZ-1201 increased dendritic spine density and the expression of PACAP/mTOR/BDNF signaling pathway proteins in the hippocampus. These findings indicate that JZ-1201 is a triple-target antidepressant compound and modulates hippocampal PACAP-related neuroplasticity. Thus, JZ-1201 could be developed as a novel therapeutic agent for the treatment of depression.