The Potential Antidepressant Action of Duloxetine Co-Administered with the TAAR1 Receptor Agonist SEP-363856 in Mice

Abstract

Here, we explored the possible interaction between duloxetine and SEP-363856 (SEP-856) in depression-related reactions. The results showed that oral administration of duloxetine showed powerful antidepressant-like effects in both the forced swimming test (FST) and the suspension tail test (TST). SEP-856 orally administered alone also exerted an antidepressant-like effect in FST and TST, especially at doses of 0.3, 1, and 10 mg/kg. In addition, duloxetine (15 mg/kg) and SEP-856 (15 mg/kg) both showed antidepressant-like effects in the sucrose preference test (SPT). Most importantly, in the above experiments, compared with duloxetine alone, the simultaneous use of duloxetine and SEP-856 caused a more significant antidepressant-like effect. It is worth noting that doses of drug combination in FST and TST did not change the motor activities of mice in the open-field test (OFT). Thus, duloxetine and SEP-856 seem to play a synergistic role in regulating depression-related behaviors and might be beneficial for refractory depression.

Unlocking the Therapeutic Potential of Ulotaront as a Trace Amine-Associated Receptor 1 Agonist for Neuropsychiatric Disorders

“…Recently, these findings were further corroborated by another group [68]. In this study, ulotaront decreased immobility time in both the FST and its analog, the tail suspension test, as well as the potentiated effects of the antidepressant duloxetine [68]. Moreover, ulotaront (15 mg/kg, p/o, for 21 days) mitigated modeled anhedonia-like states induced by chronic mild unpredictable stress in the sucrose preference test, with no effect in non-stressed mice [68].…”

“…An analysis of ulotaront's effects in the forced swim test (FST), a routine animal test performed to estimate the antidepressant-like activity of pharmacological agents, revealed that administration of the compound (dose range: 1-10 mg/kg, p/o) resulted in a reduction in immobility time in mice, indicating that ulotaront may have some antidepressant-like action [17]. Recently, these findings were further corroborated by another group [68]. In this study, ulotaront decreased immobility time in both the FST and its analog, the tail suspension test, as well as the potentiated effects of the antidepressant duloxetine [68].…”

TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis

“…In addition to the good isolated effect of Ulotaront, in combination with Duloxetine (5-HT and NE dual reuptake inhibitor), tests showed better results in experimental animals. Therefore, the synergy of TAAR1 and monoamines can be a powerful tool to improve AD action [ 96 ].…”

Protein Metabolism Changes and Alterations in Behavior of Trace Amine-Associated Receptor 1 Knockout Mice Fed a High-Fructose Diet

“…TAAR1 is being studied as a potential therapeutic target in the treatment of various mental disorders, such as schizophrenia [ 2 , 27 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT1A receptor agonist activity, currently being tested in phase III clinical development, with very promising results from the phase II trials, which led to the FDA designation as a breakthrough therapy for the treatment of schizophrenia [ 26 , 27 , 28 , 29 , 30 , 40 , 47 , 48 , 49 , 50 , 51 , 52 ].…”

“…TAAR1 agonists can play a certain role in alleviating depression-like and anxiety-like behaviors in animal models [ 27 , 28 , 47 , 49 ]. Another report showed that SEP-363856 and duloxetine could have a significant antidepressant effect in a mouse forced swim test.…”