Sclareol exerts synergistic antidepressant effects with quercetin and caffeine, possibly suppressing GABAergic...

This study evaluated the effects of sclareol (SCL) with or without caffeine (CAF) and quercetin (QUR) using in-vivo and in-silico studies. For this, 5-day-old chicks weighing between 45 and 48 g were randomly divided into five groups and treated accordingly. The chicks were monitored to compare the occurrence, latency, and duration of sleep as well as the loss and gain of righting reflex in response to SCL-10 mg/kg, CAF-10 mg/kg, and QUR-50 mg/kg using a thiopental sodium (TS)-induced sleeping model. Data were analyzed by one-way ANOVA followed by t-Student-Newman-Keuls' as a posthoc test at 95% confidence intervals with multiple comparisons. An in-silico study was also performed to investigate the possible antidepressant mechanisms of the test and/or standard drugs with different subunits of GABA_A receptors. In comparison to the SCL, CAF, and QUR individual groups, SCL+CAF+QUR significantly increased the latency while decreasing the length of sleep. The incidence of loss and gain of the righting reflex was also modulated in the combination group. SCL showed better interaction with GABA_A (α₂ and α₅) subunits than QUR with α₂, α₃, and α₅. All these compounds showed stronger interactions with the GABA_A receptor subunits than the standard CAF. Taken together, SCL, CAF, and QUR reduced the TS-induced righting reflex and sleeping time in the combination group more than in the individual treatments. SCL may show its antidepressant effects, possibly through interactions with GABA_A receptor subunits.