Biphasic Effects of α-Asarone on Immobility in the Tail Suspension Test: Evidence for the Involvement of the Noradrenergic and Serotonergic Systems in Its Antidepressant-Like Activity

Abstract

Alpha (α)-asarone is one of the main psychoactive compounds, present in Acorus species. Evidence suggests that the α-asarone possess an antidepressant-like activity in mice. However, the exact dose-dependent effect of α-asarone and mechanism(s) involved in the antidepressant-like activity are not clear. The present study aimed to investigate the dose-dependent effect of α-asarone and the underlining mechanism(s) involved in the antidepressant-like activity of α-asarone in the mouse model of tail suspension test (TST). In this study, the acute effect of α-asarone per se at different doses (10–100 mg/kg, i.p.) on immobility in the TST was studied. Additionally, the possible mechanism(s) involved in the antidepressant-like effect of α-asarone was studied using its interaction with noradrenergic and serotonergic neuromodulators in the TST. The present results reveal that the acute treatment of α-asarone elicited biphasic responses on immobility such that the duration of the immobility time is significantly reduced at lower doses (15 and 20 mg/kg, i.p.) but increased at higher doses (50 and 100 mg/kg, i.p.) in the TST. Besides, α-asarone at higher doses (50 and 100 mg/kg, i.p.) significantly decreased the spontaneous locomotor activity. Moreover, pretreatment of mice with noradrenergic neuromodulators such as AMPT (100 mg/kg, i.p., a catecholamine synthesis inhibitor), prazosin (1 mg/kg, i.p., an α1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α2-adrenoceptor antagonist) and with serotonergic neuromodulators such as PCPA (100 mg/kg, i.p., once daily for four consecutive days, a serotonin synthesis inhibitor,) and WAY100635 (0.1 mg/kg, s.c., a selective 5-HT1A receptor antagonist) significantly reversed the anti-immobility effect of α-asarone (20 mg/kg, i.p.). Taken together, our results suggest that the acute treatment with α-asarone elicited biphasic actions in the TST in which antidepressant-like effect was seen at relatively lower doses (15 and 20 mg/kg, i.p.) and depressive-like activity at relatively higher doses (50 and 100 mg/kg, i.p.). Furthermore, it has been revealed that the antidepressant-like effect of α-asarone could be mediated through both noradrenergic (α1 and α2 adrenoceptors) and serotonergic (particularly, 5-HT1A receptors) systems.

Anti-Amyloidogenic Effects of Asarone Derivatives From Perilla frutescens Leaves Against Beta-Amyloid Aggregation and Nitric Oxide Production

“…Asarone derivatives including α- and β-asarone are major bioactive phytochemicals present in the Acorus species such as Acorus calamus Linn and Acorus gramineus Solander [32,33], and Guatteria gaumeri Greenman [34]. The wide range of pharmacological activities of asarone derivatives have been reported including antiepileptic [35], antidepressant [36], anxiolytic [37], neuroprotective [38], and hypolipidemic activities [39]. Numerous clinical studies in China had reported that asarone derivatives were effective therapeutic approaches for the treatment of respiratory disorders and epilepsy [40,41].…”

The ethyl acetate fraction of a methanolic extract of unripe noni (<i>Morinda citrifolia</i> Linn.) fruit exhibits a biphasic effect on the dopaminergic system in mice

“…and depressive-like activity was seen at relatively higher doses (50 and 100 mg/kg, i.p.) [ 3 ]. Similarly, acute oral administration of a methanolic extract of Mitragyna speciosa leaf (MMS; 50–500 mg/kg) showed an inverted bell-shaped dose response in apomorphine-induced cage climbing behavior in mice [ 27 ].…”

Molecular Mechanisms and Therapeutic Potential of α- and β-Asarone in the Treatment of Neurological Disorders

“…and a depressive-like effect at higher doses (≥50 mg/kg, i.p.) [ 186 ]. The antidepressant effect of α-asarone was mediated by its interaction with the noradrenergic (α1 and α2 adrenoceptors) and serotonergic (5-HT1A receptors) systems, whereas the depressive-like effects observed following the administration of high levels of α-asarone may be mediated by interactions with the GABAergic system [ 186 ].…”

“…[ 186 ]. The antidepressant effect of α-asarone was mediated by its interaction with the noradrenergic (α1 and α2 adrenoceptors) and serotonergic (5-HT1A receptors) systems, whereas the depressive-like effects observed following the administration of high levels of α-asarone may be mediated by interactions with the GABAergic system [ 186 ]. In another study, α-asarone showed an anxiolytic effect in animal models of anxiety, as assessed by the elevated plus-maze, the light–dark transition test, the novel food consumption test, and the marble-burying test [ 187 ].…”