L-menthol exhibits antidepressive-like effects mediated by the modification of 5-HTergic, GABAergic and DAergic systems.

Major depression disorder, also known as depression, with a significant and persistent low mood as the main clinical features, is the main type of mood disorders. L-menthol (LM), the main active ingredient of mint, has been considered as safe and healthy natural ingredient by the Food and Drug Administration in the USA. In this study, LM (40 mg/kg, i.g.) produced antidepressant-like effect in the forced swimming test (FST) in mice. The sub-effective dose (5 mg/kg, i.g.) of LM combined with the sub-effective dose of fluoxetine (5 mg/kg, i.p.) or reboxetine (2.5 mg/kg, i.p.) could significantly shorten the immobility time in the FST. Pretreatment with ondansetron (a highly selective 5-HT(3) receptor antagonist, 8 mg/kg, i.p.), bicuculline [a competitive γ-aminobutyric acid (GABA) antagonist, 4 mg/kg, i.p.] and haloperidol (a non-selective D(2) receptor antagonist, 0.2 mg/kg, i.p.) significantly reversed the antidepressant-like effect of LM (40 mg/kg, i.g.). In contrast, prazosin (a α1-adrenoceptor antagonist, 1 mg/kg, i.p.) and N-methyl-d-aspartic acid (an agonist at the glutamate site, 75 mg/kg, i.p.) did not eliminate the antidepressant-like effect of LM. All of these above indicated that LM is able to induce an antidepressant-like effect mediated by the modification of 5-HTergic, GABAergic and DAergic systems in the FST. LM might be used as combination therapy in depressed patients and is a potential antidepressant.