It was recently discovered that ketamine can relieve depression in a matter of hours through an action on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This is much more rapid than the several weeks required for the available antidepressants to show therapeutic efficacy. However, ketamine has negative side effects. The aim of this study was to determine whether the natural prokinetic drug meranzin hydrate (MH) has a fast-acting antidepressant effect mediated by AMPA receptors. By means of in vivo and in vitro experiments, we found that (1) treatment of rats with MH at 9 mg/kg decreased immobility time in a forced swimming test (FST), as did the popular antidepressant fluoxetine and the AMPA receptor positive modulator aniracetam. Pretreatment of rats with NBQX (10 mg/kg), an antagonist of AMPA receptors, blocked this effect of MH. (2) MH increased number of crossings of forced swimming rats in the open field test. (3) FST enhanced hippocampal ERK1/2, p-ERK1/2 and BDNF expression levels. MH (9 mg/kg) treatment further up-regulated hippocampal p-ERK1/2 and BDNF expression levels, and this effect was prevented by NBQX. (4) MH-increased BDNF expression corresponded with MH-decreased immobility time in the FST. (5) In vitro experiments, we found that incubation of rats hippocampus slices with MH (10, 20 μM respectively) increased concentrations of BDNF and p-ERK1/2. This effect of MH (20 μM) were prevented by NBQX. In conclusion, in animals subjected to acute stress, the natural prokinetic drug MH produced a rapid effect mediated by AMPA receptors and involving BDNF modulation through the ERK1/2 pathway.