Rationale Acute restraint stress (ARS) is an experimental paradigm used for the induction of rodent models of stress-produced neuropsychiatric disorders, such as depression and anxiety. β-carbolines and serotonin (5-HT) systems are involved in the modulation of depression and anxiety behaviors. Objective This study was designed to examine the effects of intracerebroventricular (i.c.v.) injection of cinanserin (5-HT2 receptor antagonist) on harmaline-induced responses on depression- and anxiety-like behaviors in the ARS mice. Methods For i.c.v. infusion, guide cannula was surgically implanted in the left lateral ventricle of mice. The ARS model was conducted via movement restraint at a period of 4 h. Depression- and anxiety-related behaviors were evaluated by forced swim test (FST) and elevated plus maze (EPM), respectively. Results The results displayed that the ARS mice showed depressive- and anxiety-like responses. I.p. administration of different doses of harmaline (0.31, 0.625 and 1.25 mg/kg) or i.c.v. microinjection of cinanserin (1, 2.5, and 5 μg/mouse) blocked depression- and anxiogenic-like behaviors in the ARS mice. Furthermore, co-administration of harmaline (1.25 mg/kg; i.p.) and cinanserin (5 μg/mouse; i.c.v.) prevented the depression- and anxiogenic-like effects in the ARS mice. We found a synergistic antidepressant- and anxiolytic-like effects of harmaline and cinanserin in the ARS mice. Conclusions These results propose an interaction between harmaline and cinanserin to prevent depressive- and anxiogenic-like behaviors in the ARS mice.