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Background & Objective: It has been reported that, the ?-Carboline alkaloids of peganum harmala seeds have a stimulatory action on Serotonin and Catecholamines release in different brain regions. In addition, one of the most important pharmacological effects demonstrated for ?-Carboline is a revesible inhibitory action on MAO-A. These findings suggests that ?-Carboline, should alleviate at least some of the signs of depression. The purpose of present study is to determine the anti-depressant activity of ?-Carboline Harmane, Norharmane and Harmine. Materials & Methods: All experiments were carried out on male Swiss-Webster mice (25-30 g). The anti-depressant activities of the ?-Carboline were assessed using the forced swim test. This test is the most widely used tool for anti-depressant activity preclinically. In this test, mice were placed into a cylindrical glass (25 cm height, 12 cm in diameter) containing a column of 15 cm of water at 25±1°C. After 30 min of the ?-Carboline injections, the mice were subjected to forced swimming test for 8 min and their immobility time was recorded. Results: Interperitoneal (IP) injections of Harmane (5-15 mg/kg), Norharmane (2.5-10 mg/kg) and Harmine (5-15 mg/kg) significantly decreased the immobility time in the mouse forced swim test. The inhibitory effects of Harmane, Norharmane and Harmine were antagonized by Flumazenil (5 mg/kg, IP) but not by Reserpine (5 mg/kg, IP, 18 h before test). Conclusion: The results suggest that the anti-depressant activities of Harmane, Norharmane and Harmine may be mediated through an inverse agonistic mechanism.