Harmaline Attenuates Stress-Induced Depression-Like Behaviour and Biochemical Alterations in Mice

Abstract Depression is a debilitating psychiatric disorder affecting millions worldwide. The Chronic Unpredictable Mild Stress (CUMS) model is widely used to simulate depression-related behavioural and neurobiological changes in rodents. This study evaluated the antidepressant-like effects of harmaline, a monoamine oxidase (MAO) inhibitor derived from Peganum harmala , in comparison to imipramine, a standard antidepressant. Mice exposed to CUMS received daily oral doses of harmaline (15 mg/kg) or imipramine (30 mg/kg) for 21 days. Harmaline significantly improved behavioural performance in the open field test, forced swim test, and sucrose preference test, indicating a reversal of depression-like symptoms. Biochemical analyses showed that harmaline, consistent with its MAO-inhibitory activity, reduced serum corticosterone levels and increased brain concentrations of monoamines, namely, serotonin, norepinephrine, and dopamine, involved in mood regulation. Additionally, harmaline attenuated oxidative stress by lowering malondialdehyde (MDA) levels and enhancing antioxidant defences such as catalase and glutathione. It also reduced pro-inflammatory cytokines, including tumour necrosis factor-alpha and interleukin-6, suggesting an anti-neuroinflammatory effect. These outcomes were comparable to those seen with imipramine. Overall, the findings support harmaline’s potential as an agent for mitigating stress-induced depressive disorders through the modulation of monoamines, oxidative stress, and neuroinflammation.