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Affective disorders such as depression are among the main causes of disability worldwide, yet the underlying pathophysiology of depression remains poorly understood. Recently, landmark neuroimaging studies have shown that depressed patients have an increased metabolic activity in Brodmann Area 25 (BA25). Moreover, functional inactivation of this region using deep brain stimulation (DBS) could alleviate depressive symptoms in severely depressed patients. This demonstrates a key role for this cortical region in mediating antidepressant-like behaviour. Thus, we examined the effect of a similar treatment, pharmacological inactivation or activation of the infralimbic cortex, the rodent correlate of BA25, in an animal model of antidepressant-activity. The modified rat forced swim test is a widely used stressor-based animal model, which has high predictive validity. Inactivation of the infralimbic cortex using muscimol resulted in altered stress-induced coping, which manifested as a reduction in immobility, an antidepressant-like effect in the test. Furthermore, this activity was not the result of a general increase in locomotor activity, since muscimol had no effect on locomotion. Activation of the infralimbic cortex using bicuculline did not result in any alteration of behaviour in the swim test but caused a pronounced hyperactivity, which may have masked a pro-depressive effect in the swim test. These results show that it is possible to replicate findings from a clinical trial in a rodent model. Further, they support the use of the forced swim test as a paradigm to gain greater understanding of the neurocircuitry involved in depression and antidepressant-action.