•Gabra2 knockout (KO) has predictive validity in modeling SSRI-resistant depression.•Desipramine has an anxiolytic and antidepressant-like action in Gabra2 KO mice.•Fluoxetine has an anxiogenic-like action in Gabra2 KO mice.•Fluoxetine has a prodepressive-like (despair-based) action in Gabra2 KO mice. Deficits in neuronal inhibition via gamma-aminobutyric acid (GABA) type A receptors (GABAA-Rs) are implicated in the pathophysiology of major depressive disorder and the therapeutic effects of current antidepressant treatments, however, the relevant GABAA-R subtype as defined by its alpha subunit is still unknown. We previously reported anxiety- and depressive-like behavior in alpha2+/− and alpha2−/− mice, respectively (Vollenweider, 2011). We sought to determine whether this phenotype could be reversed by chronic antidepressant treatment. Adult male mice received 4 or 8 mg/kg fluoxetine or 53 mg/kg desipramine in their drinking water for four weeks before undergoing behavioral testing. In the novelty suppressed feeding test, desipramine had anxiolytic-like effects reducing the latencies to bite and to eat the pellet in both wild-type and alpha2+/− mice. Surprisingly, 4 mg/kg fluoxetine had anxiogenic-like effects in alpha2+/− mice increasing latency to bite and to eat while 8 mg/kg fluoxetine increased the latency to eat in both wild-type and alpha2+/− mice. In the forced swim and tail suspension tests, chronic desipramine treatment increased latency to immobility in wild-type and alpha2−/− mice. In contrast, chronic fluoxetine treatment increased immobility in alpha2−/− mice in both tasks while generally having no effect in wild-type mice. These findings suggest that in preclinical paradigms of anxiety and behavioral despair the antidepressant-like effects of desipramine are independent of alpha2-containing GABAA-Rs, while a reduction in alpha2 expression leads to an increased sensitivity to anxiogenic- and prodepressant-like effects with chronic fluoxetine treatment, pointing to a potential role of alpha2-containing GABAA-Rs in the response to serotonin-selective antidepressants.