Although major depressive disorder is the second leading cause of disability worldwide, with less than half of patients achieving remission, there continues to be limited mechanistic diversity among the available antidepressants. This makes it imperative to utilize recent insights into the understanding of natural resilience to social stress to develop new therapeutics. Specifically these findings have demonstrated the importance of maintaining healthy activity of the dopamine neurons of the ventral tegmental area) in regulating mood. Thus, we explored this dopamine circuit for novel therapeutic targets. We demonstrated that resilient animals homeostatically maintain healthy dopamine neuron activity through a compensatory upregulation of potassium channels. Remarkably, systemically administrated a pharmacological potentiator of potassium channel function normalized both depressive symptoms and neuronal hyperactivity seen in depression susceptible mice. Thus, these findings identify a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms.