The monoamine theory of depression proposes decreased bioavailability of monoamines, such as norepinephrine (NE), as the underlying cause of depression. Thus, the antidepressant efficacy of NE-reuptake inhibitors such as desipramine is attributed to increases in synaptic concentrations of NE. The time difference between inhibition of reuptake and therapeutic efficacy, however, argues against this being the primary mechanism. If desipramine elicits its therapeutic efficacy by increasing NE release, in turn, increasing activation of the alpha(2)-adrenergic autoinhibitory receptor, then mimicking this increase with an exogenous agonist (clonidine) should support or even enhance the efficacy of the antidepressant. Intriguingly, simultaneous administration of clonidine with desipramine prevented the cellular and behavioral effects elicited by desipramine alone, in both acute and chronic administration paradigms. These results suggest the involvement of additional factor(s) in the mechanism of antidepressant action of this drug. Desipramine administration results in a virtual ablation of neuron-derived tumor necrosis factor-alpha (TNF), thus implicating an essential role of TNF in the therapeutic efficacy of this antidepressant. Additionally, following chronic administration of desipramine, TNF-regulation of NE release is transformed, from inhibition to facilitation. Here, we demonstrate that a transformation in TNF-regulation of NE release in the brain is a key element in the efficacy of this antidepressant. Interestingly, an increase in neurotransmission prior to the antidepressant's effect on TNF production prevents the efficacy of the antidepressant drug. Thus, the efficacy of desipramine is due to decreased levels of TNF in the brain induced by this drug, ultimately modifying noradrenergic neurotransmission.