Abstract: Cytokines are involved both in various immune reactions and in controlling certain events in the central nervous system (CNS). In our earlier studies, it was shown that monoamine neurotransmitters, released in stress situations, represent a tonic sympathetic control on cytokine production and on the balance of proinflammatory/anti-inflammatory cytokines. Basic and clinical studies have provided evidence that the biophase level of monoamines, determined by the balance of their release and uptake, is involved in the pathophysiology and treatment of depression, while inflammatory mediators might also have a role in its etiology. In this work, we studied the role of changes in norepinephrine (NE) level on the lipopolysaccharide (LPS) evoked tumor necrosis factor (TNF)-α and interleukin (IL)-10 response both in the plasma and in the hippocampus of mice. We demonstrated that the LPS induced TNF-α response is in direct correlation with the biophase level of NE, as it is significantly higher when the release of NE of vesicular origin was completely inhibited in an animal model of depression (reserpine treatment) and it is significantly lower in the case of increasing biophase levels of NE by genetic (NET–KO) or chemical (desipramine) disruption of NE reuptake. IL-10 was changed inversely to TNF-α levels only in the desipramine-treated animals. Our results showed that depression is related both to changes in peripheral and in hippocampal inflammatory cytokine production and to monoamine neurotransmitter levels. Since several anti-inflammatory drugs also have antidepressant effects, we hypothesized that antidepressants are also able to modulate the LPS-induced inflammatory response, which might contribute to their antidepressant effect.