Antidepressant drug administration modifies the interactive relationship between alpha(2)-adrenergic sensitivity and levels of TNF in the rat brain

A reciprocally permissive interaction occurs between cellular responses elicited by the pleiotropic cytokine tumor necrosis factor-alpha (TNF) and alpha(2)-adrenergic receptor activation, such that each may adapt in response to modifications in the other's effects. Changes in presynaptic adrenergic sensitivity as well as neuronal sensitivity to TNF have been implicated in the mechanism of action of antidepressant drugs. The present study examines the influence of alpha(2)-adrenergic receptor activation on levels of TNF in regions of the brain associated with adrenergic function and the expression of mood. Additionally, the role of TNF as a neuromodulator is demonstrated by in vivo microinfusion of rrTNF proximal to the hippocampus. Administration to rats of an alpha(2)-adrenergic receptor agonist (clonidine) decreases levels of TNF in homogenates of rat locus coeruleus and hippocampus within 7.5 min. Chronic (14 days) administration of the antidepressant drugs desipramine or zimelidine transforms alpha(2)-adrenergic receptor-dependent decreases in TNF levels to increases in levels of TNF in the locus coeruleus. This transformation to an increase in total levels of TNF also occurs, although transiently, in the hippocampus following acute (1 day) antidepressant drug administration. The effect of TNF on presynaptic alpha(2)-adrenergic sensitivity was also investigated. Field stimulation of hippocampal slices from rats microinfused with rrTNF proximal to the hippocampus for 14 days demonstrates a decrease in fractional release of [3H]NE and an increase in alpha(2)-adrenergic autoreceptor sensitivity. These data demonstrate a mutual dependence between alpha(2)-adrenergic receptor activation and levels of TNF in the central nervous system that would culminate in an increase in neurotransmitter release following antidepressant drug administration.