Antidepressant drug-induced alterations in neuron-localized tumor necrosisfactor-alpha mRNA and alpha(2)-adrenergic receptor sensitivity

The pleiotropic cytokine tumor necrosis factor-alpha (TNF) and alpha (2)-ad renergic receptor activation regulate norepinephrine (NE) release from neur ons in the central nervous system. The present study substantiates the role of TNF as a neuromodulator and demonstrates a reciprocally permissive rela tionship between the biological effects of TNF and alpha (2)-adrenergic rec eptor activation as a mechanism of action of antidepressant drugs. Immunohi stochemical analysis and in situ hybridization reveal that administration o f the antidepressant drug desipramine decreases the accumulation of constit utively expressed TNF mRNA in neurons of the rat brain. Superfusion and ele ctrical field stimulation were applied to a series of rat hippocampal brain slices to study the regulation of [H-3] NE release. Superfusion of hippoca mpal slices obtained from rats chronically administered the antidepressant drug zimelidine demonstrates that TNF-mediated inhibition of [H-3] NE relea se is transformed, such that [H-3] NE release is potentiated in the presenc e of TNF, an effect that occurs in association with alpha (2)-adrenergic re ceptor activation. However, chronic zimelidine administration does not alte r stimulation-evoked [H-3] NE release, whereas chronic desipramine administ ration increases stimulation-evoked [H-3] NE release and concomitantly decr eases alpha (2)-adrenergic autoreceptor sensitivity. Collectively, these da ta support the hypothesis that chronic antidepressant drug administration a lters alpha (2)-adrenergic receptor-dependent regulation of NE release. Add itionally, these data demonstrate that administration of dissimilar antidep ressant drugs similarly transform alpha (2)-adrenergic autoreceptors that a re functionally associated with the neuromodulatory effects of TNF, suggest ing a possible mechanism of action of antidepressant drugs.