Vol. 297, Issue 2, 680-687, May 2001

Antidepressant Drug-Induced Alterations in Neuron-Localized Tumor Necrosis Factor- mRNA and ₂-Adrenergic Receptor Sensitivity

Tracey J. Nickola¹, Tracey A. Ignatowski, Jessica L. Reynolds and Robert N. Spengler

State University of New York at Buffalo, Department of Pathology, School of Medicine and Biomedical Sciences, Buffalo, New York

The pleiotropic cytokine tumor necrosis factor- (TNF) and ₂-adrenergic receptor activation regulate norepinephrine (NE) release from neurons in the central nervous system. The present study substantiates the role of TNF as a neuromodulator and demonstrates a reciprocally permissive relationship between the biological effects of TNF and ₂-adrenergic receptor activation as a mechanism of action of antidepressant drugs. Immunohistochemical analysis and in situ hybridization reveal that administration of the antidepressant drug desipramine decreases the accumulation of constitutively expressed TNF mRNA in neurons of the rat brain. Superfusion and electrical field stimulation were applied to a series of rat hippocampal brain slices to study the regulation of [³H]NE release. Superfusion of hippocampal slices obtained from rats chronically administered the antidepressant drug zimelidine demonstrates that TNF-mediated inhibition of [³H]NE release is transformed, such that [³H]NE release is potentiated in the presence of TNF, an effect that occurs in association with ₂-adrenergic receptor activation. However, chronic zimelidine administration does not alter stimulation-evoked [³H]NE release, whereas chronic desipramine administration increases stimulation-evoked [³H]NE release and concomitantly decreases ₂-adrenergic autoreceptor sensitivity. Collectively, these data support the hypothesis that chronic antidepressant drug administration alters ₂-adrenergic receptor-dependent regulation of NE release. Additionally, these data demonstrate that administration of dissimilar antidepressant drugs similarly transform ₂-adrenergic autoreceptors that are functionally associated with the neuromodulatory effects of TNF, suggesting a possible mechanism of action of antidepressant drugs.