Abstract
The pleiotropic cytokine tumor necrosis factor-α (TNF) and α2-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 α2-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 α2-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 α2-adrenergic autoreceptor sensitivity. Collectively, these data support the hypothesis that chronic antidepressant drug administration alters α2-adrenergic receptor-dependent regulation of NE release. Additionally, these data demonstrate that administration of dissimilar antidepressant drugs similarly transform α2-adrenergic autoreceptors that are functionally associated with the neuromodulatory effects of TNF, suggesting a possible mechanism of action of antidepressant drugs.
Footnotes
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Send reprint requests to: Dr. Robert N. Spengler, State University of New York at Buffalo, Department of Pathology, 204 Farber Hall, 3435 Main St., Buffalo, NY 14214. E-mail: spengler{at}buffalo.edu
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↵1 This work is being submitted to the Graduate School of the State University of New York at Buffalo in partial fulfillment of the requirements for the Ph.D. degree in Pathology.
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This research was funded in part by The Mark Diamond Research Fund of the Graduate Student Association at the State University of New York at Buffalo no. 34F97 (to T.J.N.), National Alliance for Research on Schizophrenia and Depression Young Investigator Award (to T.A.I.), The Charles A. Dana Foundation (to R.N.S. and T.A.I.), and The Spinal Cord Research Foundation no. 1993 (to R.N.S.).
- Abbreviations:
- TNF
- tumor necrosis factor-α
- NE
- norepinephrine
- PBS
- phosphate-buffered saline
- RT
- room temperature
- SSC
- standard saline citrate
- Received August 14, 2000.
- Accepted February 12, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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