Abstract
The present study documents a role for brain-derived tumor necrosis factor-α (TNF) in the mechanism of action of the antidepressant drug desmethylimipramine (desipramine). To establish this role, field stimulation and superfusion of rat hippocampal slices was employed to investigate the regulation of norepinephrine (NE) release by TNF. Chronic desipramine administration transforms TNF-mediated inhibition of NE release to facilitation, dependent upon α2-adrenergic receptor activation. Chronic i.c.v. microinfusion of polyclonal TNF antibody (pTNF-Ab) similarly transforms TNF inhibition of NE release to facilitation. To determine whether this transformation is due to desipramine-induced inhibition of TNF bioactivity in the brain, rats were i.c.v. microinfused with recombinant rat TNF (rrTNF) for 14 days, either alone or with simultaneous i.p. desipramine administration. TNF regulation of NE release in hippocampal slices isolated from these rats was compared with slices isolated from rats chronically administered desipramine alone. Although simultaneous microinfusion of rrTNF with chronic desipramine administration prevents the transformation induced by desipramine, microinfusion of rrTNF enhances TNF inhibition of NE release. These cellular events correspond to changes in immobility, analyzed by the forced swim test (FST). Intracerebroventricular microinfusion of rrTNF increases the duration of immobility of rats in the FST, compared with rats microinfused with aCSF. Desipramine administered chronically decreases immobility duration, which is mimicked by i.c.v. microinfusion of pTNF-Ab and prevented by simultaneous i.c.v. microinfusion of rrTNF. Thus, i.c.v. microinfusion of rrTNF with concomitant desipramine administration opposes decreases in neuron-associated TNF levels, required to transform presynaptic sensitivity to TNF, which is necessary for the drug to be efficacious.
Footnotes
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This study was funded by The Charles A. Dana Foundation (to R.N.S. and T.A.I) and by the National Institutes of Health Grant NS41352 (to R.N.S).
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This work is being submitted to the Graduate School of the University at Buffalo, The State University of New York in partial fulfillment of the requirements for the Ph.D. degree in Pathology (J.L.R.).
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This work was previously presented at Society for Neuroscience 2003, program no. 131.9.
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doi:10.1124/jpet.104.067835.
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ABBREVIATIONS: NE, norepinephrine; TNF, tumor necrosis factor-α; FST, forced swim test; rrTNF, recombinant rat tumor necrosis factor-α; pTNF-Ab, polyclonal TNF antibody; aCSF, artificial cerebral spinal fluid; rhTNF, recombinant human tumor necrosis factor-α; rmTNF, recombinant murine tumor necrosis factor-α; ANOVA, analysis of variance.
- Received March 1, 2004.
- Accepted April 12, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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