Received for publication March 1, 2004.
Revised April 9, 2004.
Accepted for publication April 12, 2004.

Brain-derived tumor necrosis factor-alpha and its involvement in adrenergic neuron functioning involved in the mechanism of action of an antidepressant

Abstract

The present study documents a role for brain-derived tumor necrosis factor-(TNF) in the mechanism of action of the antidepressant drug 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 ₂-adrenergic receptor activation. Chronic intracerebroventricular (icv) 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 icv 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 to slices isolated from rats chronically administered desipramine alone. While 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). ICV microinfusion of rrTNF increases the duration of immobility of rats in the FST, compared to rats microinfused with aCSF. Desipramine administered chronically decreases immobility duration, which is mimicked by icv microinfusion of pTNF-Ab and prevented by simultaneous icv microinfusion of rrTNF. Thus, icv 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.

Key words: adrenergic, antidepressant, desipramine, forced swim test, norepinephrine, tumor necrosis factor

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