Neuronal-associated tumor necrosis factor (TNFα): Its role in noradrenergic functioning and modification of its expression following antidepressant drug administration

Tumor necrosis factor-alpha (TNFα) and the α₂-adrenergic agonist clonidine regulate norepinephrine (NE) release from noradrenergic nerve terminals in the central nervous system (CNS). In the present study, superfusion and electrical field stimulation were applied to a series of rat hippocampal brain slices in order to investigate the regulation of [³H]-NE release. NE release had been previously determined to be decreased by TNFα in a concentration-dependent manner, an effect which was potentiated by the α₂-adrenergic antagonist idazoxan. Presently, we demonstrate that similar to α₂-adrenergic activation, TNFα regulation of NE release in a region of the brain rich in noradrenergic nerve terminals, is dependent upon the frequency of electrical stimulation applied to the hippocampal slice. Furthermore, immunoperoxidase staining has verified our previous findings of constitutive TNFα protein in the rat brain. Staining for TNFα appears to be largely localized to neurons and neuronal processes, further substantiating the proposal that TNFα is either synthesized de novo or is accumulated in and released by neurons. After administration of the tricyclic antidepressant desipramine, tissue sections obtained from the rat hippocampus and locus coeruleus are devoid of neuronal-associated TNFα immunoreactivity. TNF α localization in neurons and its modification of NE release, comparable to α₂-adrenergic receptor activation, explains a functional role for the cytokine as a neuromodulator in the CNS.