Neuronal-associated tumor necrosis factor (TNF alpha): its role in noradrenergic functioning and modification of its...

Tumor necrosis factor-alpha (TNF alpha) and the alpha 2-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 TNF alpha in a concentration-dependent manner, an effect which was potentiated by the alpha 2-adrenergic antagonist idazoxan. Presently, we demonstrate that similar to alpha 2-adrenergic activation, TNF alpha 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 TNF alpha protein in the rat brain. Staining for TNF alpha appears to be largely localized to neurons and neuronal processes, further substantiating the proposal that TNF alpha 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 TNF alpha immunoreactivity. TNF alpha localization in neurons and its modification of NE release comparable to alpha 2-adrenergic receptor activation, explains a functional role for the cytokine as a neuromodulator in the CNS.