NEURONAL-ASSOCIATED TUMOR-NECROSIS-FACTOR (TNF-ALPHA) - ITS ROLE IN NORADRENERGIC FUNCTIONING AND MODIFICATION OF ITS EXPRESSION FOLLOWING ANTIDEPRESSANT DRUG ADMINISTRATION

Tumor necrosis factor-alpha (TNF alpha) and the alpha(2)-adrenergic ag onist clonidine regulate norepinephrine (NE) release from noradrenergi c 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 reg ulation of [H-3]-NE release, NE release had been previously determined a to be decreased by TNF alpha in a concentration-dependent manner, a n effect which was potentiated by the alpha(2)-adrenergic antagonist i dazoxan. Presently, we demonstrate that similar to alpha(2)-adrenergic activation, TNF alpha regulation of NE release in a region of the bra in rich in noradrenergic nerve terminals, is dependent upon the freque ncy of electrical stimulation applied to the hippocampal slice. Furthe rmore, immunoperoxidase staining has verified our previous findings of constitutive TNF alpha protein in the rat bl ain. Staining for TNF al pha appears to be largely localized to neurons and neuronal processes, further substantiating the proposal that TNF alpha is either synthesi zed de novo or is accumulated in and released by neurons. After admini stration of the tricyclic antidepressant desipramine, tissue sections obtained from the rat hippocampus and locus coeruleus are devoid of ne uronal-associated TNF alpha immunoreactivity. TNF alpha localization i n neurons and its modification of NE release, comparable to alpha(2)-a drenergic receptor activation, explains a functional role for the cyto kine as a neuromodulator in the CNS. (C) 1997 Elsevier Science B.V.