Effect of tumor necrosis factor‐α on the reciprocal G‐protein‐induced regulation of norepinephrine release by the α 2 ‐adrenergic receptor

α 2 ‐Adrenergic receptors control norepinephrine (NE) release and tumor necrosis factor‐α (TNF) production from neurons. TNF regulates NE release, depending on α 2 ‐adrenergic receptor functioning. The relationship between TNF production in the brain and α 2 ‐adrenergic receptor activation could have profound control over NE release. TNF and α 2 ‐adrenergic regulation of NE release was investigated in rat hippocampal slices incubated with pertussis toxin (PTX). The α 2 ‐adrenergic receptor couples to Gα i/o ‐proteins to inhibit NE release; however, in slices preexposed to PTX, α 2 ‐adrenergic receptor activation facilitates NE release. TNF exposure subsequent to PTX restores α 2 ‐adrenergic inhibition of NE release. PTX exposure of hippocampal slices prevents agonist‐induced increases in Gα i/o labeling with a GTP analog; after subsequent TNF exposure, agonist‐induced increases in Gα i/o labeling are restored. TNF regulation of NE release transforms from inhibition to facilitation depending on α 2 ‐adrenergic receptor activation following PTX exposure. Therefore, TNF directs the coupling of the α 2 ‐adrenergic receptor, ultimately affecting NE release. © 2005 Wiley‐Liss, Inc.