Amitriptyline administration transforms tumor necrosis factor-alpha regulation of norepinephrine release in the brain

The present study demonstrates that the mixed action antidepressant drug amitriptyline enhances norepinephrine (NE) release by transforming the nature of the response of neurons to both tumor necrosis factor-alpha (TNF) as well as to an alpha(2)-adrenergic agonist in an area of the central nervous system (CNS) rich in adrenergic neurons. Administration of the antidepressant drug amitriptyline for 1 day or 14 days to rats significantly increases TNF bioactivity in total homogenates of the locus coeruleus (LC) and the hippocampus as assessed by the WEHI-13VAR bioassay. Superfusion and electrical field stimulation of rat hippocampal brain slices were used to study the regulation of NE release. Exposure to TNF, as well as activation of the alpha(2)-adrenergic autoreceptor inhibits stimulation-evoked norepinephrine (NE) release from adrenergic neurons of the CNS from na?ve rats. Superfusion of hippocampal slices isolated from rats chronically (14 days) administered amitriptyline demonstrates that TNF inhibition of NE release is transformed, such that TNF facilitates NE release, dependent upon alpha(2)-adrenergic activation. Furthermore, chronic administration of amitriptyline increases stimulation-evoked NE release and decreases alpha(2)-adrenergic autoreceptor inhibition of NE release, an effect not observed with acute drug administration. These data support the hypothesis that chronic antidepressant drug administration, through regulation of TNF expression, transforms alpha(2)-adrenergic receptors such that they function to facilitate NE release, suggesting a mechanism of action of antidepressant drugs.