Brain-derived TNFalpha and its involvement in neuron function associated with mood

The α₂-adrenergic autoreceptor inhibits norepinephrine (NE) release from adrenergic neurons. Additionally, the cytokine tumor necrosis factor (TNFα) also inhibits NE release. The goal of the present study was to investigate the interactive relationship between TNFα levels and α₂-adrenergic sensitivity within the brain.; Administration of antidepressant drugs to rats decrease brain-derived TNFα levels. Antidepressant drug administration is also associated with a transformation in α₂-adrenergic receptor function to support an increase in NE release upon receptor activation. Field stimulation of hippocampal slices from rats was used to assess the regulation of NE release. Stimulation of hippocampal slices isolated from rats chronically administered the antidepressant amitriptyline demonstrate that TNFα-mediated inhibition of NE release is transformed to facilitation. This is dependent upon α₂-adrenergic receptor activation. TNFα-mediated regulation of NE release from control hippocampal slices exposed to pertussis toxin (PTX) prior to electrical stimulation, is similarly transformed to facilitation of NE release. The sensitivity of the α₂-adrenergic receptor is also transformed following PTX exposure, such that activation of the α₂-adrenergic receptor increases stimulation-evoked NE release. Interestingly, in slices exposed to PTX and subsequently exposed to TNFα, activation of the α ₂-adrenergic receptor once again inhibits NE release. Photoaffinity labeling using a GTP-analog (AA-GTP) demonstrates that α₂-adrenergic receptor activation increases AA-GTP incorporation into G_i/oα-protein. This incorporation is prevented in the presence of PTX and restored in the presence of TNFα. Continual activation of the α₂-adrenergic receptor along with simultaneous administration of the antidepressant desipramine prevents both the cellular and behavioral changes that occur with desipramine administration alone. These data demonstrate that while a primary mechanism of desipramine is to increase NE release, an alternate mechanism is involved in its therapeutic efficacy.; The therapeutic efficacy of desipramine was investigated by microinfusion of rrTNF with simultaneous administration of desipramine. This paradigm prevents both the cellular and behavioral changes that occur following chronic desipramine administration alone. Furthermore, microinfusion of pTNF-Ab mimics both the cellular and behavioral changes that occur following chronic desipramine administration alone. This study established the role for the interactive relationship between TNFα and activation of the α₂-adrenergic receptor in the mechanism of action of antidepressants.