Changes in noradrenergic sensitivity to tumor necrosis factor-α in brains of rats administered clonidine

Tumor necrosis factor-alpha (TNFα) and the imidazoline clonidine modulate norepinephrine (NE) release from noradrenergic nerve terminals in the central nervous system. The present study demonstrates an intrinsic association between presynaptic α₂-adrenergic receptor sensitivity and TNFα responsiveness in governing this NE release. Superfusion and electrical field stimulation were applied to a series of rat hippocampal brain slices in order to study the regulation of [³H]-NE release. The α₂-adrenergic agonist clonidine and the cytokine TNFα concentration-dependently inhibit [³H]-NE release; whereas, the α₂-adrenergic antagonist idazoxan potentiates [³H]-NE release. The fractional release of [³H]-NE during field stimulation of control hippocampal slices was decreased by the addition of TNFα in a concentration-dependent manner, an effect which was potentiated by the α₂-adrenergic antagonist idazoxan; whereas, TNFα attenuated the concentration-dependent potentiating effect of idazoxan. Furthermore, constitutive TNFα, demonstrated to be present in several brain areas, was significantly decreased following administration of the α₂-adrenergic agonist clonidine (0.6 mg/kg, i.p., twice daily) to rats for either 1 or 14 days, without a change in TNFα mRNA accumulation. We next investigated whether the presynaptic sensitivity to TNFα was changed after clonidine administration to rats. TNFα enhanced, rather than inhibited, [³H]-NE release after 1 day of clonidine administration, while a suppressed sensitivity to TNFα was observed in the hippocampus after 14 days of clonidine administration. In addition, in the presence of idazoxan, TNFα potentiation of [³H]-NE release after 1 day clonidine administration was reversed to a decreased inhibition as compared to control slices exposed to idazoxan. Therefore, the temporary reversal in the presynaptic TNFα response after 1 day of clonidine administration illustrates a mechanism of action for its persistent antihypertensive effect, its transient sedative and antihyperpathic effects, and its acute ability to promote antidepressants. These results demonstrate a novel role for an immune mediator in the central nervous system, and demonstrates that presynaptic TNFα responsiveness is intimately associated with adrenergic receptor sensitivity.