Repeated Lipopolysaccharide (LPS) or Cytokine Treatments Sensitize Ethanol Withdrawal-Induced Anxiety-Like Behavior
Neuropsychopharmacology advance online publication 6 June 2007






Previous investigations demonstrated that repeated stresses before an ethanol exposure sensitize ethanol withdrawal-induced anxiety-like behavior ('anxiety'). In addition to activating the hypothalamic–pituitary–adrenal axis, acute stress also elevates cytokines in brain.

Initially, to test possible cytokine involvement in this stress/withdrawal protocol, cytokines were increased in brain with 2 weekly repeated lipopolysaccharide (LPS) administrations (1000 /kg) (LPS/withdrawal protocol) or with twice weekly intracerebroventricular (i.c.v.) administrations of the cytokines IL-1, CCL2 (MCP-1) or TNF (cytokine/withdrawal protocol) before exposure and withdrawal from a 5-day cycle of chronic ethanol diet.

Both protocols sensitized withdrawal-induced anxiety and confirm cytokine involvement in the sensitized anxiety response.

Testing of various doses of LPS (16–1000 g/kg) and TNF (3–100 ng, i.c.v.) demonstrated the dose-related nature of these protocols to sensitize withdrawal-induced anxiety.

Finally, just as found previously with the stress/withdrawal protocol, administration of the benzodiazepine receptor antagonist flumazenil before the LPS or TNF treatments prevented anxiety sensitization.

Together, these findings indicate that increased cytokine activity induces adaptive change that supports sensitization of ethanol withdrawal-induced anxiety that may be linked to GABA_A-receptor function.

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Reprint Request E-mail: george_breese@med.unc.edu
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