Acute diclofenac treatment attenuates lipopolysaccharide-induced alterations to basic reward behavior and HPA axis activation in rats.

RATIONALE

Non-steroidal anti-inflammatory drugs (NSAIDs) counteract stress hormone and pro-inflammatory cytokine activation, and are being considered as therapeutics for Alzheimer's and Parkinson's disease, and multiple sclerosis. Previous data from our laboratory revealed that repeated treatment with the NSAID diclofenac attenuated lipopolysaccharide (LPS)-induced alterations to reward behavior, implicating a role for NSAIDs in alleviating depressive-like behavior.

OBJECTIVES

To extend these findings, we sought to determine whether acute treatment with diclofenac would attenuate LPS-induced alterations to basic reward behavior, as well as neuroendocrine and neuroimmune function.

METHODS

Male, Wistar rats (n=8-9/grp) pressed a lever for sucrose pellet reward and after establishing a steady baseline were exposed to an injection of saline (1 ml/kg, SC) or diclofenac (2.5 mg/kg, SC) 30 min prior to a second injection of saline or LPS (20 microg/kg, IP).

RESULTS

In saline pre-treated rats, LPS significantly reduced rate of sucrose pellet self-administration and total reinforcers obtained, suggestive of an anhedonia response. In addition, LPS increased corticosterone release, increased plasma intereleukin (IL)-1beta release, increased IL-1beta and IL-6 mRNA in hippocampus, increased corticotropin releasing hormone (CRH) mRNA in pituitary, and decreased CRH-1 mRNA in pituitary. Importantly, the behavioral and neuroendocrine effects, but not neuroimmune effects, produced by LPS were significantly attenuated in rats pre-treated with diclofenac.

CONCLUSIONS

These new data provide a comprehensive assessment of the acute effects of diclofenac on LPS exposure in rats and confirm a role for NSAIDs in attenuating endotoxin-induced anhedonia. Of particular importance, the data reveal that the observed effects are mediated via the hypothalamic pituitary adrenal axis at the level of the pituitary or above.