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

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Abstract

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 μg/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)-1β release, increased IL-1β 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.

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Acknowledgements

The authors wish to thank Gina-Elena Radoi for invaluable assistance with the initial gene expression work in this laboratory that gave rise to the data published in this report. The authors also wish to thank Dr. Myles Akabas (Department of Physiology and Biophysics) for the generous use of the Fluorchem gel capture and analysis system in his laboratory. Support for this research made possible through funds provided to RD by the Department of Psychiatry and Behavioral Sciences of the Albert Einstein College of Medicine, T. Byram Karasu, MD, Chair.

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  1. Richard De La Garza II

    Present address: University of California Los Angeles, 740 Westwood Blvd, NPI, Room A8-148, Los Angeles, CA, 90024, USA

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Forchheimer Building, Room 111, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Richard De La Garza II, Gregory M. Asnis & Erika Pedrosa

  2. Department of Neuroscience, Albert Einstein College of Medicine, Forchheimer Building, Room 111, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Richard De La Garza II & Kevin R. Fabrizio

  3. Anxiety and Depression Program, Montefiore Medical Center, Albert Einstein College of Medicine, Klau Basement, 111 E. 210th Street, Bronx, NY, 0467-2490, USA

    Gregory M. Asnis

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Correspondence to Richard De La Garza II.

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De La Garza, R., Asnis, G.M., Fabrizio, K.R. et al. Acute diclofenac treatment attenuates lipopolysaccharide-induced alterations to basic reward behavior and HPA axis activation in rats. Psychopharmacology 179, 356–365 (2005). https://doi.org/10.1007/s00213-004-2053-x

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