Elsevier

Behavioural Brain Research

Volume 149, Issue 1, 4 February 2004, Pages 77-85
Behavioural Brain Research

The non-steroidal anti-inflammatory drug diclofenac sodium attenuates lipopolysaccharide-induced alterations to reward behavior and corticosterone release

https://doi.org/10.1016/S0166-4328(03)00211-0Get rights and content

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to counteract stress hormone and pro-inflammatory cytokine activation. To extend these findings, we tested whether the NSAID diclofenac sodium would attenuate lipopolysaccharide (LPS)-induced reductions in reward behavior. In the first experiment, male, Wistar rats pressed a lever for food reward and subsequently received 10 days treatment of saline (1 ml/kg, s.c.) or diclofenac (2.5 mg/kg, s.c.). On the subsequent test day, rats were given a final injection of saline or diclofenac 30 min prior to LPS (20 μg/kg, i.p.). LPS significantly reduced rate of food self-administration and total reinforcers obtained and increased corticosterone levels in saline-treated rats, while these effects were significantly attenuated in diclofenac-treated rats. In the second experiment, rats pressed a lever for sweetened milk. In contrast to food self-administration, acute LPS exposure did not reduce rate of responding or total reinforcers obtained in either saline- or diclofenac-treated rats. In the third experiment, rats trained to press a lever for sweetened milk were pre-exposed to a high dose of LPS (250 μg/kg, i.p.) 2 weeks prior to a challenge injection of LPS. In this case, LPS challenge significantly reduced rate of sweetened milk self-administration, but not total reinforcers obtained, in saline-treated rats. Rats treated with diclofenac did not exhibit reductions in rate of responding or total reinforcers obtained. Overall, the data indicate that the NSAID diclofenac sodium counteracts LPS-induced reductions in reward behavior and corticosterone release, and may therefore have therapeutic potential for specific components of endotoxin-induced sickness behavior, including anhedonia.

Introduction

Endotoxins are potent stimulators of the synthesis and release of pro-inflammatory cytokines, and acute exposure induces several pronounced behavioral alterations, referred to as “sickness behaviors” [22], [27]. In rodents, sickness behaviors include anhedonia, increased sleep, and decreased food intake, body weight, locomotor activity, social interaction, sexual behavior, and grooming. These behavioral responses, accompanied by neuroimmune and neuroendocrine activation, have been associated with non-specific inflammatory processes in animals [27]. In humans, neuroendocrine and neuroimmune activation induces a number of neuropsychological symptoms, collectively referred to as “flu-like syndrome” (synonymous with sickness behavior in animals), which consist of anhedonia, anorexia, fever, fatigue, increased pain, sleep disturbances, and confusion [22].

The degree of overlap between flu-like syndrome and depression in humans is significant and a close linkage between these has been predicted to arise due to hypersecretion of pro-inflammatory cytokines [2], [30], [33], and/or chronic activation of the hypothalamic–pituitary–adrenal (HPA) axis [19], [34], [36], [40], [43]. Conventional antidepressants (i.e. selective serotonin reuptake inhibitors and tricyclics) may produce ameliorative effects by suppressing pro-inflammatory cytokine production and stress hormone release [10], [26], [29], [52], and may additionally stimulate anti-inflammatory cytokine release [23]. Recent evidence suggests that non-steroidal anti-inflammatory drugs (NSAIDs) also attenuate neuroimmune and neuroendocrine activation. Of particular interest, studies using rats have revealed that the NSAID zaltoprofen reduced sickness behavior and body weight loss induced by concanavalin-A (an activator of T-cells and cytokines) [38], and the NSAIDs celocoxib and indomethacin attenuated lipopolysaccharide (LPS)-induced and interleukin type-1β (IL-1β)-induced reductions in food and sweetened milk intake [45], [47], [48].

To extend these findings, we sought to determine if the NSAID diclofenac sodium, a cyclooxygenase type-1 (COX-1) inhibitor, would attenuate LPS-induced anhedonia and/or corticosterone release. LPS is an endotoxin that is a major component of the outer cell wall of gram-negative bacteria and acute exposure precipitates a sickness behavior syndrome that is accompanied by increased levels of stress hormones and cytokines, and decreased food and sweetened milk intake [17], [21], [22]. Pre-clinical investigations in rodents have demonstrated that anhedonia may be measured as reduced motivation to respond for naturally rewarding stimuli (i.e. food or sweetened milk intake) [50]. This is a relevant animal model since a major symptom associated with major depressive disorder in humans is anhedonia, which is characterized by a loss of interest in, or ability to derive pleasure from, rewarding stimuli (or activities) [1].

Section snippets

Experiment 1

The first experiment was designed to assess the effects of diclofenac on LPS-induced alterations to food self-administration behavior and corticosterone release. Male, Wistar rats (225–250 g, 8 weeks of age; Charles-River, NC) were trained to press a lever for food reward (45 mg pellets containing sucrose and dextrose; Noyes, New Brunswick, NJ) in a typical two-lever operant chamber. The data presented are the combined results from two independent studies performed in our laboratory.

Experiment 1

With a single exception (1 of 24 rats), rats rapidly learned the food self-administration task and each developed stable responding by the end of the second week of training. During the subsequent 2 weeks, repeated injections with saline or diclofenac (as determined after two, five, or nine injections) did not significantly alter baseline RATE of food self-administration (Table 1). Specifically, a main effect was not observed for PRE-TREATMENT (F1,21=0.12, P=0.73) or RATE (F3,63=2.54, P=0.06),

Discussion

The current report demonstrates that the NSAID diclofenac sodium attenuated LPS-induced reductions in reward-related behavior and increased corticosterone release. Stress, endotoxins (including LPS), and pro-inflammatory cytokines (e.g. IL-1β and interferon-α (IFN-α)) reduce motivation toward hedonic stimuli and the resulting behavioral effects are predicted to model an integral feature of depressive-like behavior in humans. These new data compliment and extend prior work showing that

Acknowledgements

The authors wish to acknowledge the work of Alicia McCaskie (SUNY Binghamton) and Avi Wittlin (Yeshiva University) who performed the initial behavioral experiments that led to this more thorough series of investigations. Support for this research made possible through funds provided to R.D. by the Department of Psychiatry and Behavioral Sciences of the Albert Einstein College of Medicine, T. Byram Karasu, M.D., Chair.

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