Chronic treatment with the antidepressant tianeptine attenuates lipopolysaccharide-induced Fos expression in the rat paraventricular nucleus and HPA axis activation

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Abstract

The antidepressant tianeptine has been shown to decrease the response of the hypothalamic–pituitary–adrenal (HPA) axis to stress and to attenuate the behavioral effects of the cytokine inducer, lipopolysaccharide (LPS). Since LPS also activates the HPA axis, the objective of this study was to assess the effects of tianeptine on the HPA axis activation and Fos expression induced by intraperitoneal (ip) administration of LPS (30 and 250 μg/kg respectively). Chronic, but not acute, tianeptine treatment (10 mg/kg twice a day for 15 days, ip) attenuated LPS-induced increase of plasma ACTH and corticosterone in rats bearing an indwelling catheter in the jugular vein and Fos immunoreactivity in the paraventricular nucleus (PVN). These results open new vistas on the pharmacological activity of tianeptine and provide further insights on the action mechanisms of antidepressants in clinics.

Introduction

Antidepressants have important immunoregulatory effects (see for review Maes, 2001), as evidenced by normalization of the immune alterations observed in depressed patients (see for review Neveu and Castanon, 1999) and modifications of stimulated cytokine production in rodents (Shen et al., 1999, Connor et al., 2000, Kubera et al., 2000, Kubera et al., 2001b). However, little is known on the mechanisms underlying these regulations, as well as their relevance to the therapeutic efficacy of antidepressants. Chronic treatment with different antidepressants alters some of the behavioral and neuroendocrine changes induced by lipopolysaccharide (LPS), the active fragment of endotoxin from Gram-negative bacteria (Yirmiya, 1996, Connor et al., 2000), although noteworthy differences of efficacy have been observed between distinct classes of molecules (Shen et al., 1999, Yirmiya et al., 2001). The ‘anti-inflammatory’ profile of antidepressant drugs seems to slightly differ according to their structural class (monoamine oxydase inhibitors, tricyclics, monoamine reuptake inhibitors…) and the variable under study (behavioral or neuroendocrine responses) (see for review Castanon et al., 2002). Therefore, it is necessary to compare the effects of antidepressants from different pharmacological classes, on a complete panel of cytokine-induced changes, in order to find common characteristics that may reflect possible action mechanisms shared by these drugs.

Many experimental and clinical studies have shown that tianeptine, a modified tricyclic antidepressant (TCAs), presents a therapeutic efficacy and delay of action (several weeks) similar to that known for common antidepressants, but is devoid of the important side effects characterizing TCAs (see for review Wagstaff et al., 2001). Despite this interesting therapeutic profile, the mechanisms of action of tianeptine are still unknown. Tianeptine increases the reuptake of serotonin (5-HT) into rat brain (Fattaccini et al., 1990) and into human and rat platelets (Kato and Weitsch, 1988, Ortiz et al., 1993) after acute, but not chronic, treatment (Kelly and Leonard, 1994, Piñeyro et al., 1995). Moreover, it does not interfere with the reuptake of noradrenaline, or with the activity of monoamine oxydases (see for review Wilde and Benfield, 1995). Another peculiarity of tianeptine is that, in contrast to most TCAs, it decreases the HPA axis response to stress (Fontanges et al., 1993, Guillaume et al., 1993, Delbende et al., 1994), and protects the hippocampus against the deleterious effects of stress and glucocorticoids (McEwen et al., 1997, Magariños et al., 1999, Czéh et al., 2001). However, little is known on the potential modulation of neuro–immune interactions by tianeptine and the role that this modulation could play in its therapeutic efficacy. As a first attempt to answer this question, we have recently shown that chronic tianeptine attenuated sickness behavior induced by LPS and IL-1β (Castanon et al., 2001). In order to further assess the effect of tianeptine on the central actions of cytokines, we have investigated whether tianeptine is also able to attenuate LPS-induced activation of the HPA axis measured by activation of the immediate early gene c-fos in the parvoventricular nucleus of the hypothalamus (Wan et al., 1994, Konsman et al., 1999) and by increased plasma levels of ACTH and corticosterone (Turnbull and Rivier, 1999). We show here that chronic, but not acute, treatment of rats with tianeptine does attenuate LPS-induced activation of the HPA axis.

Section snippets

Animals and housing conditions

Animals used in the present study were male Wistar rats (200–300 g) obtained from Charles River (Saint-Aubin-les-Elbeuf, France). They were housed in groups of five in polypropylene cages, until the beginning of the experiments, under a normal 12:12h light:dark cycle (lights on at 0800h). Food and water were available ad libitum, and room temperature was controlled (22±1°C). Rats were isolated in individual cages 2–4 days before the test. All rats were handled daily during the week before the

Experiment 1: Effects of acute or chronic tianeptine on LPS-induced activation of the HPA axis

LPS treatment significantly increased plasma levels of ACTH [treatment: F(1,36)=28.3, P<0.0001] (Fig. 1A) and corticosterone [treatment: F(1,36)=33.4, P<0.0001] in both saline- and tianeptine-treated rats (Fig. 1B). Acute tianeptine administration did not alter ACTH nor corticosterone levels, whatever the treatment condition).

Rats chronically treated with tianeptine gained less weight than control rats, this difference increasing progressively with time [pretreatment×days: F(13,494)=2.37, P

Discussion

The present findings demonstrate that chronic treatment with the antidepressant tianeptine attenuates the activation of the HPA axis and the induction of Fos immunoreactivity in the paraventricular nucleus of the hypothalamus, which are caused by systemic administration of LPS. The attenuation of central actions of cytokines by tianeptine, as assessed by its effect on LPS-induced HPA axis activation, appeared after chronic, but not acute treatment. This result matches with the delay of

Acknowledgements

Funded by INRA, INSERM, Pôle Aquitaine Santé, Biomed 2 (CT 97-2492), and Institut de Recherches Internationales Servier (IRIS). Many thanks to Dr Michael Spedding (IRIS) for encouragement and stimulating discussion. The expert technical assistance of Viviane Tridon is greatly appreciated.

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