Effects of desipramine and tramadol in a chronic mild stress model in mice are altered by yohimbine but not by pindolol

Abstract

This study investigated the antidepressant-like effects of a chronic treatment with either tramadol (20 mg/kg, i.p.) or desipramine (10 mg/kg, i.p.) in the unpredictable chronic mild stress model of depression in BALB/c mice. Mice were first submitted to a 2 week drug-free unpredictable chronic mild stress before the onset of the treatments. The unpredictable chronic mild stress regimen induced a degradation of the state of the coat and decreased the grooming behaviour in the splash test. These physical and behavioural abnormalities were counteracted by tramadol and desipramine. Furthermore, we observed neither a significant acceleration nor diminution by pindolol (5-HT_1A/1B receptor antagonist, 10 mg/kg, i.p.) on the antidepressant-like actions of desipramine and tramadol whereas yohimbine (α₂-adrenergic receptor antagonist, 2 mg/kg, i.p.) antagonized the antidepressant-like effects of both drugs during the unpredictable chronic mild stress regimen.

The results of the study support the suggestion that antidepressant-like effect of tramadol and desipramine in mice in the unpredictable chronic mild stress model is mediated by the noradrenergic system rather than the serotonergic system.

Introduction

Tramadol is a centrally acting (Friderichs et al., 1978) and clinically effective analgesic, which is used mainly for the treatment of moderate or severe pain (Sindrup et al., 1999). It has a relatively weak opioid receptor affinity (Hennies et al., 1988) and selectivity for μ-subtype with a Ki in the micromolar range (Raffa et al., 1992). It has been shown that tramadol enhances the extraneuronal concentrations of the monoamine neurotransmitters, noradrenaline and serotonin, by interfering with the reuptake and release mechanisms (Driessen et al., 1993, Raffa et al., 1992). Unlike other opioid receptor agonists, tramadol is a racemic mixture of two enantiomers, each one having distinct but complementary mechanisms of action: (+) tramadol enantiomer is a selective agonist for the μ-opioid receptor which preferentially inhibits serotonin reuptake and enhances serotonin efflux in the brain whereas the (−) enantiomer mainly inhibits noradrenaline reuptake (Frink et al., 1996, Codd et al., 1995). The mechanism of action and structure of tramadol is very similar to that of some antidepressants such as venlafaxine (Markowitz and Patrick, 1998). In addition, tramadol elicits antidepressant-like effects in the forced swimming test in mice (Rojas-Corrales et al., 1998) and in the learned helplessness model in rats (Rojas-Corrales et al., 2002). But to our knowledge, the mechanism of antidepressant-like effect of tramadol still remains unclear.

Among the numerous serotonin and noradrenaline receptors, the 5-HT_1A receptors and the α₂-adrenoceptors seem to be particularly remarkable targets on to the action of antidepressants. Santarelli et al. (2003) reported that 5-HT_1A receptors are required for fluoxetine, a serotonin selective reuptake inhibitor (SSRI)-induced neurogenesis, a process necessary to its antidepressant effects, but not imipramine-induced neurogenesis. Furthermore, several studies have demonstrated that combination of a 5-HT_1A receptor antagonist with SSRIs potentiates the effect of antidepressant drug on the serotonin release (Romero and Artigas, 1997, Blier et al., 1997). On the other hand, the inhibition of neuronal activity of locus coeruleus by the noradrenaline reuptake inhibitors has been interpreted as a consequence of the increased concentration of synaptic noradrenaline, leading to an increased activation of α₂-adrenoceptors (Mongeau et al., 1998, Szabo et al., 2000). Furthermore, it has been shown that the effect of desipramine, a tricyclic antidepressant which preferentially blocks the reuptake of noradrenaline on extracellular noradrenaline in the brain cortex is modulated by α₂-adrenoceptors in the locus coeruleus (Mateo et al., 1998).

The unpredictable chronic mild stress is generally thought to be the most promising and valuable model to study depression in animals, mimicking several human depressive symptoms (Willner, 1997). It has been reported that the unpredictable chronic mild stress regimen decreases the consumption of or preference for a sucrose solution (anhedonia) (Willner et al., 1987) and induces a degradation of the physical state of the coat (Ducottet et al., 2003). However, these degradations can be reversed by the antidepressants such as fluoxetine (Ducottet et al., 2003, Santarelli et al., 2003).

The present study was designed to examine the possible antidepressant-like effects of tramadol and desipramine using the unpredictable chronic mild stress, a model that is more valid in terms of face and construct validity than the other tests such as the forced swimming test, the tail suspension and the learned helplessness model. Moreover, we aimed to clarify the mechanisms underlying the antidepressant-like actions of tramadol and desipramine. For this purpose, we tested the effects of the 5-HT_1A/1B antagonist pindolol and the α₂-adrenergic receptor antagonist yohimbine, alone or in combination with either tramadol or desipramine, to reveal the contribution of the serotonergic and the noradrenergic systems on the antidepressant-like actions of these drugs. In order to determine the effects of the unpredictable chronic mild stress regimen and the drug treatment, we used two parameters in our experiments: the coat state and splash test. The state of the coat was used to evaluate grooming behaviour indirectly whereas the splash test determined this behaviour directly (Santarelli et al., 2003).