Reboxetine attenuates forced swim test-induced behavioural and neurochemical alterations in the rat

Abstract

The forced swim test is a behavioural paradigm that is predicative of antidepressant activity in rodents. Until recently, research has focused on the ability of antidepressant drugs to decrease immobility in the forced swim test paradigm, but the neurochemical sequelae induced by swim stress, or the neurochemical basis of antidepressant-induced behavioural changes have received little attention. In this regard, we have recently demonstrated that forced swim test exposure increases serotonergic activity in the amygdala, frontal cortex and hippocampus and dopamine turnover in the striatum. In addition, forced swim test-exposure activates the hypothalamic pituitary adrenal axis. The purpose of the present study was to examine the effect of treatment with the selective noradrenaline reuptake inhibitor reboxetine (3, 10 and 30 mg/kg; i.p.) on immobility and defaecation scores in the forced swim test, and on forced swim test-induced neurochemical and hypothalamic pituitary adrenal axis changes in the rat. Reboxetine treatment (10 and 30 mg/kg) significantly decreased immobility and defaecation in the forced swim test in dose dependent manner. Furthermore, reboxetine produced a dose dependent attenuation of forced swim test-induced increases in serotonin turnover in the amygdala and frontal cortex and dopamine turnover in the striatum. Reboxetine (30 mg/kg) produced a modest, but non-significant, attenuation of forced swim test-induced increases in serum corticosterone concentrations. These data demonstrate that, in addition to the behavioural activity of reboxetine in the rat forced swim test paradigm, a dose-dependent attenuation of swim stress-induced increases in serotonergic and dopaminergic activity occurred in a region specific manner. These are the first data to demonstrate that treatment with the selective noradrenaline reuptake inhibitor, reboxetine can impact on the activity of other neurotransmitter systems in response to stress. Moreover, these data further demonstrate that this paradigm is a valuable tool in studying the effect of antidepressants, on both behaviour and swim stress-related alterations in central neurotransmitter function and hypothalamic pituitary adrenal axis activity in the rat.

Introduction

Given the clinical evidence associating stress with depression (Anisman and Zacharko, 1982; Bidzinska, 1984; Dinan, 1994; Holsboer and Barden, 1996), many of the preclinical models for assessing antidepressant activity have been based on abnormal behaviours precipitated by stress (Willner, 1990). One such paradigm is the forced swim test which was developed 20 years ago as a screening test for antidepressants in rodents (Porsolt et al., 1978). When rodents are exposed to the forced swim test, they typically display an immobile posture which is said to reflect a state of “behavioural despair” (Porsolt et al., 1978). Therefore, exposure to swim stress produces a change in behaviour which is thought to model a key symptom of the depressive state, namely that of despair or helplessness.

Until recently, research has focused on the ability of antidepressant drugs to increase escape motivated behaviour in the forced swim test paradigm, with little examination of the neurochemical consequences of swim stress or the neurochemical basis of antidepressant-induced behavioural changes that occur in this test. However, we have recently demonstrated that forced swim test exposure produces a number of region specific and time dependent neurochemical changes in the rat (Connor et al., 1997). The most consistent neurochemical changes observed following forced swim test-exposure are increased dopaminergic activity in the striatum and increased serotonergic activity in the frontal cortex and amygdala (Connor et al., 1997; Kelliher et al., 1998a, Kelliher et al., 1998b). Such stress-related changes in central dopaminergic and serotonergic activity are consistent with previous findings following swim stress exposure (Jordan et al., 1994; Petty et al., 1997) and exposure to other stressors (Dunn, 1988; Inoue et al., 1993; Kawahara et al., 1993; Davis et al., 1994; Inoue et al., 1994; Ge et al., 1997).

There is substantial evidence to suggest that noradrenaline is involved in the aetiology of depression and in the mechanism of action of antidepressant drugs (Potter, 1996; Leonard, 1997; Redmond and Leonard, 1997). It has been shown that increasing synaptic noradrenaline concentrations by means of reuptake inhibitors such as desipramine, or by antagonism of presynaptic α₂-adrenoceptors using mianserin or mirtazapine, is effective in the treatment of depression (Potter, 1996; Nutt and Pinder, 1996). Reboxetine, (RS)-2-[(RS)-α-(2-ethoxyphenoxy) benzyl] morpholine sulphonate [FCE 20124], is a new selective noradrenaline reuptake inhibitor (Riva et al., 1989; Wong et al., 1997) shown to be active in pharmacological and biochemical models predicative of antidepressant activity (Melloni et al., 1984; Riva et al., 1989; Harkin et al., 1999). However, in contrast to tricyclic antidepressants such as desipramine, it lacks affinity for α-adrenergic, histaminergic and muscarinic cholinergic receptors (Riva et al., 1989; Wong et al., 1997), and therefore represents an effective and safe option for antidepressant therapy. In addition to its antidepressant activity, the selectivity of reboxetine for noradrenaline reuptake inhibition makes it a particularly useful psychopharmacological tool for investigating the role of noradrenaline in modulating other neurotransmitter systems.

The purpose of the present study was to examine the dose related effect of treatment with reboxetine (3, 10 and 30 mg/kg; i.p.) on immobility and defaecation in the forced swim test, and also on forced swim test-induced serotonergic alterations in the amygdala, frontal cortex and hippocampus and dopaminergic changes in the striatum. In addition, the effect of reboxetine treatment on forced swim test-induced hypothalamic pituitary adrenal axis activation was evaluated.