Antidepressants and REM sleep in Wistar–Kyoto and Sprague–Dawley rats

Abstract

Compared to other rat strains, the Wistar–Kyoto rats show increased amount of REM sleep, one of the characteristic sleep changes observed in depressed patients. The aims of this study were firstly to validate a simple sleep stage discriminator and then compare the effect of antidepressants on suppression of rapid eye movement (REM) sleep in Wistar–Kyoto rats and an outbred rat strain (Sprague–Dawley). Rats were implanted with telemetry transmitters with electroencephalogram/electromyogram electrodes. Following recovery, the animals were orally dosed at light onset with either desipramine (20 mg/kg), fluoxetine (10 mg/kg), citalopram (10 or 40 mg/kg) or vehicle in a cross-over design. Every 12-s epoch was automatically scored as WAKE, NREM or REM sleep. Results confirm that Wistar–Kyoto rats show increased amount of REM sleep and decreased REM latency compared with Sprague–Dawley rats. All antidepressants significantly suppressed REM sleep in Sprague–Dawley rats, but only the high dose of citalopram suppressed REM sleep in Wistar–Kyoto rats. These findings suggest that the enhanced REM activity in Wistar–Kyoto rats is less sensitive to the effect of antidepressants and therefore does not provide any additional predictive validity for assessing antidepressant efficacy.

Introduction

Polysomnography studies in depressed patients have consistently shown alterations in sleep architecture and a number of different characteristic changes have been identified. The most consistent findings include changes in rapid eye movement (REM) sleep with shortened REM latency and increased amount of REM sleep early during the night (Vogel et al., 1980, Kupfer, 1984, Reynolds and Kupfer, 1987, Berger et al., 2003). Antidepressant drugs of different categories including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs) have been shown to consistently cause suppression of REM sleep in both healthy volunteers and depressed patients (for review see Winokur et al., 2001, Sharpley and Cowen, 1995).

The Wistar–Kyoto (WKY) rat is a normotensive progenitor strain of the spontaneously hypertensive rat (Louis and Howes, 1990) that has been shown to exhibit a number of hormonal, behavioural and circadian rhythm abnormalities often associated with depression. For example WKY rats display larger endocrine responses and enhanced vulnerability to the effect of stressors compared to other rat strains e.g. Sprague–Dawley, Wistars, Long–Evans (Pare, 1989, Pare and Redei, 1993, Lahmame and Armario, 1996, Lopez-Rubalcava and Lucki, 2000, Solberg et al., 2001). Interestingly, in addition to being more susceptible to stress the WKY rat also show endogenous depression-like behaviour such as reduced investigatory behaviour (Pare, 2000). It has also been shown that the WKY rats display a more depression-like behaviour in the Porsolt forced swim test and other tests of learned helplessness (Pare, 1989, Pare and Redei, 1993, Lahmame et al., 1997). Taken together, these findings have led to the suggestion that WKY rats could be an animal model of depression. Studies assessing the effect of different classes of antidepressants on the depression-like behaviour of WKY rats have not resulted in a clear conclusion as to whether the WKY rats are more sensitive than a control rat strain in detecting antidepressants. It has been shown that chronic treatment with tricyclic antidepressants decreases depression-like behaviour of WKY rats as measured with decreased immobility and increased struggling in the forced swim test (Pare, 1992, Lopez-Rubalcava and Lucki, 2000), but other studies have shown that the WKY rats are resistant to acute and repeated administration of tricyclic antidepressants and fluoxetine (Lahmame and Armario, 1996, Lahmame et al., 1997, Griebel et al., 1999). Recently, Dugovic et al. (2000) showed that under baseline conditions the WKY rats show sleep abnormalities particularly in REM sleep similar to those found in depressive patients. The most consistent findings with antidepressants in patients with affective disorder is a suppression of early REM sleep and increased REM onset latency. Therefore the main aims of this study were to confirm that WKY rats show a significant increase in REM sleep during the light phase compared to an outbred rat strain and to test whether the increased REM sleep in the WKY rats was more sensitive to antidepressant drugs. If so, the REM suppression in WKY rat could potentially be a more sensitive biomarker for testing novel antidepressants. In addition, a simple sleep stage discriminator is described that enables a reliable way of detecting and quantifying three vigilance states in rats.