Depression is a multifactorial illness and genetic factors play a role in its etiology. The understanding of its physiopathology relies on the availability of experimental models potentially mimicking the disease. Here we describe a model built up by selective breeding of mice with strikingly different responses in the tail suspension test, a stress paradigm aimed at screening potential antidepressants. Indeed, ''helpless'' mice are essentially immobile in the tail suspension test, as well as the Porsolt forced-swim test, and they show reduced consumption of a palatable 2% sucrose solution. In addition, helpless mice exhibit sleep-wakefulness alterations resembling those classically observed in depressed patients, notably a lighter and more fragmented sleep, with an increased pressure of rapid eye movement sleep. Compared with ''nonhelpless'' mice, they display higher basal seric corticosterone levels and lower serotonin metabolism index in the hippocampus. Remarkably, serotonin 1A autoreceptor stimulation induces larger hypothermia and inhibition of serotoninergic neuronal firing in the nucleus raphe dorsalis in helpless than in nonhelpless mice. Thus, helpless mice exhibit a decrease in serotoninergic tone, which evokes that associated with endogenous depression in humans. Finally, both the behavioral impairments and the serotoninergic dysfunction can be improved by chronic treatment with the antidepressant fluoxetine. The helpless line of mice may provide an opportunity to approach genes influencing susceptibility to depression and to investigate neurophysiological and neurochemical substrates underlying antidepressant effects.T he prevalence of depression worldwide is such that this disorder represents a major health problem. It is estimated, for example, that Ϸ10% of men and 20% of women in Western Europe will suffer from a major depressive episode at some time in their life. The monoamine hypothesis of depression suggests that one of the biological bases of affective disorders is a deficiency in the neurotransmitter serotonin (5-HT). During the past 40 yr, this hypothesis has been refined, as more experimental and clinical evidence has emerged. The selective 5-HT reuptake inhibitors, in particular, allowed important progress in our understanding of the role of 5-HT in depression. To some extent, the mechanism of action of 5-HT reuptake inhibitors, which are the most widely prescribed antidepressant drugs today, can be anticipated from our knowledge of the anatomy and chemistry of the central serotoninergic system. However, it must be accepted that extensive investigations have so far failed to find convincing evidence of a primary dysfunction of the serotoninergic system in patients with depression. Disturbances of sleep are typical for most depressed patients and belong to the core symptoms of the disorder. Polysomnographic sleep research has demonstrated that, besides disturbances of sleep continuity, depression is associated with a reduction of slow-wave sleep and a shortening of rapid eye movement (REM...

Dysfunction of the serotonin system is implicated in sleep and emotional disorders. To test whether these impairments could arise during development, we studied the impact of early-life, transient versus genetic, permanent alterations of serotonin reuptake on sleep-wakefulness patterns, depression-related behavior, and associated physiological features. Here, we show that female mice treated neonatally with a highly selective serotonin reuptake inhibitor, escitalopram, exhibited signs of depression in the form of sleep anomalies, anhedonia, increased helplessness reversed by chronic antidepressant treatment, enhanced response to acute stress, and increased serotoninergic autoinhibitory feedback. This syndrome was not reproduced by treatment in naive adults but resembled the phenotype of mutant mice lacking the serotonin transporter, except that these exhibited decreased serotonin autoreceptor sensitivity and additional anxietylike behavior. Thus, alteration of serotonin reuptake during development, whether induced by external or genetic factors, causes a depressive syndrome lasting into adulthood. Such early-life impairments might predispose individuals to sleep and/or mood disorders.

For the last two decades, the involvement of 5-HT(1A) receptors in the regulation of vigilance states has been studied extensively thanks to pharmacological tools, but clear-cut conclusion has not been reached yet. By studying mutant mice that do not express this receptor type (5-HT(1A)-/-) and their wild-type 129/Sv counterparts, we herein demonstrate that 5-HT(1A) receptors play key roles in the control of spontaneous sleep-wakefulness cycles, as well as in homeostatic regulation and stress-induced adaptive changes of paradoxical sleep. Both strains of mice exhibited a diurnal sleep-wakefulness rhythm, but 5-HT(1A)-/- animals expressed higher amounts of paradoxical sleep than wild-type mice during both the light and the dark phases. In wild-type mice, pharmacological blockade of 5-HT(1A) receptors by WAY 100635 (0.5 mg/kg, i.p.) promoted paradoxical sleep, whereas the 5-HT(1A) agonist 8-OH-DPAT (0.25-1 mg/kg, s.c.) had an opposite effect. In contrast, none of the 5-HT(1A) receptor ligands affected sleep significantly in 5-HT(1A)-/- mice. However, 5-HT(1B) receptor stimulation by CP 94253 (1-3 mg/kg, i.p.) induced a reduction in paradoxical sleep in both strains, this effect being more pronounced in 5-HT(1A)-/- mutants. Finally, in contrast to wild-type mice, 5-HT(1A)-/- mutants did not exhibit any rebound of paradoxical sleep after either a 9 hr instrumental paradoxical sleep deprivation or a 90 min immobilization stress. Altogether, these data indicate that, in the mouse, 5-HT(1A) receptors participate in the spontaneous and homeostatic regulation, as well as in stress-induced adaptive changes of paradoxical sleep.

No abstract

No abstract