Increasing amounts of paradoxical sleep following a period of sleep deprivation is known as what

Changes in the expression of group-II metabotropic glutamate receptor subtypes (mGlu2 and mGlu3 receptors) are consistently reported in the brain of mice and rats modeling psychiatric disorders, such as depression and schizophrenia. Mice with a low resilience to stress show a reduced expression of mGlu2 receptors in the hippocampus [1], [2], and prenatal stressful events, which induce a psychotic-like phenotype, cause an epigenetic down-regulation of mGlu2 receptors in the mouse frontal cortex [3], [4], [5], [6]. Low expression levels of mGlu2 receptors are also found in inbred strains of rats characterized by high levels of impulsivity [7]. Mice with genetic deletion of mGlu3 receptors show a deficit in working memory and an abnormal behavioral response to MK-801 [8]. In humans, polymorphic variants of the mGlu3 receptor gene have been associated with schizophrenia [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], and alterations in mGlu3 receptor dimerization have been reported in the prefrontal cortex of patients affected by schizophrenia [19].

An association between mGlu3 receptor expression or function and bipolar disorder (BP) is suggested by genetic studies in humans [20], [21], [22], [18]. To our knowledge, there are no studies examining mGlu2 or mGlu3 receptor expression in animal models of BD or mania (the clinical hallmark of BD). Our selection of the most appropriate animal model moved from the clinical evidence that a decreased need for sleep is one of the most characteristic features of mania [23], [24] and that sleep deprivation is a triggering factor for manic episodes, and can induce switches from depression to mania in patients affected by BD [25], [26]. Paradoxical sleep deprivation in animals induces manic-like behaviors, such as insomnia and motor hyperactivity, which are corrected by lithium treatment [27], [28]. Hence, paradoxical sleep deprivation has face, construct, and predictive validity as model of manic episodes. While the study of how mGlu receptors regulate sleep architecture has been the subject of extensive investigation [29], [30], [31], [32], [33], [34], [35], [36], only two studies examined the effect of sleep deprivation on mGlu receptor expression. Positron emission tomography (PET) analysis with the mGlu5 receptor ligand, 11C-ABP688, showed an increased mGlu5 receptor binding in limbic regions of healthy subjects after 33 h of controlled wakefulness [37]. In rats, sleep deprivation caused an increased expression of mGlu1α receptors and an increased dimerization between mGlu1α and either type-1 or type-2 GABAB receptors in the hippocampal CA1 region [38]. Information on how paradoxical sleep deprivation affects the expression of mGlu2 and mGlu3 receptors is lacking. We now report that paradoxical sleep deprivation in rats causes a selective down-regulation of mGlu2 receptors in the hippocampus, and that treatment with a drug that amplifies mGlu2 receptor function corrects the manic-like phenotype observed after sleep deprivation.

Animals

We used male Sprague-Dawley rats (Charles River, Milan, Italy) of six weeks, an age that corresponds to mid-adolescence [39], ranging in weight from 150 to 180 gr. They were housed two or three per polycarbonate rat cage under a 12 h light/dark cycle (light on at 7:00 a.m.) with free access to food and water. Rats were allowed to acclimate for one week prior to experiments, and were gently handled every day for three days before the sleep deprivation procedure to minimize stress effects. Animal

Results

For the induction of paradoxical sleep deprivation we used a single-platform method that is known to nearly abolish REM sleep [46], [47].

In experiment #1, SD rats showed an increased locomotor activity in the open field as compared to both Ctrl (unstressed rats) and LP rats (immobility stress-control rats). The increase was significant after 20–30 min of observation (Fig. 1). Rats of experiment #1 were killed at the end of the open field session for measurements of mGlu receptor mRNA and protein

Discussion

The study of mGlu receptors in psychiatric disorders has been mainly focused on mGlu2 and mGlu5 receptors in the last few years. On the basis of promising data obtained in preclinical models, mGlu2/3 receptor agonists, and mGlu2 or mGlu5 receptor PAMs are currently under clinical development for the treatment of schizophrenia [59], [60], [61], [62], whereas negative allosteric modulators (NAMs) of mGlu2 and mGlu5 receptor are potential drug candidates for the treatment of major depression [63],

Conclusions

We have found that paradoxical sleep deprivation causes a reduction in mGlu2 receptor expression in the hippocampus, which might contribute to the resulting manic-like phenotype. The molecular nature of these changes remains to be clarified. Our findings also suggest that mGlu2 receptor PAMs may be of potential value in the experimental treatment of mania acting either at hippocampal level or in other brain regions. However, it will be important to test different chemical classes of mGlu2

Acknowledgement

We wish to thank Manuela Zinni for her valuable help in performing EPM test.

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