Distinct pro-vigilant profile induced in rats by the mGluR5 potentiator LSN2814617

Abstract

While treatment options are available, excessive daytime sleepiness (EDS) remains a significant unmet medical need for many patients. Relatively little rodent behavioural pharmacology has been conducted in this context to assess potential pro-vigilant compounds for their ability to restore functional capacity following experimentally induced sleep loss. Male Wistar rats were prepared for electroencephalographic (EEG) recording and subject to 11 h of sleep restriction using a biofeedback-induced cage rotation protocol. A simple response latency task (SRLT) was used to behaviourally index sleep restriction and the effects of pro-vigilant compounds: modafinil, d-amphetamine, caffeine, and the mGlu5-positive allosteric modulator LSN2814617. Sleep restriction resulted in a consistent, quantified loss of non-rapid eye movement (NREM) and REM sleep that impaired SRLT performance in a manner suggestive of progressive task disengagement. In terms of EEG parameters, all compounds induced wakefulness. Amphetamine treatment further decreased SRLT performance capacity, whereas the other three compounds decreased omissions and allowed animals to re-engage in the task. Caffeine and modafinil also significantly increased premature responses during this period, an effect not observed for LSN2814617. While all compounds caused compensatory sleep responses, the magnitude of compensation observed for LSN2814617 was much smaller than would be predicted to result from the prolongation of wakefulness exhibited. Using simple response latencies to index performance, an mGlu5 PAM dramatically increased wakefulness and improved functional capacity of sleep-restricted animals, without eliciting a proportionate compensatory sleep response. This effect was qualitatively distinct from that of amphetamine, caffeine and modafinil.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-015-3936-8) contains supplementary material, which is available to authorized users.

Modelling maintenance of wakefulness in rats: comparing potential non‐invasive sleep‐restriction methods and their effects on sleep and attentional performance

“…The EEG‐based Biofeedback protocol progressively reduced the capacity of rats to maintain bouts of wakefulness, an effect comparable to that measured in humans using the multiple sleep latency test (Bonnet and Arand, ). This protocol also produced deficits in performance for a SRLT, indexed by progressive task disengagement, as previously described (Loomis et al ., ). These findings potentially show translational correspondence when compared with the effects of sleep deprivation in humans on psychomotor vigilance test performance (Lo et al ., ; Van Dongen et al ., ).…”

“…Simple response latency task training was performed as described in Data S1 and based upon previous methodology (Loomis et al ., ). Briefly, the task is structured as follows: a house light acts as a preparatory cue, followed by a variable interval (range 4–6 s), after which the magazine light is illuminated.…”

“…In order to expedite mechanistic insights and discovery of novel therapies, accurate modelling of sleep restriction in animals remains a significant research area. As the physiological properties of sleep and consequences of its restriction seem well conserved across several species (Phillips et al ., ), rodent sleep restriction experiments are considered a valuable model of impairment to screen putative pharmacotherapies (Loomis et al ., ; McCoy and Strecker, ).…”

Circadian variation of metabotropic glutamate receptor 5 availability in the rat brain

“…Moreover, mGluR5‐specific positive and negative allosteric modulators either increased waking and reduced sleep or consolidated sleep, respectively (Ahnaou et al ., ). Similarly, in sleep‐deprived animals a positive allosteric modulator increased wakefulness and response latencies without provoking a subsequent compensatory sleep response (Loomis et al ., ), and in mGluR5 knockout animals the sleep propensity and slow wave activity were reduced after sleep deprivation (Ahnaou et al ., ). These novel findings strongly suggest a causal relation between sleep and mGluR5 regulation in the central nervous system, and understanding its daily regulation might help to gain further insight into sleep wake functioning.…”

Pharmaco-EEG Studies in Animals: A History-Based Introduction to Contemporary Translational Applications

“…The central activity of ligands acting at 5HT7, mGluR2, mGluR5, mGluR7 and MCH1 has been characterised in rodents: inhibition of REM sleep occurrence was observed with 5HT7 antagonists [79,80,81], mGuR2 agonist and positive allosteric modulators (PAMs) [82,83], and with mGluR7 PAMs [84]. While mGluR2 antagonists and negative allosteric modulators (NAMs) and mGluR5 PAMs exhibit arousal-promoting properties [85,86,87], mGluR5 NAMs consolidated deep sleep time and cortical delta activity in preclinical as well as clinical studies [85,88,89]. Lastly, MCH1 antagonists decreased deep sleep without homeostatic recovery sleep [48].…”