title: 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Co. Ltd, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, England, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Loomis
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Co. Ltd, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, England, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: McCarthy
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Co. Ltd, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, England, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Baxter
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Co. Ltd, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, England, UK.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Kellett
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Co. Ltd, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, England, UK.
authors.forename: Dale M
authors.initials: DM
authors.lastname: Edgar
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Co. Ltd, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, England, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Tricklebank
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Co. Ltd, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, England, UK. gilmour_gary@lilly.com.
authors.forename: Gary
authors.initials: G
authors.lastname: Gilmour
mesh_terms: D000818:Animals; D001143:Arousal / Q000187:drug effects*; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001676:Biofeedback, Psychology; D002110:Caffeine / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003913:Dextroamphetamine / Q000494:pharmacology; D004569:Electroencephalography / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D008297:Male; D000077408:Modafinil; D010069:Oxadiazoles / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists*; D012890:Sleep / Q000187:drug effects; D012892:Sleep Deprivation; D012895:Sleep, REM / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D018690:Excitatory Amino Acid Agonists; C578937:Grm5 protein, rat; C000608094:LSN2814617; D010069:Oxadiazoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D014230:Triazoles; D002110:Caffeine; D000077408:Modafinil; D003913:Dextroamphetamine
keywords: Amphetamine; EEG; Metabotropic; Modafinil; Potentiator; RAT; Translation; Vigilance; Wake; mGlu5