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Distinct pro-vigilant profile induced in rats by the mGluR5 potentiator LSN2814617
Sally Loomis1, Andrew McCarthy1, Christopher Baxter1
1Lilly Research Laboratories, Eli Lilly & Co. Ltd, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, England, UK.
Psychopharmacology
|April 24, 2015
Summary
Excessive daytime sleepiness (EDS) treatment is explored using rodent models. An mGlu5 positive allosteric modulator (PAM) improved wakefulness and function in sleep-restricted rats, distinct from other stimulants.
Area of Science:
- Neuroscience
- Pharmacology
- Sleep Medicine
Background:
- Excessive daytime sleepiness (EDS) presents a significant unmet medical need.
- Rodent behavioral pharmacology for pro-vigilant compounds is underexplored.
- Assessing compounds to restore function after sleep loss is crucial.
Purpose of the Study:
- To evaluate pro-vigilant compounds in a rodent model of sleep restriction.
- To compare the effects of modafinil, amphetamine, caffeine, and an mGlu5 PAM on functional capacity.
- To investigate the distinct mechanisms of action for these compounds.
Main Methods:
- Male Wistar rats underwent 11-hour sleep restriction via cage rotation.
- Electroencephalographic (EEG) recording monitored sleep states.
- A simple response latency task (SRLT) assessed behavioral performance.
- Effects of modafinil, D-amphetamine, caffeine, and LSN2814617 (mGlu5 PAM) were analyzed.
Main Results:
- Sleep restriction impaired SRLT performance, indicating task disengagement.
- All tested compounds induced wakefulness.
- LSN2814617 improved functional capacity and reduced omissions without excessive compensatory sleep.
- Amphetamine worsened SRLT performance, unlike other compounds.
- LSN2814617 demonstrated a qualitatively distinct effect from amphetamine, caffeine, and modafinil.
Conclusions:
- An mGlu5 PAM significantly enhanced wakefulness and functional capacity in sleep-restricted rats.
- This mGlu5 PAM exhibited a unique pro-vigilant profile, differing from traditional stimulants.
- Findings suggest novel therapeutic potential for mGlu5 modulators in treating EDS.
