RESEARCH ARTICLE mGlu2 Receptor Agonism, but Not Positive Allosteric Modulation, Elicits Rapid Tolerance towards Their Primary Efficacy on Sleep Measures in Rats Abdallah Ahnaou1*, Hilde Lavreysen1, Gary Tresadern2, Jose M. Cid2, Wilhelmus H. Drinkenburg1 1 Dept. of Neuroscience, Janssen Research & Development, A Division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340, Beerse, Belgium, 2 Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A., Jarama 75, Polígono Industrial, 45007, Toledo, Spain *
[email protected] Abstract OPEN ACCESS G-protein-coupled receptor (GPCR) agonists are known to induce both cellular adaptations Citation: Ahnaou A, Lavreysen H, Tresadern G, Cid resulting in tolerance to therapeutic effects and withdrawal symptoms upon treatment dis- JM, Drinkenburg WH (2015) mGlu2 Receptor continuation. Glutamate neurotransmission is an integral part of sleep-wake mechanisms, Agonism, but Not Positive Allosteric Modulation, Elicits Rapid Tolerance towards Their Primary which processes have translational relevance for central activity and target engagement. Efficacy on Sleep Measures in Rats. PLoS ONE 10 Here, we investigated the efficacy and tolerance potential of the metabotropic glutamate (12): e0144017. doi:10.1371/journal.pone.0144017 receptors (mGluR2/3) agonist LY354740 versus mGluR2 positive allosteric modulator Editor: James Porter, University of North Dakota, (PAM) JNJ-42153605 on sleep-wake organisation in rats. In vitro, the selectivity and UNITED STATES potency of JNJ-42153605 were characterized. In vivo, effects on sleep measures were Received: July 12, 2015 investigated in rats after once daily oral repeated treatment for 7 days, withdrawal and con- Accepted: November 12, 2015 secutive re-administration of LY354740 (1–10 mg/kg) and JNJ-42153605 (3–30 mg/kg).