MGlu2 Receptor Agonism, but Not Positive Allosteric Modulation, Elicits Rapid Tolerance towards Their Primary Efficacy on Sleep Measures in Rats.

Abdallah Ahnaou,Wilhelmus H Drinkenburg,Hilde Lavreysen,Jose M Cid,Gary Tresadern,James Porter

doi:10.1371/journal.pone.0144017

Abdallah Ahnaou, Wilhelmus H Drinkenburg + Show 4 more

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https://doi.org/10.1371/journal.pone.0144017

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Journal: PloS one	Publication Date: Dec 11, 2015
Citations: 16	License type: CC BY 4.0

Affiliation: Janssen (Belgium)

Abstract

G-protein-coupled receptor (GPCR) agonists are known to induce both cellular adaptations resulting in tolerance to therapeutic effects and withdrawal symptoms upon treatment discontinuation. Glutamate neurotransmission is an integral part of sleep-wake mechanisms, which processes have translational relevance for central activity and target engagement. Here, we investigated the efficacy and tolerance potential of the metabotropic glutamate receptors (mGluR2/3) agonist LY354740 versus mGluR2 positive allosteric modulator (PAM) JNJ-42153605 on sleep-wake organisation in rats. In vitro, the selectivity and potency of JNJ-42153605 were characterized. In vivo, effects on sleep measures were investigated in rats after once daily oral repeated treatment for 7 days, withdrawal and consecutive re-administration of LY354740 (1–10 mg/kg) and JNJ-42153605 (3–30 mg/kg). JNJ-42153605 showed high affinity, potency and selectivity at mGluR2. Binding site analyses and knowledge-based docking confirmed the specificity of JNJ-42153605 at the mGluR2 allosteric binding site. Acute LY354740 and JNJ-42153605 dose-dependently decreased rapid eye movement (REM) sleep time and prolonged its onset latency. Sub chronic effects of LY354740 on REM sleep measures disappeared from day 3 onwards, whereas those of JNJ-42153605 were maintained after repeated exposure. LY354740 attenuated REM sleep homeostatic recovery, while this was preserved after JNJ-42153605 administration. JNJ-42153605 enhanced sleep continuity and efficiency, suggesting its potential as an add-on medication for impaired sleep quality during early stages of treatment. Abrupt cessation of JNJ-42153605 did not induce withdrawal phenomena and sleep disturbances, while the initial drug effect was fully reinstated after re-administration. Collectively, long-term treatment with JNJ-42153605 did not induce tolerance phenomena to its primary functional effects on sleep measures, nor adverse effects at withdrawal, while it promoted homeostatic recovery sleep. From the translational perspective, the present rodent findings suggest that mGluR2 positive allosteric modulation has therapeutic potential based on its superior long term efficacy over agonists in psychiatric disorders, particularly of those commonly occurring with REM sleep overdrive.

Highlights

Abnormalities in glutamate balance have been recently implicated in the mechanisms underlying neuropsychiatric illnesses
Final assay mixtures contained 7 or 10 μg of membrane protein were pre-incubated with JNJ-42153605 alone or together with an EC20 concentration (4 μM) of glutamate for 30 min at 30°C. [35S]GTPγS was added at a concentration of 0.1 nM and Filter-bound radioactivity according to an earlier protocol [31]
To confirm whether JNJ-42153605 binds at a site distinct from the glutamate recognition site, we evaluated the potency of the compound to displace binding of [3H]LY341495, an orthosteric mGluR antagonist [37]. [3H]LY341495 binding to the human metabotropic glutamate receptor 2 (mGluR2) was inhibited by LY404039, an mGluR2/3 orthosteric agonist, but not by JNJ-42153605 (Fig 1D), clearly indicating that JNJ-42153605 does not bind to the orthosteric mGluR2 binding site

Summary

Introduction

Abnormalities in glutamate balance have been recently implicated in the mechanisms underlying neuropsychiatric illnesses. Given the potential for induction of tolerance with GPCR agonists, an important question remains unanswered regarding efficacy and safety following longer term use of the mGluR2 agonist, as well as the duration of its effectiveness. Preclinical studies have reported behavioral data with differential effects regarding the potential for tolerance development following chronic dosing with mGluR2 agonists, depending on behavioural pharmacology assessed: LY379268 had motor depressant effect, to which animals developed rapid tolerance following repeated administration [10,11]. In drug abuse model, repeated administration of LY379268 reduced tolueneinduced hyperlocomotion [12], whereas repeated dosing with LY379268 had no effect on PCPinduced hyperlocomotor activity [10]. Acute LY379268 was effective in pain models; while tolerance developed against its analgesic effect upon repeated dosing [13]

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