mGlu2 Receptor Agonism, but Not Positive Allosteric Modulation, Elicits Rapid Tolerance towards Their Primary Efficacy on Sleep Measures in XXXX .

@entity13288 @entity3264 @entity146 @entity35 @entity72411 @entity25 @entity9449
UNASSIGNED: 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. @entity3264 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 @entity3264 receptors ( @entity9449 /3) agonist @entity13288 versus @entity9449 positive allosteric modulator (PAM) @entity72411 on sleep-wake organisation in @entity35 . In vitro, the selectivity and potency of @entity72411 were characterized. In vivo, effects on sleep measures were investigated in @entity35 after once daily oral repeated treatment for 7 days, withdrawal and consecutive re-administration of @entity13288 (1-10 mg/kg) and @entity72411 (3-30 mg/kg). @entity72411 showed high affinity, potency and selectivity at @entity9449 . Binding site analyses and knowledge-based docking confirmed the specificity of @entity72411 at the @entity9449 allosteric binding site. Acute @entity13288 and @entity72411 dose-dependently decreased rapid eye movement (REM) sleep time and prolonged its onset latency. Sub chronic effects of @entity13288 on REM sleep measures disappeared from day 3 onwards, whereas those of @entity72411 were maintained after repeated exposure. @entity13288 attenuated REM sleep homeostatic recovery, while this was preserved after @entity72411 administration. @entity72411 enhanced sleep continuity and efficiency, suggesting its potential as an add-on medication for @entity25 during early stages of treatment. Abrupt cessation of @entity72411 did not induce @entity25 , while the initial drug effect was fully reinstated after re-administration. Collectively, long-term treatment with @entity72411 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 @entity9449 positive allosteric modulation has therapeutic potential based on its superior long term efficacy over agonists in @entity146 , particularly of those commonly occurring with REM sleep overdrive.
