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

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.已知G蛋白偶联受体（G-protein-coupled receptor, GPCR）激动剂可诱导两类细胞适应性变化：一是对治疗效应产生药物耐受，二是在停药后引发戒断症状。谷氨酸能神经传递是睡眠-觉醒机制的核心组成部分，其相关过程与中枢活动及靶点结合（target engagement）具有转化研究价值。本研究旨在探究代谢型谷氨酸受体（metabotropic glutamate receptors, mGluR2/3）激动剂LY354740与mGluR2正变构调节剂（positive allosteric modulator, PAM）JNJ-42153605对大鼠睡眠-觉醒结构的疗效与耐受潜力。 体外实验中，我们对JNJ-42153605的选择性与效力进行了表征；体内实验则针对大鼠开展每日一次口服重复给药（连续7天），随后停药并依次给予LY354740（1~10 mg/kg）与JNJ-42153605（3~30 mg/kg），探究二者对睡眠指标的影响。结果显示，JNJ-42153605对mGluR2具有高亲和力、高效力与高选择性；结合位点分析与基于知识的分子对接实验证实，其特异性结合于mGluR2的变构结合位点。 急性给药阶段，LY354740与JNJ-42153605均可剂量依赖性地缩短快速眼动（rapid eye movement, REM）睡眠时间，并延长其发作潜伏期。亚慢性给药期间，LY354740对REM睡眠指标的影响自第3天起逐渐消退，而JNJ-42153605的相关效应在重复给药后仍得以维持。LY354740会削弱REM睡眠的稳态恢复过程，而JNJ-42153605给药后该稳态过程得以保留。此外，JNJ-42153605可改善睡眠连续性与睡眠效率，提示其有望作为治疗早期睡眠质量受损的附加治疗药物。 突然停用JNJ-42153605并未引发戒断现象与睡眠障碍，且再次给药后其初始药效可完全恢复。综上，长期给予JNJ-42153605不会对其睡眠相关的核心功能效应产生药物耐受，停药后亦无不良反应，同时可促进稳态恢复睡眠。从转化医学视角来看，本啮齿类动物实验结果表明，相较于激动剂，mGluR2正变构调节具有更优的长期疗效，在精神疾病——尤其是伴随快速眼动睡眠过度活跃的常见精神疾病——中具备治疗潜力。