Blockade of the metabotropic glutamate (mGluR2) modulates arousal through vigilance states transitions: evidence from sleep-wake EEG in rodents.

ABSTRACT

Accumulating data continue to support the therapeutic potential of glutamate metabotropic (mGluR2) receptors for treatment of psychiatric disorders such as depression, anxiety and schizophrenia. Glutamate neurotransmission is an integral component of sleep-wake mechanisms, which have translational relevance to assess on-target activity of drugs. Here, we investigated the influence of mGluR2 inactivation upon sleep-wake electroencephalogram (EEG) in rodents. Rats were administered with vehicle, the specific mGluR2 antagonist LY341495 (2.5, 5, 10mg/kg) or negative allosteric modulator (NAM) Ro-4491533 (2.5, 10 and 40 mg/kg) at lights onset. mGluR2 (-/-) mice were used to confirm the selectivity of functional response. Both LY341495 and Ro-4491533 induced an immediate and endured desynchronized cortical activity during 3-6h associated with enhanced theta and gamma oscillations and depressed slow oscillations during sleep. The arousal-promoting effect is consistent with the marked lengthening of sleep onset latency, an increased number of state transitions from light sleep to waking and the gradual increase in homeostatic compensatory sleep. The arousal response to mGluR2 blockade was not accompanied by sharp rebound hypersomnolence as found with the classical psycho-stimulant amphetamine. mGluR2 (-/-) mice and their WT littermates exhibited similar sleep-wake phenotype, while Ro-4491533 (40 mg/kg) enhanced waking associated with increased locomotor activity and body temperature in WT but not in mGluR2 (-/-) mice, which confirm the role of mGluR2 inactivation in the arousal response. Our results lend support for a role of mGluR2 blockade in promoting cortical arousal associated with theta/gamma oscillations as well as high thresholds transitions from sleep to waking.