Changes in Extracellular Glutamate Levels in Rat Orbitofrontal Cortex During Sleep and Wakefulness

Rodríguez, Fernando López; Medina‐Ceja, Laura; Wilson, Charles L.; Jhung, Donald; Morales‐Villagrán, Alberto

doi:10.1016/j.arcmed.2006.07.004

Cited by 49 publications

(35 citation statements)

References 23 publications

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“…A recent report using microdialysis also demonstrated an increase in the concentration of glutamate in the rat orbitofrontal cortex during REM sleep (26). We also found increased glutamate levels during AW and REM sleep in the PF-LH.…”

Section: Discussionsupporting

confidence: 64%

Rapid changes in glutamate levels in the posterior hypothalamus across sleep-wake states in freely behaving rats

John

Ramanathan²,

Siegel³

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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John J, Ramanathan L, Siegel JM. Rapid changes in glutamate levels in the posterior hypothalamus across sleep-wake states in freely behaving rats. Am J Physiol Regul Integr Comp Physiol 295: R2041-R2049, 2008. First published September 24, 2008 doi:10.1152/ajpregu.90541.2008The histamine-containing posterior hypothalamic region (PH-TMN) plays a key role in sleep-wake regulation. We investigated rapid changes in glutamate release in the PH-TMN across the sleep-wake cycle with a glutamate biosensor that allows the measurement of glutamate levels at 1-to 4-s resolution. In the PH-TMN, glutamate levels increased in active waking (AW) and rapid eye movement (REM) sleep compared with quiet waking and nonrapid eye movement (NREM) sleep. There was a rapid (0.6 Ϯ 1.8 s) and progressive increase in glutamate levels at REM sleep onset. A reduction in glutamate levels consistently preceded the offset of REM sleep by 8 Ϯ 3 s. Short-duration sleep deprivation resulted in a progressive increase in glutamate levels in the PH-TMN, perifornical-lateral hypothalamus (PF-LH), and cortex. We found that in the PF-LH, glutamate levels took a longer time to return to basal values compared with the time it took for glutamate levels to increase to peak values during AW onset. This is in contrast to other regions we studied in which the return to baseline values after AW was quicker than their rise with waking onset. In summary, we demonstrated an increase in glutamate levels in the PH-TMN with REM/AW onset and a drop in glutamate levels before the offset of REM. High temporal resolution measurement of glutamate levels reveals dynamic changes in release linked to the initiation and termination of REM sleep. rapid eye movement sleep; histamine; microdialysis; biosensor; cortex VARIOUS STUDIES HAVE IMPLICATED glutamatergic mechanisms in the control of sleep-wake states. In vitro experiments reported a differential glutamate release in brain regions of long-sleep and short-sleep mice (11). Glutamate release was higher during wakefulness than during sleep in the pedunculopontine tegmental nucleus (22), whereas enhanced glutamate release during rapid eye movement (REM) sleep was observed in the rostromedial medulla (24). Paradoxical sleep deprivation increased the content of glutamate and glutamine in the rat cerebral cortex (3).Glutamate excites both cortical and subcortical neurons and enhances the in vivo release of histamine (HA) through presynaptic N-methyl-D-aspartate receptors in the anterior hypothalamus of the rat (32). Single cell recording and microdialysis experiments demonstrate that HA cell activity is reduced in nonrapid eye movement (NREM) sleep and REM sleep compared with waking (7,20). We hypothesized that changes in glutamate release in the posterior hypothalamus histaminergic tuberomammillary nucleus (PH-TMN) and in the terminal regions of HA neurons could affect HA release and sleep-wake states. Dysfunction of the Hcrt system produces the sleep disorder narcolepsy (35,38,44). Hcrt neurons contain glutamate as a cotransmit...

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Section: Discussionsupporting

confidence: 64%

Rapid changes in glutamate levels in the posterior hypothalamus across sleep-wake states in freely behaving rats

John

Ramanathan²,

Siegel³

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Thus, REM sleep as observed on a polysomnogram may be useful as a sensitive biomarker for mGlu2 receptor activation. Glutamate levels reportedly increase during REM sleep in the orbitofrontal and cerebral cortex of rats (25,26). Therefore, the inhibition of glutamate release elicited by the stimulation of mGlu2 receptors may result in a decrease in the duration of REM sleep, and mGlu2 receptor positive allosteric modulators may share the same neuronal mechanisms for their effects on the reduction in REM sleep and their antipsychotic actions.…”

Section: Discussionmentioning

confidence: 97%

Antipsychotic profiles of TASP0443294, a novel and orally active positive allosteric modulator of metabotropic glutamate 2 receptor

Hikichi

Hiyoshi

Marumo

et al. 2015

Journal of Pharmacological Sciences

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Glutamatergic dysfunction has been implicated in psychiatric disorders such as schizophrenia. The stimulation of metabotropic glutamate (mGlu) 2 receptor has been shown to be effective in a number of animal models of schizophrenia. In this study, we investigated the antipsychotic profiles of (2S)-5-methyl-2-{[4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]methyl}-2,3-dihydroimidazo[2,1-b][1,3]oxazole-6-carboxamide (TASP0443294), a newly synthesized positive allosteric modulator of the mGlu2 receptor. TASP0443294 potentiated the response of human mGlu2 and rat mGlu2 receptors to glutamate with EC50 values of 277 and 149 nM, respectively, without affecting the glutamate response of human mGlu3 receptor. TASP0443294 was distributed in the brain and cerebrospinal fluid after peroral administration in rats. The peroral administration of TASP0443294 inhibited methamphetamine-induced hyperlocomotion in rats, which was attenuated by an mGlu2/3 receptor antagonist, and improved social memory impairment induced by 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) in rats. Furthermore, TASP0443294 reduced the ketamine-induced basal gamma hyperactivity in the prefrontal cortex and suppressed rapid eye movement (REM) sleep in rats. These findings indicate that TASP0443294 is an mGlu2 receptor positive allosteric modulator with antipsychotic activity, and that the suppression of aberrant gamma oscillations and REM sleep could be considered as neurophysiological biomarkers for TASP0443294.

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“…Consistent with these data, we found that JNJ-40068782 dose-dependently decreased the amount of REM sleep in rats when dosed early in the light phase. The effects on sleep-wake organization in rats may well reflect the modulation of physiologic glutamatergic signaling because it has been shown that glutamate levels are increased during REM sleep in rat orbitofrontal and cerebral cortex (Lopez-Rodriguez et al, 2007;Dash et al, 2009). Moreover, because of the translational nature of the sleep-wake EEG paradigm, polysomnography measurements in man may be used as a reproducible and sensitive biomarker.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Characterization of JNJ-40068782, a New Potent, Selective, and Systemically Active Positive Allosteric Modulator of the mGlu2 Receptor and Its Radioligand [³H]JNJ-40068782

Lavreysen

Langlois

Ahnaou

et al. 2013

J Pharmacol Exp Ther

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Changes in Extracellular Glutamate Levels in Rat Orbitofrontal Cortex During Sleep and Wakefulness

Cited by 49 publications

References 23 publications

Rapid changes in glutamate levels in the posterior hypothalamus across sleep-wake states in freely behaving rats

Rapid changes in glutamate levels in the posterior hypothalamus across sleep-wake states in freely behaving rats

Antipsychotic profiles of TASP0443294, a novel and orally active positive allosteric modulator of metabotropic glutamate 2 receptor

Pharmacological Characterization of JNJ-40068782, a New Potent, Selective, and Systemically Active Positive Allosteric Modulator of the mGlu2 Receptor and Its Radioligand [³H]JNJ-40068782

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Changes in Extracellular Glutamate Levels in Rat Orbitofrontal Cortex During Sleep and Wakefulness

Cited by 49 publications

References 23 publications

Rapid changes in glutamate levels in the posterior hypothalamus across sleep-wake states in freely behaving rats

Rapid changes in glutamate levels in the posterior hypothalamus across sleep-wake states in freely behaving rats

Antipsychotic profiles of TASP0443294, a novel and orally active positive allosteric modulator of metabotropic glutamate 2 receptor

Pharmacological Characterization of JNJ-40068782, a New Potent, Selective, and Systemically Active Positive Allosteric Modulator of the mGlu2 Receptor and Its Radioligand [3H]JNJ-40068782

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Pharmacological Characterization of JNJ-40068782, a New Potent, Selective, and Systemically Active Positive Allosteric Modulator of the mGlu2 Receptor and Its Radioligand [³H]JNJ-40068782