Sleep duration varies as a function of glutamate and GABA in rat pontine reticular formation

Abstract

The oral part of the pontine reticular formation (PnO) is a component of the ascending reticular activating system and plays a role in the regulation of sleep and wakefulness. The PnO receives glutamatergic and GABAergic projections from many brain regions that regulate behavioral state. Indirect, pharmacological evidence has suggested that glutamatergic and GABAergic signaling within the PnO alters traits that characterize wakefulness and sleep. No previous studies have simultaneously measured endogenous glutamate and GABA from rat PnO in relation to sleep and wakefulness. The present study utilized in vivo microdialysis coupled on-line to capillary electrophoresis with laser-induced fluorescence to test the hypothesis that concentrations of glutamate and GABA in the PnO vary across the sleep/wake cycle. Concentrations of glutamate and GABA were significantly higher during wakefulness than during NREM sleep and REM sleep. Regression analysis revealed that decreases in glutamate and GABA accounted for a significant portion of the variance in the duration of NREM sleep and REM sleep episodes. These data provide novel support for the hypothesis that endogenous glutamate and GABA in the PnO contribute to the regulation of sleep duration.

Neuropharmacology of Sleep and Wakefulness

“…21–24 Similarly, pharmacologically increasing the concentration of endogenous GABA within the pontine reticular formation increases the time required for isoflurane to induce general anesthesia. 25 Consistent with this finding are data showing that endogenous GABA levels in the pontine reticular formation are greater during wakefulness than during REM sleep 26, 27 (Figure 2) or during the loss of wakefulness caused by isoflurane. 25 Inhibiting GABAergic signaling at GABA A receptors within the pontine reticular formation causes an increase in REM sleep and a decrease in wakefulness.…”

“…For example, glutamate levels in some areas of rat cortex show increases in concentration during wakefulness and REM sleep, and decreases during NREM sleep, 128 and glutamate concentrations in rat pontine reticular formation are higher during wakefulness than during NREM sleep and REM sleep. 27 Sleep deprivation increases glutamate concentrations in rat dorsal hippocampus and medial thalamus. 129 Microinjection and electrophysiological studies provide evidence that glutamate acts within the laterodorsal tegmental nucleus and pedunculopontine tegmental nucleus 130–132 (Fig.…”

“…GABA levels shown in A and B reflect differences in microdialysis flowrate (0.4 μL/min for rat and 2.0 μL/min for cat), molecular weight cut-off of the microdialysis probe membrane (18000 Daltons for rat and 6 Daltons for cat) and possibly membrane material (regenerated cellulose for rat and cuprophane for cat). Figures modified from Watson et al, 2011 27 and Vanini et al, 2011 26 with permission.…”

Behavior Genetics of Psychopathology

“…One line of research has focussed on genes involved in glutamatergic neurotransmission, and such genes have been linked to both depression and sleep disturbances (Utge et al, 2011 ). Glutamate is involved in synaptic excitability in brain areas implicated in depression and sleep, such as the limbic system (Watson, Lydic, & Baghdoyan, 2011 ;Witkin, Marek, Johnson, & Schoepp, 2007 ). Furthermore, several animal studies have demonstrated that levels of glutamate are highest during wakefulness and REM sleep in numerous brain regions and highest in non-REM sleep in the thalamus, implicating glutamatergic neurotransmission in sleep-wake regulation (Dash, Douglas, Vyazovskiy, Cirelli, & Tononi, 2009 ;John, Ramanathan, & Siegel, 2008 ;Lena et al, 2005 ;Lopez-Rodriguez, Medine-Ceja, Wilson, Jhung, & Morales-Villagran, 2007 ).…”

Synthesis and proton NMR spectroscopy of intra-vesicular gamma-aminobutyric acid (GABA)

“…In the case of GABA (Fig. 1), the amount of neurotransmitter detected in vivo likely represents the intracellular content of GABAergic neurons [3,4], where GABA exists packaged within vesicles reported to measure from 29 to 36 nm in diameter [5]. A non-invasive and reliable way of measuring, and calibrating, intracellular GABA would be of great clinical interest.…”