Changes in Inhibitory Amino Acid Release Linked to Pontine-Induced Atonia: AnIn VivoMicrodialysis Study

Abstract

We hypothesized that cessation of brainstem monoaminergic systems and an activation of brainstem inhibitory systems are both involved in pontine inhibitory area (PIA) stimulation-induced muscle atonia. In our previous study (Lai et al., 2001), we found a decrease in norepinephrine and serotonin release in motoneuron pools during PIA stimulation-induced muscle tone suppression. We now demonstrate an increase in inhibitory amino acid release in motor nuclei during PIA stimulation in the decerebrate cat using in vivo microdialysis and HPLC analysis techniques. Microinjection of acetylcholine into the PIA elicited muscle atonia and simultaneously produced a significant increase in both glycine and GABA release in both the hypoglossal nucleus and the lumbar ventral horn. Glycine release increased by 74% in the hypoglossal nucleus and 50% in the spinal cord. GABA release increased by 31% in the hypoglossal nucleus and 64% in the spinal cord during atonia induced by cholinergic stimulation of the PIA. As with cholinergic stimulation, 300 msec train electrical stimulation of the PIA elicited a significant increase in glycine release in the hypoglossal nucleus and ventral horn. GABA release was significantly increased in the hypoglossal nucleus but not in the spinal cord during electrical stimulation of the PIA. Glutamate release in the motor nuclei was not significantly altered during atonia induced by electrical or acetylcholine stimulation of the PIA. We suggest that both glycine and GABA play important roles in the regulation of upper airway and postural muscle tone. A combination of decreased monoamine and increased inhibitory amino acid release in motoneuron pools causes PIA-induced atonia and may be involved in atonia linked to rapid eye-movement sleep.

Glycinergic and GABAA-Mediated Inhibition of Somatic Motoneurons Does Not Mediate Rapid Eye Movement Sleep Motor Atonia

“…Although motoneurons are hyperpolarized during REM sleep (Nakamura et al, 1978) and glycine and GABA are released onto them during REM-like atonia (Kodama et al, 2003), we demonstrate that glycinergic and GABA A -mediated inhibition of trigeminal motoneurons does not mediate REM sleep atonia. Multiple lines of evidence indicate that muscle atonia in REM (and cataplexy) may result from disfacilitation of noradrenergic inputs onto motoneurons (Aston-Jones and Bloom, 1981;Mignot et al, 1993;Wu et al, 1999;Lai et al, 2001;Fenik et al, 2005).…”

“…However, because motoneurons are concurrently inhibited by GABA and glycine during natural REM sleep (Soja et al, 1987) and because both transmitters are coreleased onto motoneurons (O'Brien and Berger, 1999), especially during pharmacologically induced REM-like sleep (Kodama et al, 2003), we hypothesized that both transmitters may be required to induce REM atonia. Therefore, we simultaneously antagonized glycine and GABA A receptors in the left trigeminal motor pool by perfusing 0.1 mM strychnine and 0.1 mM bicuculline (n ϭ 11).…”

Paradoxical (REM) sleep genesis by the brainstem is under hypothalamic control

“…Further when these recordings were combined with local iontophoretic application of strychnine (a specific antagonist of the inhibitory neurotransmitter, glycine), motoneurons hyperpolarization was strongly decreased indicating that they are tonically inhibited by glycinergic neurons during PS [12][13][14]. It has then been shown that the levels of glycine but also that of GABA increase within hypoglossal and spinal motor pools during PS-like atonia suggesting that GABA in addition to glycine might contribute to motoneurons hyperpolarization during PS [15]. In addition, it has been shown that the SLD sends direct efferent projections to GABA/glycinergic neurons located in the nucleus raphe magnus (RMg) and the ventral (GiV), alpha (Gia) gigantocellular and lateral paragigantocellular (LPGi) reticular nuclei [7,18].…”

An Endogenous Glutamatergic Drive onto Somatic Motoneurons Contributes to the Stereotypical Pattern of Muscle Tone across the Sleep–Wake Cycle

“…anism (Chase et al, 1989;Kodama et al, 2003). This contention is strengthened by the fact that glutamatergic activation during REM sleep failed to increase muscle twitch amplitude; this lack of effect probably occurs because motoneurons are maximally hyperpolarized during periods of phasic REM sleep (Chase et al, 1989), which obviates the excitatory actions of glutamate on motoneurons, thereby limiting muscle twitch magnitude.…”

“…Intracellular studies show that somatic motoneurons are bombarded by inhibitory glycinergic and GABAergic potentials during natural REM sleep (Nakamura et al, 1978;Soja et al, 1987), and microdialysis studies demonstrate that glycine and GABA release onto motoneurons is increased during pharmacologically induced muscle atonia (Kodama et al, 2003). However, neither glycinergic nor GABAergic inhibition are sufficient to induce motor suppression in REM because antagonism of glycine and GABA A receptors at either the trigeminal or hypoglossal motor pools does not reverse REM atonia (Morrison et al, 2003;Brooks and Peever, 2008).…”