Noradrenergic modulation of masseter muscle activity during natural rapid eye movement sleep requires glutamatergic signalling at the trigeminal motor nucleus.

Noradrenergic neurotransmission in the brainstem is closely coupled to changes in muscle activity across the sleep-wake cycle, and noradrenaline is considered to be a key excitatory neuromodulator that reinforces the arousal-related stimulus on motoneurons to drive movement. However, it is unknown if α-1 noradrenoceptor activation increases motoneuron responsiveness to excitatory glutamate (AMPA) receptor-mediated inputs during natural behaviour. We studied the effects of noradrenaline on AMPA receptor-mediated motor activity at the motoneuron level in freely behaving rats, particularly during rapid eye movement (REM) sleep, a period during which both AMPA receptor-triggered muscle twitches and periods of muscle quiescence in which AMPA drive is silent are exhibited. Male rats were subjected to electromyography and electroencephalography recording to monitor sleep and waking behaviour. The implantation of a cannula into the trigeminal motor nucleus of the brainstem allowed us to perfuse noradrenergic and glutamatergic drugs by reverse microdialysis, and thus to use masseter muscle activity as an index of motoneuronal output. We found that endogenous excitation of both α-1 noradrenoceptor and AMPA receptors during waking are coupled to motor activity; however, REM sleep exhibits an absence of endogenous α-1 noradrenoceptor activity. Importantly, exogenous α-1 noradrenoceptor stimulation cannot reverse the muscle twitch suppression induced by AMPA receptor blockade and nor can it elevate muscle activity during quiet REM, a phase when endogenous AMPA receptor activity is subthreshold. We conclude that the presence of an endogenous glutamatergic drive is necessary for noradrenaline to trigger muscle activity at the level of the motoneuron in an animal behaving naturally.

Dopamine triggers skeletal muscle tone by activating D1-like receptors on somatic motoneurons.

The dopamine system plays an integral role in motor physiology. Dopamine controls movement by modulation of higher-order motor centers (e.g., basal ganglia) but may also regulate movement by directly controlling motoneuron function. Even though dopamine cells synapse onto motoneurons, which themselves express dopamine receptors, it is unknown whether dopamine modulates skeletal muscle activity. Therefore, we aimed to determine whether changes in dopaminergic neurotransmission at a somatic motor pool affect motor outflow to skeletal muscles. We used microinjection, neuropharmacology, electrophysiology, and histology to determine whether manipulation of D(1)- and D(2)-like receptors on trigeminal motoneurons affects masseter and/or tensor palatini muscle tone in anesthetized rats. We found that apomorphine (a dopamine analog) activated trigeminal motoneurons and triggered a potent increase in both masseter and tensor palatini tone. This excitatory effect is mediated by D(1)-like receptors because specific D(1)-like receptor activation strengthened muscle tone and blockade of these receptors prevented dopamine-driven activation of motoneurons. Blockade of D(1)-like receptors alone had no detectable effect on basal masseter/tensor palatini tone, indicating the absence of a functional dopamine drive onto trigeminal motoneurons, at least during isoflurane anesthesia. Finally, we showed that D(2)-like receptors do not affect either trigeminal motoneuron function or masseter/tensor palatini muscle tone. Our results provide the first demonstration that dopamine can directly control movement by manipulating somatic motoneuron behavior and skeletal muscle tone.

Noradrenergic control of trigeminal motoneurons in sleep: relevance to sleep apnea.

Using rapid-eye-movement (REM) sleep as a model state, we sought to determine whether noradrenaline functions to strengthen upper airway muscle tone by amplifying glutamatergic excitation on to trigeminal motoneurons. We report that noradrenaline cannot trigger motoneuron excitability on its own, instead acting to facilitate glutamatergic motor excitation.

Noradrenaline triggers muscle tone by amplifying glutamate-driven excitation of somatic motoneurones in anaesthetized rats.

Postural muscle tone is potently suppressed during sleep and cataplexy. Since brainstem noradrenergic cell discharge activity is tightly coupled with state-dependent changes in muscle activity, it is assumed that noradrenergic drive on to somatic motoneurones modulates basal muscle tone. However, it has never been determined whether noradrenergic neurotransmission acts to directly regulate motoneurone activity or whether it functions to modulate prevailing synaptic activity. This is an important distinction because noradrenaline regulates cell excitability by both directly depolarizing neurones and by indirectly potentiating glutamate-mediated excitation. We used reverse-microdialysis, electrophysiology, neuro-pharmacological and histological techniques in anaesthetized rats to determine whether strengthening noradrenergic drive (via exogenous noradrenaline application) on to trigeminal motoneurones affects masseter muscle tone by increasing spontaneous motoneurone activity or whether it acts to amplify prevailing glutamate-driven excitation. Although noradrenaline is hypothesized to modulate motor activity, we found that direct stimulation of trigeminal motoneurones by alpha(1)-adrenoceptor activation had no direct effect on basal masseter tone. However, when glutamate-driven excitation was increased at the trigeminal motor pool by either endogenous glutamate release (induced by the monosynaptic masseteric reflex) or exogenous AMPA application, noradrenaline triggered a potent increase in basal masseter tone. The stimulatory effects of noradrenaline were unmasked and rapidly switched on only in the presence of glutamatergic transmission. Blockade of AMPA receptors abolished this excitatory effect, indicating that noradrenergic drive requires ongoing glutamatergic activity. Our data indicate that exogenous noradrenergic drive does not directly affect spontaneous motoneurone discharge activity in anaesthetized rats; rather, it triggers postural muscle tone by amplifying prevailing glutamate-driven excitation.