Urotensin II Modulates Rapid Eye Movement Sleep through Activation of Brainstem Cholinergic Neurons

Abstract

Urotensin II (UII) is a cyclic neuropeptide with strong vasoconstrictive activity in the peripheral vasculature. UII receptor mRNA is also expressed in the CNS, in particular in cholinergic neurons located in the mesopontine tegmental area, including the pedunculopontine tegmental (PPT) and lateral dorsal tegmental nuclei. This distribution suggests that the UII system is involved in functions regulated by acetylcholine, such as the sleep-wake cycle. Here, we tested the hypothesis that UII influences cholinergic PPT neuron activity and alters rapid eye movement (REM) sleep patterns in rats. Local administration of UII into the PPT nucleus increases REM sleep without inducing changes in the cortical blood flow. Intracerebroventricular injection of UII enhances both REM sleep and wakefulness and reduces slow-wave sleep 2. Intracerebroventricular, but not local, administration of UII increases cortical blood flow. Moreover, whole-cell recordings from rat-brain slices show that UII selectively excites cholinergic PPT neurons via an inward current and membrane depolarization that were accompanied by membrane conductance decreases. This effect does not depend on action potential generation or fast synaptic transmission because it persisted in the presence of TTX and antagonists of ionotropic glutamate, GABA, and glycine receptors. Collectively, these results suggest that UII plays a role in the regulation of REM sleep independently of its cerebrovascular actions by directly activating cholinergic brainstem neurons.

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

“…The presence of UT mRNA and UII binding sites in cholinergic neurons of the pedunculopontine tegmental nucleus (PPT) and the lateral dorsal tegmental area (Clark et al, 2001), two structures of the pons-midbrain transition area involved in the control of rapid eye movement (REM) sleep (Baghdoyan et al, 1984;Webster and Jones, 1988;Quattrochi et al, 1989;Steriade and McCarley, 1990), lends credence to the idea that the UII system may be implicated in the regulation of the sleep-wake cycle. Consistent with this hypothesis, intracerebroventricular administration of UII or local bilateral injection of UII into the PPT increases the number of REM sleep episodes in rat (Huitron-Resendiz et al, 2005;de Lecea and Bourgin, 2008). Interestingly, only a low dose (0.6 pmol) of UII significantly augments the amount of REM sleep, whereas a 10-fold higher dose is ineffective.…”

“…The UT antagonist SB-710411 blocks the UII-induced REM sleep response. Whole cell recording from rat brain slices revealed that UII triggers cholinergic PPT neurons by activating a slow inward current (Huitron-Resendiz et al, 2005).…”

“…These findings indicate that the central cardiac actions of UII are mediated through cholinergic and/or adrenergic neuronal pathways. Intracerebroventricular injection of UII also causes a robust increase in cortical blood flow (Huitron-Resendiz et al, 2005;Chuquet et al, 2008). After induction of cerebral ischemia by occlusion of the right cerebral artery in rat, intracerebroventricular injection of UII induces a significant increase of hemispheric infarction volume, suggesting that UII exacerbates brain damage caused by an ischemic insult (Chuquet et al, 2008).…”

Role of urotensin II in health and disease

“…For example, UII is becoming increasingly implicated in a variety of mood and sleep processes. UII plays a role in releasing norepinephrine in the cerebral cortex (62), influences rapid eye movement in the rat via direct cholinergic activation (53), and alters behavior in mice upon central administration (30). UII is also implicated in digestive behavior.…”

A resource of potential drug targets and strategic decision‐making for obstructive sleep apnoea pharmacotherapy

“…For instance, expression of the gene for 5-hydroxytryptamine 2c (5-HT 2c ) receptors is enhanced in the PRE-HMN but not in the HMN (Table 1), yet we do not know what effect the selective agonism of these receptors would have on hypoglossal motor output, or if 5-HT 2c receptor-positive neurons innervate the HMN. Similarly, the effect of modulating the activity of Urotensin II receptors on hypoglossal motor output has not been determined but would be worth investigating given that Urotensin II receptor RNA shows a high degree of differential expression at the HMN (being 12.6 fold higher than for the rest of the brain), and that Urotensin II receptor activation has potent excitatory effects on central cholinergic neurons 63–65 .…”