Nicotinic acid promotes sleep through prostaglandin synthesis in mice

Éva Szentirmai,Levente Kapás

doi:10.1038/s41598-019-53648-7

Abstract

Nicotinic acid has been used for decades for its antiatherogenic properties in humans. Its actions on lipid metabolism intersect with multiple sleep regulatory mechanisms, but its effects on sleep have never been documented. For the first time, we investigated the effects of acute systemic administration of nicotinic acid on sleep in mice. Intraperitoneal and oral gavage administration of nicotinic acid elicited robust increases in non-rapid-eye movement sleep (NREMS) and decreases in body temperature, energy expenditure and food intake. Preventing hypothermia did not affect its sleep-inducing actions suggesting that altered sleep is not secondary to decreased body temperature. Systemic administration of nicotinamide, a conversion product of nicotinic acid, did not affect sleep amounts and body temperature, indicating that it is not nicotinamide that underlies these actions. Systemic administration of monomethyl fumarate, another agonist of the nicotinic acid receptor GPR109A, fully recapitulated the somnogenic and thermoregulatory effects of nicotinic acid suggesting that they are mediated by the GPR109A receptor. The cyclooxygenase inhibitor indomethacin completely abolished the effects of nicotinic acid indicating that prostaglandins play a key role in mediating the sleep and thermoregulatory responses of nicotinic acid.

Highlights

Nicotinic acid has been used for decades for its antiatherogenic properties in humans
The effects of 100 mg/kg nicotinic acid were manifested after a latency of one hour; starting from h 2, non-rapid-eye movement sleep (NREMS) increased 41% above baseline for 4 hours (NREMS amounts in h 2–5, baseline: 82.7 ± 7.3 min, treatment: 116.8 ± 9.6 min, p < 0.01)
NREMS increases were accompanied by decreased electroencephalographic (EEG) slow-wave activity (SWA) and suppressed motor activity (Fig. 1, Table 1)

Summary

Introduction

Nicotinic acid has been used for decades for its antiatherogenic properties in humans. Metabolic signals play an important role in sleep regulation Positive energy balance, such as postprandial state, overfeeding and obesity, is accompanied by increased sleep[1,2,3,4], while negative energy states, such as fasting, promote wakefulness[5,6,7,8]. Given the long history of the clinical use of nicotinic acid and its complex actions on lipid metabolism, it is remarkable that its effects on sleep has never been documented. We report that systemic administration of nicotinic acid and another GPR109A receptor agonist, monomethyl fumarate, induces robust sleep and hypothermic responses in mice. Preventing the nicotinic acid-induced hypothermia with β3-AR agonist pretreatment did not attenuate the sleep responses, but the inhibition of prostaglandin synthesis abolished both the sleep and thermoregulatory actions of nicotinic acid

Methods

Results

Conclusion