The nuclear receptor retinoid X receptor (RXR) belongs to a nuclear receptor superfamily that modulates diverse functions via homodimerization with itself or several other nuclear receptors, including PPARα. While the activation of PPARα by natural or synthetic agonists regulates the sleep-wake cycle, the role of RXR in the sleep modulation is unknown.
We investigated the effects of bexarotene (Bexa, a RXR agonist) or UVI 3003 (UVI, a RXR antagonist) on sleep, sleep homeostasis, levels of neurochemical related to sleep modulation, and c-Fos and NeuN expression.
The sleep-wake cycle and sleep homeostasis were analyzed after application of Bexa or UVI. Moreover, we also evaluated whether Bexa or UVI could induce effects on dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine contents, collected from either the nucleus accumbens or basal forebrain. In addition, c-Fos and NeuN expression in the hypothalamus was determined after Bexa or UVI treatments.
Systemic application of Bexa (1 mM, i.p.) attenuated slow-wave sleep and rapid eye movement sleep. In addition, Bexa increased the levels of dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine sampled from either the nucleus accumbens or basal forebrain. Moreover, Bexa blocked the sleep rebound period after total sleep deprivation, increased in the hypothalamus the expression of c-Fos, and decreased NeuN activity. Remarkably, UVI 3003 (1 mM, i.p.) induced opposite effects in sleep, sleep homeostasis, neurochemicals levels, and c-Fos and NeuN activity.
The administration of RXR agonist or antagonist significantly impaired the sleep-wake cycle and exerted effects on the levels of neurochemicals related to sleep modulation. Moreover, Bexa or UVI administration significantly affected c-Fos and NeuN expression in the hypothalamus. Our findings highlight the neurobiological role of RXR on sleep modulation.
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This work was supported by the Escuela de Medicina, Universidad Anáhuac Mayab (PresInvEMR2018), given to E. MR.
The experimental protocols were approved by the Research and Ethics Committee of Universidad Anáhuac Mayab (Mérida, Yucatán, México), and the protocols met the requirements of Animal Welfare including the Mexican Standards Related to Use and Management of Laboratory Animals (DOF. NOM-062-Z00-1999), the National Institutes of Health (NIH Publication No. 80-23, revised 1996), and the ARRIVE (Animal Research: Reporting of in vivo Experiments) guidelines, the commonly accepted “3Rs” Guidelines.
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Murillo-Rodríguez, E., Millán-Aldaco, D., Arankowsky-Sandoval, G. et al. The retinoid X receptor: a nuclear receptor that modulates the sleep-wake cycle in rats. Psychopharmacology 237, 2055–2073 (2020). https://doi.org/10.1007/s00213-020-05518-8
- Retinoid X receptor