Plasticity of the hypocretinergic/orexinergic system after a chronic treatment with suvorexant in rats. Role of the hypocretinergic/orexinergic receptor 1 as an autoreceptor.

Abstract

The hypothalamic hypocretinergic/orexinergic (Hcrt/Ox) system is involved in many physiological and pathophysiological processes. Malfunction of Hcrt/Ox transmission results in narcolepsy, a sleep disease caused in humans by progressive neurodegeneration of hypothalamic neurons containing Hcrt/Ox. To explore the Hcrt/Ox system plasticity we systemically administered suvorexant (a dual Hcrt/Ox receptor antagonist) in rats to chronically block Hcrt/Ox transmission without damaging Hcrt/Ox cells. Three groups of eight rats (four males and four females) received daily i.p. injections of suvorexant (10 or 30 mg/kg) or vehicle (DMSO) over a period of 7 days in which the body weight was monitored. After the treatments cerebrospinal fluid (CSF) Hcrt1/OxA concentration was measured by ELISA, and hypothalamic Hcrt/OxR1 and Hcrt/OxR2 levels by western blot. The systemic blockade of the Hcrt/Ox transmission with the suvorexant high dose produced a significant increase in body weight at the end of the treatment, and a significant decrease in CSF Hcrt1/OxA levels, both features typical in human narcolepsy type 1. Besides, a significant overexpression of hypothalamic Hcrt/OxR1 occurred. For the Hcrt/OxR2 two very close bands were detected, but they did not show significant changes with the treatment. Thus, the plastic changes observed in the Hcrt/Ox system after the chronic blockade of its transmission were a decrease in CSF Hcrt1/OXA levels and an overexpression of hypothalamic Hcrt/OxR1. These findings support an autoregulatory role of Hcrt/OxR1 within the hypothalamus, which would induce the synthesis/release of Hcrt/Ox, but also decrease its own availability at the plasma membrane after binding Hcrt1/OxA to preserve Hcrt/Ox system homeostasis.