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Article Abstract
The hypothalamic hypocretinergic/orexinergic (Hcrt/Ox) system comprises two neuropeptides -Hcrt1/OxA and Hcrt2/OxB- and two receptors -Hcrt/OxR1 and Hcrt/OxR2- which perform multiple modulatory actions. Its neurotransmission mechanism remains poorly understood despite its malfunction entails narcolepsy and low cerebrospinal fluid (CSF)-Hcrt1/OxA levels is the most specific biomarker of the disease. This work examines: (1) synaptic and volume Hcrt/Ox transmission types; (2) Hcrt/Ox receptors involvement in Hcrt/Ox-peptide release/synthesis; and (3) Hcrt/Ox system sexual dimorphism. Axonal central/peripheral distribution of dense-core vesicles (dcv) containing Hcrt1/OxA and small synaptic vesicles (ssv) loaded with glutamate was analyzed by electron microscopy in naïve rats immunolabeled for Hcrt1/OxA at the locus coeruleus area. In addition, two sets of mixed male and female rats receiving intraperitoneal (i.p.) injections of either DMSO (vehicle) or 30 mg/kg suvorexant (a dual Hcrt/Ox receptor antagonist) for 7 days were used. Hcrt1/OxA was measured in CSF and in synaptic terminals (synaptosome preparations) from the oral pontine tegmentum (OPT) of these rats using ELISA. Hcrt1/OxA-loaded dcv were more clustered in the axonal periphery than ssv, and Hcrt1/OxA enrichment was higher in CSF than in OPT-synaptosome preparations. Hcrt/Ox transmission blockade with suvorexant produced intracellular accumulation of Hcrt1/OxA, in parallel to its previously reported decrease in CSF. Female rats showed higher Hcrt1/OxA basal levels than males in CSF but not in OPT-Syn samples. Our results support the notion that: (1) volume/extrasynaptic Hcrt/Ox-peptide release is greater than synaptic/perisynaptic release, (2) Hcrt/OxR1 controls Hcrt/Ox-peptide release rather than synthesis in Hcrt/Ox neurons, and (3) Hcrt/Ox volume neurotransmission is enhanced in females.
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| http://dx.doi.org/10.1016/j.expneurol.2025.115438 | DOI Listing |
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