Hypocretin/orexin peptide release occurs mostly extrasynaptically, is self-controlled, and specifically enhanced in female rats

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 narcole...

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Detalles Bibliográficos
Autores: Carrera Cañas, Carlos, Andrés, Isabel de, Callejo, Marta, Garzón García, Miguel
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/731240
Acceso en línea:https://hdl.handle.net/10486/731240
https://dx.doi.org/10.1016/j.expneurol.2025.115438
Access Level:acceso abierto
Palabra clave:Narcolepsy
Hypocretin
Orexin
Hypothalamus
Suvorexant
Rat
Medicina
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spelling Hypocretin/orexin peptide release occurs mostly extrasynaptically, is self-controlled, and specifically enhanced in female ratsCarrera Cañas, CarlosAndrés, Isabel deCallejo, MartaGarzón García, MiguelNarcolepsyHypocretinOrexinHypothalamusSuvorexantRatMedicinaThe 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 femalesThis research was funded by the Eugenio Rodríguez Pascual Foundation (FERP2021) and Ministerio de Ciencia, Innovación y Universidades MCIU/AEI 10.13039/501100011033/FEDER, UE (CPP2023–010422). C. Carrera-Cañas received a predoctoral fellowship from the Tatiana PGB FoundationElsevierDepartamento de Anatomía, Histología y NeurocienciaFacultad de Medicina20252025-12-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10486/731240https://dx.doi.org/10.1016/j.expneurol.2025.115438reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7312402026-06-23T12:46:27Z
dc.title.none.fl_str_mv Hypocretin/orexin peptide release occurs mostly extrasynaptically, is self-controlled, and specifically enhanced in female rats
title Hypocretin/orexin peptide release occurs mostly extrasynaptically, is self-controlled, and specifically enhanced in female rats
spellingShingle Hypocretin/orexin peptide release occurs mostly extrasynaptically, is self-controlled, and specifically enhanced in female rats
Carrera Cañas, Carlos
Narcolepsy
Hypocretin
Orexin
Hypothalamus
Suvorexant
Rat
Medicina
title_short Hypocretin/orexin peptide release occurs mostly extrasynaptically, is self-controlled, and specifically enhanced in female rats
title_full Hypocretin/orexin peptide release occurs mostly extrasynaptically, is self-controlled, and specifically enhanced in female rats
title_fullStr Hypocretin/orexin peptide release occurs mostly extrasynaptically, is self-controlled, and specifically enhanced in female rats
title_full_unstemmed Hypocretin/orexin peptide release occurs mostly extrasynaptically, is self-controlled, and specifically enhanced in female rats
title_sort Hypocretin/orexin peptide release occurs mostly extrasynaptically, is self-controlled, and specifically enhanced in female rats
dc.creator.none.fl_str_mv Carrera Cañas, Carlos
Andrés, Isabel de
Callejo, Marta
Garzón García, Miguel
author Carrera Cañas, Carlos
author_facet Carrera Cañas, Carlos
Andrés, Isabel de
Callejo, Marta
Garzón García, Miguel
author_role author
author2 Andrés, Isabel de
Callejo, Marta
Garzón García, Miguel
author2_role author
author
author
dc.contributor.none.fl_str_mv Departamento de Anatomía, Histología y Neurociencia
Facultad de Medicina
dc.subject.none.fl_str_mv Narcolepsy
Hypocretin
Orexin
Hypothalamus
Suvorexant
Rat
Medicina
topic Narcolepsy
Hypocretin
Orexin
Hypothalamus
Suvorexant
Rat
Medicina
description 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
publishDate 2025
dc.date.none.fl_str_mv 2025
2025-12-01
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10486/731240
https://dx.doi.org/10.1016/j.expneurol.2025.115438
url https://hdl.handle.net/10486/731240
https://dx.doi.org/10.1016/j.expneurol.2025.115438
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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