Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice

Background: Gamma-aminobutyric acid (GABA) type A receptors are positively allosterically modulated by benzodiazepine binding, leading to a potentiated response to GABA. Diazepam (DZP, a benzodiazepine) is widely prescribed for anxiety, epileptic discharge, and insomnia, and is also used as a muscle...

Description complète

Enregistré dans:

Détails bibliographiques
Auteurs principaux:	Tomonori Furukawa, Yoshikazu Nikaido, Shuji Shimoyama, Nozomu Masuyama, Ayaka Notoya, Shinya Ueno
Format:	article
Langue:	EN
Publié:	Frontiers Media S.A. 2021
Sujets:	benzodiazepine chronic diazepam middle-aged cognitive function exercise LTP (long-term potentiation) Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Accès en ligne:	https://doaj.org/article/22c0615e4b604b4b81e1443b6dbc2ae5
Tags:	Ajouter un tag Pas de tags, Soyez le premier à ajouter un tag!

id	oai:doaj.org-article:22c0615e4b604b4b81e1443b6dbc2ae5
record_format	dspace
spelling	oai:doaj.org-article:22c0615e4b604b4b81e1443b6dbc2ae52021-12-01T07:57:23ZImpaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice1663-436510.3389/fnagi.2021.777404https://doaj.org/article/22c0615e4b604b4b81e1443b6dbc2ae52021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnagi.2021.777404/fullhttps://doaj.org/toc/1663-4365Background: Gamma-aminobutyric acid (GABA) type A receptors are positively allosterically modulated by benzodiazepine binding, leading to a potentiated response to GABA. Diazepam (DZP, a benzodiazepine) is widely prescribed for anxiety, epileptic discharge, and insomnia, and is also used as a muscle relaxant and anti-convulsant. However, some adverse effects – such as tolerance, dependence, withdrawal effects, and impairments in cognition and learning – are elicited by the long-term use of DZP. Clinical studies have reported that chronic DZP treatment increases the risk of dementia in older adults. Furthermore, several studies have reported that chronic DZP administration may affect neuronal activity in the hippocampus, dendritic spine structure, and cognitive performance. However, the effects of chronic DZP administration on cognitive function in aged mice is not yet completely understood.Methods: A behavioral test, immunohistochemical analysis of neurogenic and apoptotic markers, dendritic spine density analysis, and long-term potentiation (LTP) assay of the hippocampal CA1 and CA3 were performed in both young (8 weeks old) and middle-aged (12 months old) mice to investigate the effects of chronic DZP administration on cognitive function. The chronic intraperitoneal administration of DZP was performed by implanting an osmotic minipump. To assess spatial learning and memory ability, the Morris water maze test was performed. Dendritic spines were visualized using Lucifer yellow injection into the soma of hippocampal neurons, and spine density was analyzed. Moreover, the effects of exercise on DZP-induced changes in spine density and LTP in the hippocampus were assessed.Results: Learning performance was impaired by chronic DZP administration in middle-aged mice but not in young mice. LTP was attenuated by DZP administration in the CA1 of young mice and the CA3 of middle-aged mice. The spine density of hippocampal neurons was decreased by chronic DZP administration in the CA1 of both young and middle-aged mice as well as in the CA3 of middle-aged mice. Neither neurogenesis nor apoptosis in the hippocampus was affected by chronic DZP administration.Conclusion: The results of this study suggest that the effects of chronic DZP are different between young and middle-aged mice. The chronic DZP-induced memory retrieval performance impairment in middle-aged mice can likely be attributed to decreased LTP and dendritic spine density in hippocampal neurons in the CA3. Notably, prophylactic exercise suppressed the adverse effects of chronic DZP on LTP and spine maintenance in middle-aged mice.Tomonori FurukawaYoshikazu NikaidoYoshikazu NikaidoShuji ShimoyamaShuji ShimoyamaNozomu MasuyamaAyaka NotoyaShinya UenoShinya UenoFrontiers Media S.A.articlebenzodiazepinechronic diazepammiddle-agedcognitive functionexerciseLTP (long-term potentiation)Neurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Aging Neuroscience, Vol 13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	benzodiazepine chronic diazepam middle-aged cognitive function exercise LTP (long-term potentiation) Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	benzodiazepine chronic diazepam middle-aged cognitive function exercise LTP (long-term potentiation) Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Tomonori Furukawa Yoshikazu Nikaido Yoshikazu Nikaido Shuji Shimoyama Shuji Shimoyama Nozomu Masuyama Ayaka Notoya Shinya Ueno Shinya Ueno Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice
description	Background: Gamma-aminobutyric acid (GABA) type A receptors are positively allosterically modulated by benzodiazepine binding, leading to a potentiated response to GABA. Diazepam (DZP, a benzodiazepine) is widely prescribed for anxiety, epileptic discharge, and insomnia, and is also used as a muscle relaxant and anti-convulsant. However, some adverse effects – such as tolerance, dependence, withdrawal effects, and impairments in cognition and learning – are elicited by the long-term use of DZP. Clinical studies have reported that chronic DZP treatment increases the risk of dementia in older adults. Furthermore, several studies have reported that chronic DZP administration may affect neuronal activity in the hippocampus, dendritic spine structure, and cognitive performance. However, the effects of chronic DZP administration on cognitive function in aged mice is not yet completely understood.Methods: A behavioral test, immunohistochemical analysis of neurogenic and apoptotic markers, dendritic spine density analysis, and long-term potentiation (LTP) assay of the hippocampal CA1 and CA3 were performed in both young (8 weeks old) and middle-aged (12 months old) mice to investigate the effects of chronic DZP administration on cognitive function. The chronic intraperitoneal administration of DZP was performed by implanting an osmotic minipump. To assess spatial learning and memory ability, the Morris water maze test was performed. Dendritic spines were visualized using Lucifer yellow injection into the soma of hippocampal neurons, and spine density was analyzed. Moreover, the effects of exercise on DZP-induced changes in spine density and LTP in the hippocampus were assessed.Results: Learning performance was impaired by chronic DZP administration in middle-aged mice but not in young mice. LTP was attenuated by DZP administration in the CA1 of young mice and the CA3 of middle-aged mice. The spine density of hippocampal neurons was decreased by chronic DZP administration in the CA1 of both young and middle-aged mice as well as in the CA3 of middle-aged mice. Neither neurogenesis nor apoptosis in the hippocampus was affected by chronic DZP administration.Conclusion: The results of this study suggest that the effects of chronic DZP are different between young and middle-aged mice. The chronic DZP-induced memory retrieval performance impairment in middle-aged mice can likely be attributed to decreased LTP and dendritic spine density in hippocampal neurons in the CA3. Notably, prophylactic exercise suppressed the adverse effects of chronic DZP on LTP and spine maintenance in middle-aged mice.
format	article
author	Tomonori Furukawa Yoshikazu Nikaido Yoshikazu Nikaido Shuji Shimoyama Shuji Shimoyama Nozomu Masuyama Ayaka Notoya Shinya Ueno Shinya Ueno
author_facet	Tomonori Furukawa Yoshikazu Nikaido Yoshikazu Nikaido Shuji Shimoyama Shuji Shimoyama Nozomu Masuyama Ayaka Notoya Shinya Ueno Shinya Ueno
author_sort	Tomonori Furukawa
title	Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice
title_short	Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice
title_full	Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice
title_fullStr	Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice
title_full_unstemmed	Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice
title_sort	impaired cognitive function and hippocampal changes following chronic diazepam treatment in middle-aged mice
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/22c0615e4b604b4b81e1443b6dbc2ae5
work_keys_str_mv	AT tomonorifurukawa impairedcognitivefunctionandhippocampalchangesfollowingchronicdiazepamtreatmentinmiddleagedmice AT yoshikazunikaido impairedcognitivefunctionandhippocampalchangesfollowingchronicdiazepamtreatmentinmiddleagedmice AT yoshikazunikaido impairedcognitivefunctionandhippocampalchangesfollowingchronicdiazepamtreatmentinmiddleagedmice AT shujishimoyama impairedcognitivefunctionandhippocampalchangesfollowingchronicdiazepamtreatmentinmiddleagedmice AT shujishimoyama impairedcognitivefunctionandhippocampalchangesfollowingchronicdiazepamtreatmentinmiddleagedmice AT nozomumasuyama impairedcognitivefunctionandhippocampalchangesfollowingchronicdiazepamtreatmentinmiddleagedmice AT ayakanotoya impairedcognitivefunctionandhippocampalchangesfollowingchronicdiazepamtreatmentinmiddleagedmice AT shinyaueno impairedcognitivefunctionandhippocampalchangesfollowingchronicdiazepamtreatmentinmiddleagedmice AT shinyaueno impairedcognitivefunctionandhippocampalchangesfollowingchronicdiazepamtreatmentinmiddleagedmice
_version_	1718405400766709760

Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice

Documents similaires