title: Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats.
abstract: Nutritional ketosis has been proven effective for seizure disorders and other neurological disorders. The focus of this study was to determine the effects of ketone supplementation on anxiety-related behavior in Sprague-Dawley (SPD) and Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. We tested exogenous ketone supplements added to food and fed chronically for 83 days in SPD rats and administered sub-chronically for 7 days in both rat models by daily intragastric gavage bolus followed by assessment of anxiety measures on elevated plus maze (EPM). The groups included standard diet (SD) or SD + ketone supplementation. Low-dose ketone ester (LKE; 1,3-butanediol-acetoacetate diester, ~10 g/kg/day, LKE), high dose ketone ester (HKE; ~25 g/kg/day, HKE), beta-hydroxybutyrate-mineral salt (βHB-S; ~25 g/kg/day, KS) and βHB-S + medium chain triglyceride (MCT; ~25 g/kg/day, KSMCT) were used as ketone supplementation for chronic administration. To extend our results, exogenous ketone supplements were also tested sub-chronically on SPD rats (KE, KS and KSMCT; 5 g/kg/day) and on WAG/Rij rats (KE, KS and KSMCT; 2.5 g/kg/day). At the end of treatments behavioral data collection was conducted manually by a blinded observer and with a video-tracking system, after which blood βHB and glucose levels were measured. Ketone supplementation reduced anxiety on EPM as measured by less entries to closed arms (sub-chronic KE and KS: SPD rats and KSMCT: WAG/Rij rats), more time spent in open arms (sub-chronic KE: SPD and KSMCT: WAG/Rij rats; chronic KSMCT: SPD rats), more distance traveled in open arms (chronic KS and KSMCT: SPD rats) and by delayed latency to entrance to closed arms (chronic KSMCT: SPD rats), when compared to control. Our data indicates that chronic and sub-chronic ketone supplementation not only elevated blood βHB levels in both animal models, but reduced anxiety-related behavior. We conclude that ketone supplementation may represent a promising anxiolytic strategy through a novel means of inducing nutritional ketosis.
authors.affiliation: Department of Molecular Pharmacology and Physiology, Hyperbaric Biomedical Research Laboratory, Morsani College of Medicine, University of South Florida Tampa, FL, USA.
authors.forename: Csilla
authors.initials: C
authors.lastname: Ari
authors.affiliation: Department of Zoology, University of West Hungary Szombathely, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Kovács
authors.affiliation: Proteomics Laboratory, Eotvos Lorand University Budapest, Hungary.
authors.forename: Gabor
authors.initials: G
authors.lastname: Juhasz
authors.affiliation: Department of Molecular Pharmacology and Physiology, Hyperbaric Biomedical Research Laboratory, Morsani College of Medicine, University of South Florida Tampa, FL, USA.
authors.forename: Cem
authors.initials: C
authors.lastname: Murdun
authors.affiliation: Department of Molecular Pharmacology and Physiology, Hyperbaric Biomedical Research Laboratory, Morsani College of Medicine, University of South Florida Tampa, FL, USA.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Goldhagen
authors.affiliation: Department of Molecular Pharmacology and Physiology, Hyperbaric Biomedical Research Laboratory, Morsani College of Medicine, University of South Florida Tampa, FL, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Koutnik
authors.affiliation: Department of Molecular Pharmacology and Physiology, Hyperbaric Biomedical Research Laboratory, Morsani College of Medicine, University of South Florida Tampa, FL, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Poff
authors.affiliation: Department of Molecular Pharmacology and Physiology, Hyperbaric Biomedical Research Laboratory, Morsani College of Medicine, University of South Florida Tampa, FL, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Kesl
authors.affiliation: Department of Molecular Pharmacology and Physiology, Hyperbaric Biomedical Research Laboratory, Morsani College of Medicine, University of South Florida Tampa, FL, USA.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: D'Agostino
keywords: animal models; anxiety; elevated plus maze; exogenous ketone supplements; ketones