Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats

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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.

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Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects.

Kieran Clarke, Kirill Tchabanenko, Robert J. Pawlosky … (2012)

Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of β-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714 mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1-2h, reaching 3.30 mM and 1.19 mM for β-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8-3.1h for β-hydroxybutyrate and 8-14 h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714 mg/kg body weight, three times daily, over 5 days (equivalent to 0.42, 1.07, and 2.14 g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet. Copyright © 2012 Elsevier Inc. All rights reserved.

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Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor.

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Adenosine is released from metabolically active cells by facilitated diffusion, and is generated extracellularly by degradation of released ATP. It is a potent biological mediator that modulates the activity of numerous cell types, including various neuronal populations, platelets, neutrophils and mast cells, and smooth muscle cells in bronchi and vasculature. Most of these effects help to protect cells and tissues during stress conditions such as ischaemia. Adenosine mediates its effects through four receptor subtypes: the A1, A2a, A2b and A3 receptors. The A2a receptor (A2aR) is abundant in basal ganglia, vasculature and platelets, and stimulates adenylyl cyclase. It is a major target of caffeine, the most widely used psychoactive drug. Here we investigate the role of the A2a receptor by disrupting the gene in mice. We found that A2aR-knockout (A2aR-/-) mice were viable and bred normally. Their exploratory activity was reduced, whereas caffeine, which normally stimulates exploratory behaviour, became a depressant of exploratory activity. Knockout animals scored higher in anxiety tests, and male mice were much more aggressive towards intruders. The response of A2aR-/- mice to acute pain stimuli was slower. Blood pressure and heart rate were increased, as well as platelet aggregation. The specific A2a agonist CGS 21680 lost its biological activity in all systems tested.

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The ketogenic diet: metabolic influences on brain excitability and epilepsy.

Andrew Lutas, Gary Yellen (2012)

A dietary therapy for pediatric epilepsy known as the ketogenic diet has seen a revival in its clinical use during the past decade. Although the underlying mechanism of the diet remains unknown, modern scientific approaches, such as the genetic disruption of glucose metabolism, are allowing for more detailed questions to be addressed. Recent work indicates that several mechanisms may exist for the ketogenic diet, including disruption of glutamatergic synaptic transmission, inhibition of glycolysis, and activation of ATP-sensitive potassium channels. Here, we describe on-going work in these areas that is providing a better understanding of metabolic influences on brain excitability and epilepsy. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Author and article information

Contributors

Csilla Ari: URI : http://loop.frontiersin.org/people/378383/overview

Zsolt Kovács: URI : http://loop.frontiersin.org/people/378344/overview

Gabor Juhasz: URI : http://loop.frontiersin.org/people/378861/overview

Cem Murdun: URI : http://loop.frontiersin.org/people/378240/overview

Craig R. Goldhagen: URI : http://loop.frontiersin.org/people/378348/overview

Andrew M. Koutnik: URI : http://loop.frontiersin.org/people/378263/overview

Angela M. Poff: URI : http://loop.frontiersin.org/people/364252/overview

Shannon L. Kesl: URI : http://loop.frontiersin.org/people/378229/overview

Dominic P. D’Agostino: URI : http://loop.frontiersin.org/people/364178/overview

Journal

Journal ID (nlm-ta): Front Mol Neurosci

Journal ID (iso-abbrev): Front Mol Neurosci

Journal ID (publisher-id): Front. Mol. Neurosci.

Title: Frontiers in Molecular Neuroscience

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1662-5099

Publication date (Electronic): 06 December 2016

Publication date Collection: 2016

Volume: 9

Electronic Location Identifier: 137

Affiliations

[1] ¹Department of Molecular Pharmacology and Physiology, Hyperbaric Biomedical Research Laboratory, Morsani College of Medicine, University of South Florida Tampa, FL, USA

[2] ²Department of Zoology, University of West Hungary Szombathely, Hungary

[3] ³Proteomics Laboratory, Eotvos Lorand University Budapest, Hungary

Author notes

Edited by: Susan A. Masino, Trinity College, USA

Reviewed by: David Ruskin, Trinity College, USA; Mark Beenhakker, University of Virginia, USA

*Correspondence: Csilla Ari cdrari@ 123456health.usf.edu ; csari2000@ 123456yahoo.com

Article

DOI: 10.3389/fnmol.2016.00137

PMC ID: 5138218

PubMed ID: 27999529

SO-VID: bcf1a767-0310-4c0d-823a-82d186f09ffe

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 15 September 2016

Date accepted : 22 November 2016

Page count

Figures: 4, Tables: 0, Equations: 0, References: 67, Pages: 10, Words: 8151

Funding

Funded by: Office of Naval Research 10.13039/100000006

Award ID: N000141310062

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Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats

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The Dynamic Brain

Most cited references 46

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects.

Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor.

The ketogenic diet: metabolic influences on brain excitability and epilepsy.

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