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

Csilla Ari,Zsolt Kovács,Cem Murdun,Shannon L Kesl,Craig R Goldhagen,Andrew M Koutnik,Dominic P D’Agostino,Gabor Juhasz,Angela M Poff

doi:10.3389/fnmol.2016.00137

Csilla Ari, Zsolt Kovács + Show 7 more

Open Access

https://doi.org/10.3389/fnmol.2016.00137

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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.

Highlights

Anxiety disorders, such as generalized anxiety disorder, phobia and panic disorder, are the most prevalent type of mental disorders (Li, 2012)
More Time Spent in Open Arms with Ketone Supplements After chronic feeding of ketone supplementation in SPD rats the time spent in the open arms was significantly more in KSMCT group (p = 0.0094), while time spent in the closed arms was significantly less in low-dose ketone ester (LKE), KS and KSMCT groups (p = 0.0389, 0.0077 and 0.0019, respectively), compared to the control (SD) in SPD rats
The current study demonstrated the anxiolytic effect of chronic (13 weeks) and sub-chronic (7 days) administration of several forms of ketone supplementation in both SPD and Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats

Summary

Introduction

Anxiety disorders, such as generalized anxiety disorder, phobia and panic disorder, are the most prevalent type of mental disorders (Li, 2012). Anxiety can be associated with psychiatric morbidity, disability, increased healthcare burden and mortality in the general population (Teri et al, 1999). These symptoms can cause significant distress interfering with a person’s quality of life, while they commonly occur along with other mental or physical illnesses, which may mask anxiety symptoms or aggravate them. The same brain regions involved in a significant proportion of patients with focal epilepsy, such as the amygdala and the hippocampus, play a key role in the neurobiology of anxiety (Li, 2012; Dias et al, 2013)

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