Effects of beta-hydroxybutyrate administration on MK-801-induced schizophrenia-like behaviour in mice

Kraeuter, Ann-Katrin, Mashavave, Tadiwa, Suvarna, Aditya, van den Buuse, Maarten, and Sarnyai, Zoltan (2020) Effects of beta-hydroxybutyrate administration on MK-801-induced schizophrenia-like behaviour in mice. Psychopharmacology, 237. pp. 1397-1405.

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Abstract

Rationale: Impaired cerebral glucose metabolism is a core pathological feature of schizophrenia. We recently demonstrated that a ketogenic diet, causing a shift from glycolysis to ketosis, normalized schizophrenia-like behaviours in an acute N-methyl-D-aspartate (NMDA) receptor antagonist model of the illness. Ketogenic diet produces the ketone body, β-hydroxybutyrate (BHB), which may serve as an alternative fuel source in its own right without a strict dietary regime.

Objective: We hypothesized that chronic administration of BHB replicates the therapeutic effects of ketogenic diet in an acute NMDA receptor hypofunction model of schizophrenia in mice.

Methods: C57Bl/6 mice were either treated with acute doses of 2 mmol/kg, 10 mmol/kg, or 20 mmol/kg BHB or received daily intraperitoneal injections of 2 mmol/kg BHB or saline for 3 weeks. Behavioural testing assessed the effect of acute challenge with 0.2 mg/kg MK-801 or saline on open field behaviour, social interaction, and prepulse inhibition of startle (PPI).

Results: Acute BHB administration dose-dependently increased BHB plasma levels, whereas the 2 mmol/kg dose increased plasma glucose levels. The highest acute dose of BHB supressed spontaneous locomotor activity, MK-801-induced locomotor hyperactivity and MK-801-induced disruption of PPI. Chronic BHB treatment normalized MK-801-induced hyperlocomotion, reduction of sociability, and disruption of PPI.

Conclusion: In conclusion, BHB may present a novel treatment option for patients with schizophrenia by providing an alternative fuel source to normalize impaired glucose metabolism in the brain.

Item ID: 63653
Item Type: Article (Research - C1)
ISSN: 1432-2072
Keywords: N-Methyl-D-aspartate (NMDA) receptor hypofunction, Ketogenic diet, Beta-hydroxybutyrate (BHB), Schizophrenia, MK-801, Sensorimotor gating, Sociability
Copyright Information: © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Funders: Far North Queensland Hospital Foundation (FNQHF), James Cook University (JCU), National Health and Medical Research Council of Australia (NHMRC)
Projects and Grants: FNQHF research grant (JCU-QLD-584321), JCU Postgraduate Research Scholarship, JCU Higher Degree Research Enhancement Scheme, NHMRC Senior Research Fellowship
Date Deposited: 30 Jun 2020 04:11
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1109 Neurosciences > 110903 Central Nervous System @ 70%
11 MEDICAL AND HEALTH SCIENCES > 1103 Clinical Sciences > 110319 Psychiatry (incl Psychotherapy) @ 30%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920111 Nervous System and Disorders @ 100%
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