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Accepted manuscript

Escitalopram alters tryptophan metabolism, plasma lipopolysaccharide, and the inferred functional potential of the gut microbiome in deer mice showing compulsive-like rigidity

Published online by Cambridge University Press:  03 April 2025

Larissa Karsten ,
Brian H Harvey ,
Dan J. Stein ,
Benjamín Valderrama ,
Thomaz F. S. Bastiaanssen ,
Gerard Clarke ,
John F. Cryan ,
Rencia van der Sluis ,
Heather Jaspan  and
Anna-Ursula Happel
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Larissa Karsten
Affiliation:
Centre of Excellence for Pharmaceutical Sciences2, Faculty of Health, North-West University, Potchefstroom, South Africa
Brian H Harvey
Affiliation:
Centre of Excellence for Pharmaceutical Sciences2, Faculty of Health, North-West University, Potchefstroom, South Africa SAMRC Unit on Risk and Resilience in Mental Disorders, Dept of Psychiatry and Mental Health and Neuroscience Institute, University of Cape Town, Cape Town, South Africa IMPACT Strategic Research Centre, School of Medicine, Deakin University, Barwon Health, Geelong, Australia
Dan J. Stein
Affiliation:
SAMRC Unit on Risk and Resilience in Mental Disorders, Dept of Psychiatry and Mental Health and Neuroscience Institute, University of Cape Town, Cape Town, South Africa
Benjamín Valderrama
Affiliation:
APC Microbiome Ireland, University College Cork, Ireland Department of Anatomy and Neuroscience, University College Cork, Ireland.
Thomaz F. S. Bastiaanssen
Affiliation:
APC Microbiome Ireland, University College Cork, Ireland Department of Anatomy and Neuroscience, University College Cork, Ireland.
Gerard Clarke
Affiliation:
APC Microbiome Ireland, University College Cork, Ireland Department of Psychiatry and Neurobehavioural Science, University College Cork, Ireland.
John F. Cryan
Affiliation:
APC Microbiome Ireland, University College Cork, Ireland Department of Anatomy and Neuroscience, University College Cork, Ireland.
Rencia van der Sluis
Affiliation:
Biomedical and Molecular Metabolism Research (BioMMet), North-West University, Potchefstroom, South Africa
Heather Jaspan
Affiliation:
Department of Pathology, University of Cape Town, Cape Town, South Africa Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, South Africa Seattle Children’s Research Institute, Seattle, WA USA University of Washington, Departments of Pediatrics and Global Health, Seattle, WA
Anna-Ursula Happel
Affiliation:
Department of Pathology, University of Cape Town, Cape Town, South Africa Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, South Africa
De Wet Wolmarans*
Affiliation:
Centre of Excellence for Pharmaceutical Sciences2, Faculty of Health, North-West University, Potchefstroom, South Africa
*
*Correspondence to: De Wet Wolmarans, Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa, Email: dewet.wolmarans@nwu.ac.za, Phone: +27 (0) 18 299 2230
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Abstract

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Objective:

Compulsive-like rigidity may be associated with hyposerotonergia and increased kynurenine (KYN) pathway activity. Conversion of tryptophan (TRP) to kynurenine (KYN), which may contribute to hyposerotonergia, is bolstered by inflammation, and could be related to altered gut microbiota composition. Here, we studied these mechanisms in a naturalistic animal model of compulsive-like behavioural rigidity, i.e., large nest building (LNB) in deer mice (Peromyscus sp.).

Methods:

Twenty-four (24) normal nest building (NNB)- and 24 LNB mice (both sexes) were chronically administered either escitalopram (a selective serotonin reuptake inhibitor; 50 mg/kg/day) or a control solution, with nesting behaviour analysed before and after intervention. After endpoint euthanising, frontal cortices and striata were analysed for TRP and its metabolites, plasma for microbiota derived lipopolysaccharide (LPS) and its binding protein (LBP), and stool samples for microbial DNA.

Results:

LNB, but not NNB, decreased after escitalopram exposure. At baseline, LNB associated with reduced frontal cortical TRP concentrations and hyposerotonergia that was unrelated to altered KYN pathway activity. In LNB mice, escitalopram significantly increased frontal-cortical and striatal TRP without altering serotonin concentrations. Treated LNB, compared to untreated LNB- and treated NNB mice, had significantly reduced plasma LPS as well as a microbiome showing a decreased inferred potential to synthesise short-chain fatty acids and degrade TRP.

Conclusion:

These findings support the role of altered serotonergic mechanisms, inflammatory processes, and gut microbiome involvement in compulsive-like behavioural rigidity. Our results also highlight the importance of gut-brain crosstalk mechanisms at the level of TRP metabolism in the spontaneous development of such behaviour.

Keywords

Deer mouseobsessive-compulsive disorderrigidityserotoninmicrobiome
Type
Original Article
Information
Acta Neuropsychiatrica , Accepted manuscript , pp. 1 - 37
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
© The Author(s), 2025. Published by Cambridge University Press on behalf of Scandinavian College of Neuropsychopharmacology