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Methamphetamine exposure and its cessation alter gut microbiota and induce depressive-like behavioral effects on rats

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Abstract

Rationale

Methamphetamine is a highly abused psychostimulant drug and its use remains a major public health concern worldwide with limited effective treatment options. Accumulative evidence reveals the influence of gut microbiota on the brain, behavior, and health as a part of the gut-brain axis but its involvement in modulating this substance use disorder remains poorly understood.

Objective

We sought to determine whether methamphetamine exposure and cessation or withdrawal alter the intestinal gut microbiota as well as characterize cessation-induced behavioral changes.

Methods

Male, Sprague-Dawley rats were administered methamphetamine (2 mg/kg; s.c.) or vehicle (n = 8 per group) twice per day for 14 consecutive days. On various days before, during, and after administration, fecal samples were collected and tests of anxiety- and depressive-like behaviors were conducted.

Results

Methamphetamine administration and cessation did not alter the relative abundance of bacteria but significantly changed the composition of gut bacteria through 16S rRNA sequencing. These changes were normalized after 7 days of methamphetamine cessation. Moreover, acute methamphetamine cessation induced depressive-like behavior, with an increase in immobility in the forced swim test but did not alter anxiety-like behaviors in tests of open field test or elevated plus maze.

Conclusions

These findings provide direct evidence that methamphetamine and its cessation cause gut dysbiosis and that the latter associates with depressive-like behavior in rodents. Our observation will contribute to a better understanding of the function of gut microbiota in the process of substance use disorders and guide the choice of target therapeutics.

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Acknowledgments

We thank Dr. Richard Meisch for insightful comments on the manuscript.

Funding

This research was supported by a grant from the Division of Research at the University of Houston and the Toomin Family Fund (TAK).

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Authors and Affiliations

  1. Department of Psychology, Texas Institute for Measurement, Evaluation and Statistics (TIMES), University of Houston, Health and Biomedical Sciences Building 1, 4849 Calhoun Road, Houston, TX, 77204-6022, USA

    Shadab Forouzan & Therese A. Kosten

  2. Molecular VIrology and Microbiology Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA

    Kristi L. Hoffman

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  1. Shadab Forouzan
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  2. Kristi L. Hoffman
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Correspondence to Therese A. Kosten.

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The Institutional Animal Care and Use Committee at the University of Houston approved the experimental procedures in accordance with the guidelines set forth in Guide for the Care and Use of Laboratory Animals (8th Edition) (Council NR 2011).

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Forouzan, S., Hoffman, K.L. & Kosten, T.A. Methamphetamine exposure and its cessation alter gut microbiota and induce depressive-like behavioral effects on rats. Psychopharmacology 238, 281–292 (2021). https://doi.org/10.1007/s00213-020-05681-y

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