Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats

INTRODUCTION: Depression is characterized by behavioral, cognitive and physiological changes, imposing a major burden on the overall wellbeing of the patient. Some evidence indicates that social stress, changes in growth factors (e.g., brain-derived neurotrophic factor (BDNF)), and neuroinflammation...

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Autores principales: Giacobbo, Bruno Lima, Doorduin, Janine, Moraga-Amaro, Rodrigo, Nazario, Luiza Reali, Schildt, Anna, Bromberg, Elke, Dierckx, Rudi A.J.O., de Vries, Erik F.J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239822/
https://www.ncbi.nlm.nih.gov/pubmed/32088835
http://dx.doi.org/10.1007/s00213-020-05483-2
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author Giacobbo, Bruno Lima
Doorduin, Janine
Moraga-Amaro, Rodrigo
Nazario, Luiza Reali
Schildt, Anna
Bromberg, Elke
Dierckx, Rudi A.J.O.
de Vries, Erik F.J.
author_facet Giacobbo, Bruno Lima
Doorduin, Janine
Moraga-Amaro, Rodrigo
Nazario, Luiza Reali
Schildt, Anna
Bromberg, Elke
Dierckx, Rudi A.J.O.
de Vries, Erik F.J.
author_sort Giacobbo, Bruno Lima
collection PubMed
description INTRODUCTION: Depression is characterized by behavioral, cognitive and physiological changes, imposing a major burden on the overall wellbeing of the patient. Some evidence indicates that social stress, changes in growth factors (e.g., brain-derived neurotrophic factor (BDNF)), and neuroinflammation are involved in the development and progression of the disease. The monoamine oxidase A inhibitor drug harmine was suggested to have both antidepressant and anti-inflammatory properties and may, therefore, be a potential candidate for treatment of depression. AIM: The goal of this study was to assess the effects of harmine on behavior, brain BDNF levels, and microglia activation in control rats and a rat model of social stress. MATERIAL AND METHODS: Rats were submitted to 5 consecutive days of repeated social defeat (RSD) or control conditions. Animals were treated daily with harmine (15 mg/kg) or vehicle from day 3 until the end of the experiment. To assess the effects of harmine treatment on behavior, the sucrose preference test (SPT) was performed on days 1, 6, and 15, the open field test (OFT) on days 6 and 14, and the novel object recognition test (NOR) on day 16. Brain microgliosis was assessed using [(11)C]PBR-28 PET on day 17. Animals were terminated on day 17, and BDNF protein concentrations in the hippocampus and frontal cortex were analyzed using ELISA. RESULTS: RSD significantly decreased bodyweight and increased anxiety and anhedonia-related parameters in the OFT and SPT on day 6, but these behavioral effects were not observed anymore on day 14/15. Harmine treatment caused a significant reduction in bodyweight gain in both groups, induced anhedonia in the SPT on day 6, and significantly reduced the mobility and exploratory behavior of the animals in the OFT mainly on day 14. PET imaging and the NOR test did not show any significant effects on microglia activation and memory, respectively. BDNF protein concentrations in the hippocampus and frontal cortex were not significantly affected by either RSD or harmine treatment. DISCUSSION: Harmine was not able to reverse the acute effects of RSD on anxiety and anhedonia and even aggravated the effect of RSD on bodyweight loss. Moreover, harmine treatment caused unexpected side effects on general locomotion, both in RSD and control animals, but did not influence glial activation status and BDNF concentrations in the brain. In this model, RSD-induced stress was not strong enough to induce long-term effects on the behavior, neuroinflammation, or BDNF protein concentration. Thus, the efficacy of harmine treatment on these delayed parameters needs to be further evaluated in more severe models of chronic stress.
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spelling pubmed-72398222020-05-27 Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats Giacobbo, Bruno Lima Doorduin, Janine Moraga-Amaro, Rodrigo Nazario, Luiza Reali Schildt, Anna Bromberg, Elke Dierckx, Rudi A.J.O. de Vries, Erik F.J. Psychopharmacology (Berl) Original Investigation INTRODUCTION: Depression is characterized by behavioral, cognitive and physiological changes, imposing a major burden on the overall wellbeing of the patient. Some evidence indicates that social stress, changes in growth factors (e.g., brain-derived neurotrophic factor (BDNF)), and neuroinflammation are involved in the development and progression of the disease. The monoamine oxidase A inhibitor drug harmine was suggested to have both antidepressant and anti-inflammatory properties and may, therefore, be a potential candidate for treatment of depression. AIM: The goal of this study was to assess the effects of harmine on behavior, brain BDNF levels, and microglia activation in control rats and a rat model of social stress. MATERIAL AND METHODS: Rats were submitted to 5 consecutive days of repeated social defeat (RSD) or control conditions. Animals were treated daily with harmine (15 mg/kg) or vehicle from day 3 until the end of the experiment. To assess the effects of harmine treatment on behavior, the sucrose preference test (SPT) was performed on days 1, 6, and 15, the open field test (OFT) on days 6 and 14, and the novel object recognition test (NOR) on day 16. Brain microgliosis was assessed using [(11)C]PBR-28 PET on day 17. Animals were terminated on day 17, and BDNF protein concentrations in the hippocampus and frontal cortex were analyzed using ELISA. RESULTS: RSD significantly decreased bodyweight and increased anxiety and anhedonia-related parameters in the OFT and SPT on day 6, but these behavioral effects were not observed anymore on day 14/15. Harmine treatment caused a significant reduction in bodyweight gain in both groups, induced anhedonia in the SPT on day 6, and significantly reduced the mobility and exploratory behavior of the animals in the OFT mainly on day 14. PET imaging and the NOR test did not show any significant effects on microglia activation and memory, respectively. BDNF protein concentrations in the hippocampus and frontal cortex were not significantly affected by either RSD or harmine treatment. DISCUSSION: Harmine was not able to reverse the acute effects of RSD on anxiety and anhedonia and even aggravated the effect of RSD on bodyweight loss. Moreover, harmine treatment caused unexpected side effects on general locomotion, both in RSD and control animals, but did not influence glial activation status and BDNF concentrations in the brain. In this model, RSD-induced stress was not strong enough to induce long-term effects on the behavior, neuroinflammation, or BDNF protein concentration. Thus, the efficacy of harmine treatment on these delayed parameters needs to be further evaluated in more severe models of chronic stress. Springer Berlin Heidelberg 2020-02-22 2020 /pmc/articles/PMC7239822/ /pubmed/32088835 http://dx.doi.org/10.1007/s00213-020-05483-2 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Investigation
Giacobbo, Bruno Lima
Doorduin, Janine
Moraga-Amaro, Rodrigo
Nazario, Luiza Reali
Schildt, Anna
Bromberg, Elke
Dierckx, Rudi A.J.O.
de Vries, Erik F.J.
Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats
title Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats
title_full Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats
title_fullStr Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats
title_full_unstemmed Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats
title_short Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats
title_sort chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239822/
https://www.ncbi.nlm.nih.gov/pubmed/32088835
http://dx.doi.org/10.1007/s00213-020-05483-2
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