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Mitragynine (kratom)-induced cognitive impairments in mice resemble delta 9-THC and morphine effects: Reversal by cannabinoid CB1 receptor antagonism

Kratom is a widely abused plant-based drug preparation with a global interest in recent years, well beyond its native grounds in Southeast Asia. Mitragynine, its major psychoactive constituent is known to exhibit opioid-like behavioral effects with resultant neuroplasticity in the brain reward syste...

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Main Authors: Iman, Ismail Nurul, Ahmad, Nur Aimi Zawami, Yusof, Nurul Aiman Mohd, Talib, Ummi Nasrah, Norazit, Anwar, Kumar, Jaya, Mehat, Muhammad Zulfadli, Hassan, Zurina, Mueller, Christian P., Muzaimi, Mustapha
Format: Article
Published: Frontiers Media 2021
Subjects:
R Medicine
RS Pharmacy and materia medica
Online Access:http://eprints.um.edu.my/34351/
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spelling my.um.eprints.343512022-09-13T01:14:03Z http://eprints.um.edu.my/34351/ Mitragynine (kratom)-induced cognitive impairments in mice resemble delta 9-THC and morphine effects: Reversal by cannabinoid CB1 receptor antagonism Iman, Ismail Nurul Ahmad, Nur Aimi Zawami Yusof, Nurul Aiman Mohd Talib, Ummi Nasrah Norazit, Anwar Kumar, Jaya Mehat, Muhammad Zulfadli Hassan, Zurina Mueller, Christian P. Muzaimi, Mustapha R Medicine RS Pharmacy and materia medica Kratom is a widely abused plant-based drug preparation with a global interest in recent years, well beyond its native grounds in Southeast Asia. Mitragynine, its major psychoactive constituent is known to exhibit opioid-like behavioral effects with resultant neuroplasticity in the brain reward system. Its chronic administration is associated with cognitive impairments in animal studies. However, the underlying molecular mechanism for such a deficit remains elusive. In this study, the involvement of cannabinoid type-1 (CB1) receptors in cognitive deficits after chronic mitragynine exposures was investigated for 28 days (with incremental dose sensitization from 1 to 25 mg/kg) in adult male Swiss albino mice using the IntelliCage(R) system. Chronic high-dose mitragynine exposure (5-25 mg/kg, intraperitoneal i.p.]), but not low-dose exposure (1-4 mg/kg, i.p.), induced hyperlocomotion, potentiated the preference for sucrose reward, increased resistance to punishment, and impaired place learning and its reversal. Comparable deficits were also observed after chronic treatments with ?-9-tetrahydrocannabinol (THC, 2 mg/kg, i.p.) or morphine (5 mg/kg, subcutaneous). Mitragynine-, morphine-, and THC-induced learning and memory deficits were reversed by co-treatment with the CB1 receptor antagonist, NIDA-41020 (10 mg/kg, i.p.). A significant upregulation of CB1 receptor expression was found in the hippocampal CA1 region and ventral tegmental area after chronic high-dose mitragynine and morphine, whereas a downregulation was observed after chronic THC. In conclusion, the present study suggests a plausible role of the CB1 receptor in mediating the dose-dependent cognitive deficits after chronic high-dose mitragynine exposure. This also highlights the potential of CB1 receptor antagonism in ameliorating the cognitive deficits associated with long-term kratom/mitragynine consumption in humans. Frontiers Media 2021-09-16 Article PeerReviewed Iman, Ismail Nurul and Ahmad, Nur Aimi Zawami and Yusof, Nurul Aiman Mohd and Talib, Ummi Nasrah and Norazit, Anwar and Kumar, Jaya and Mehat, Muhammad Zulfadli and Hassan, Zurina and Mueller, Christian P. and Muzaimi, Mustapha (2021) Mitragynine (kratom)-induced cognitive impairments in mice resemble delta 9-THC and morphine effects: Reversal by cannabinoid CB1 receptor antagonism. Frontiers in Pharmacology, 12. ISSN 1663-9812, DOI https://doi.org/10.3389/fphar.2021.708055 <https://doi.org/10.3389/fphar.2021.708055>. 10.3389/fphar.2021.708055
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
topic R Medicine
RS Pharmacy and materia medica
spellingShingle R Medicine
RS Pharmacy and materia medica
Iman, Ismail Nurul
Ahmad, Nur Aimi Zawami
Yusof, Nurul Aiman Mohd
Talib, Ummi Nasrah
Norazit, Anwar
Kumar, Jaya
Mehat, Muhammad Zulfadli
Hassan, Zurina
Mueller, Christian P.
Muzaimi, Mustapha
Mitragynine (kratom)-induced cognitive impairments in mice resemble delta 9-THC and morphine effects: Reversal by cannabinoid CB1 receptor antagonism
description Kratom is a widely abused plant-based drug preparation with a global interest in recent years, well beyond its native grounds in Southeast Asia. Mitragynine, its major psychoactive constituent is known to exhibit opioid-like behavioral effects with resultant neuroplasticity in the brain reward system. Its chronic administration is associated with cognitive impairments in animal studies. However, the underlying molecular mechanism for such a deficit remains elusive. In this study, the involvement of cannabinoid type-1 (CB1) receptors in cognitive deficits after chronic mitragynine exposures was investigated for 28 days (with incremental dose sensitization from 1 to 25 mg/kg) in adult male Swiss albino mice using the IntelliCage(R) system. Chronic high-dose mitragynine exposure (5-25 mg/kg, intraperitoneal i.p.]), but not low-dose exposure (1-4 mg/kg, i.p.), induced hyperlocomotion, potentiated the preference for sucrose reward, increased resistance to punishment, and impaired place learning and its reversal. Comparable deficits were also observed after chronic treatments with ?-9-tetrahydrocannabinol (THC, 2 mg/kg, i.p.) or morphine (5 mg/kg, subcutaneous). Mitragynine-, morphine-, and THC-induced learning and memory deficits were reversed by co-treatment with the CB1 receptor antagonist, NIDA-41020 (10 mg/kg, i.p.). A significant upregulation of CB1 receptor expression was found in the hippocampal CA1 region and ventral tegmental area after chronic high-dose mitragynine and morphine, whereas a downregulation was observed after chronic THC. In conclusion, the present study suggests a plausible role of the CB1 receptor in mediating the dose-dependent cognitive deficits after chronic high-dose mitragynine exposure. This also highlights the potential of CB1 receptor antagonism in ameliorating the cognitive deficits associated with long-term kratom/mitragynine consumption in humans.
format Article
author Iman, Ismail Nurul
Ahmad, Nur Aimi Zawami
Yusof, Nurul Aiman Mohd
Talib, Ummi Nasrah
Norazit, Anwar
Kumar, Jaya
Mehat, Muhammad Zulfadli
Hassan, Zurina
Mueller, Christian P.
Muzaimi, Mustapha
author_facet Iman, Ismail Nurul
Ahmad, Nur Aimi Zawami
Yusof, Nurul Aiman Mohd
Talib, Ummi Nasrah
Norazit, Anwar
Kumar, Jaya
Mehat, Muhammad Zulfadli
Hassan, Zurina
Mueller, Christian P.
Muzaimi, Mustapha
author_sort Iman, Ismail Nurul
title Mitragynine (kratom)-induced cognitive impairments in mice resemble delta 9-THC and morphine effects: Reversal by cannabinoid CB1 receptor antagonism
title_short Mitragynine (kratom)-induced cognitive impairments in mice resemble delta 9-THC and morphine effects: Reversal by cannabinoid CB1 receptor antagonism
title_full Mitragynine (kratom)-induced cognitive impairments in mice resemble delta 9-THC and morphine effects: Reversal by cannabinoid CB1 receptor antagonism
title_fullStr Mitragynine (kratom)-induced cognitive impairments in mice resemble delta 9-THC and morphine effects: Reversal by cannabinoid CB1 receptor antagonism
title_full_unstemmed Mitragynine (kratom)-induced cognitive impairments in mice resemble delta 9-THC and morphine effects: Reversal by cannabinoid CB1 receptor antagonism
title_sort mitragynine (kratom)-induced cognitive impairments in mice resemble delta 9-thc and morphine effects: reversal by cannabinoid cb1 receptor antagonism
publisher Frontiers Media
publishDate 2021
url http://eprints.um.edu.my/34351/
_version_ 1744649174244130816
score 13.211869

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