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Mitragynine (Kratom)-induced cognitive impairments in mice resemble Δ9-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: Ismail, Nurul Iman, Ahmad, Nur Aimi Zawami, Mohd Yusof, Nurul Aiman, Talib, Ummi Nasrah, Norazit, Anwar, Kumar, Jaya, Mehat, Muhammad Zulfadli, Hassan, Zurina, Muller, Christian P., Muzaimi, Mustapha
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Published: Frontiers Media 2021
Online Access:http://psasir.upm.edu.my/id/eprint/94208/
https://www.frontiersin.org/articles/10.3389/fphar.2021.708055/full
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spelling my.upm.eprints.942082023-05-18T08:16:14Z http://psasir.upm.edu.my/id/eprint/94208/ Mitragynine (Kratom)-induced cognitive impairments in mice resemble Δ9-THC and morphine effects: reversal by cannabinoid CB1 receptor antagonism Ismail, Nurul Iman Ahmad, Nur Aimi Zawami Mohd Yusof, Nurul Aiman Talib, Ummi Nasrah Norazit, Anwar Kumar, Jaya Mehat, Muhammad Zulfadli Hassan, Zurina Muller, Christian P. Muzaimi, Mustapha 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® 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 Δ-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 Ismail, Nurul Iman and Ahmad, Nur Aimi Zawami and Mohd Yusof, Nurul Aiman and Talib, Ummi Nasrah and Norazit, Anwar and Kumar, Jaya and Mehat, Muhammad Zulfadli and Hassan, Zurina and Muller, Christian P. and Muzaimi, Mustapha (2021) Mitragynine (Kratom)-induced cognitive impairments in mice resemble Δ9-THC and morphine effects: reversal by cannabinoid CB1 receptor antagonism. Frontiers in Pharmacology, 12. art. no. 708055. pp. 1-21. ISSN 1663-9812 https://www.frontiersin.org/articles/10.3389/fphar.2021.708055/full 10.3389/fphar.2021.708055
institution Universiti Putra Malaysia
building UPM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Putra Malaysia
content_source UPM Institutional Repository
url_provider http://psasir.upm.edu.my/
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® 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 Δ-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 Ismail, Nurul Iman
Ahmad, Nur Aimi Zawami
Mohd Yusof, Nurul Aiman
Talib, Ummi Nasrah
Norazit, Anwar
Kumar, Jaya
Mehat, Muhammad Zulfadli
Hassan, Zurina
Muller, Christian P.
Muzaimi, Mustapha
spellingShingle Ismail, Nurul Iman
Ahmad, Nur Aimi Zawami
Mohd Yusof, Nurul Aiman
Talib, Ummi Nasrah
Norazit, Anwar
Kumar, Jaya
Mehat, Muhammad Zulfadli
Hassan, Zurina
Muller, Christian P.
Muzaimi, Mustapha
Mitragynine (Kratom)-induced cognitive impairments in mice resemble Δ9-THC and morphine effects: reversal by cannabinoid CB1 receptor antagonism
author_facet Ismail, Nurul Iman
Ahmad, Nur Aimi Zawami
Mohd Yusof, Nurul Aiman
Talib, Ummi Nasrah
Norazit, Anwar
Kumar, Jaya
Mehat, Muhammad Zulfadli
Hassan, Zurina
Muller, Christian P.
Muzaimi, Mustapha
author_sort Ismail, Nurul Iman
title Mitragynine (Kratom)-induced cognitive impairments in mice resemble Δ9-THC and morphine effects: reversal by cannabinoid CB1 receptor antagonism
title_short Mitragynine (Kratom)-induced cognitive impairments in mice resemble Δ9-THC and morphine effects: reversal by cannabinoid CB1 receptor antagonism
title_full Mitragynine (Kratom)-induced cognitive impairments in mice resemble Δ9-THC and morphine effects: reversal by cannabinoid CB1 receptor antagonism
title_fullStr Mitragynine (Kratom)-induced cognitive impairments in mice resemble Δ9-THC and morphine effects: reversal by cannabinoid CB1 receptor antagonism
title_full_unstemmed Mitragynine (Kratom)-induced cognitive impairments in mice resemble Δ9-THC and morphine effects: reversal by cannabinoid CB1 receptor antagonism
title_sort mitragynine (kratom)-induced cognitive impairments in mice resemble δ9-thc and morphine effects: reversal by cannabinoid cb1 receptor antagonism
publisher Frontiers Media
publishDate 2021
url http://psasir.upm.edu.my/id/eprint/94208/
https://www.frontiersin.org/articles/10.3389/fphar.2021.708055/full
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score 13.211869

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