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

• 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/
• Institution: Universiti Malaya

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.