Mitragynine (Kratom)-Induced Cognitive Impairments in Mice Resemble Δ9-THC and Morphine Effects: Reversal by Cannabinoid CB1 Receptor Antagonism.

Ismail Nurul Iman,Zurina Hassan,Nurul Aiman Mohd Yusof,Ummi Nasrah Talib,Anwar Norazit,Mustapha Muzaimi,Christian P Müller,Jaya Kumar,Muhammad Zulfadli Mehat,Nur Aimi Zawami Ahmad

doi:10.3389/fphar.2021.708055

Abstract

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.

Highlights

Kratom (Mitragyna speciosa Korth) is a native plant to the Philippine islands, New Guinea, and Southeast Asia, predominantly Malaysia, Thailand, and Indonesia
The mice in the high-dose mitragynine group showed a similar preference for sucrose reward as those in the morphine and THC groups (p 0.9857 vs morphine, p 0.9979 vs THC), which may suggest comparable reward-seeking traits associated with prolonged high-dose mitragynine administration
The data of the present study demonstrate that high-dose mitragynine can induce spatial/place learning deficits in mice that resemble those of morphine and THC

Summary

Introduction

Kratom (Mitragyna speciosa Korth) is a native plant to the Philippine islands, New Guinea, and Southeast Asia, predominantly Malaysia, Thailand, and Indonesia. It is recognized as a local medicinal plant because of its antinociceptive and psychostimulant effects (Jansen and Prast, 1988; Hassan et al, 2013; Raffa, 2014). The majority of long-term kratom users (over three-quarters) report developing dependence and an inability to cease its use, mainly due to its unpleasant withdrawal symptoms (Suwanlert, 1975; Boyer et al, 2008; Vicknasingam et al, 2010; Ahmad and Aziz, 2012; Saingam et al, 2013; Grundmann, 2017; Singh et al, 2019). The United States Drug and Enforcement Administration and Food and Drug Administration remain vigilant in considering to place kratom into Schedule I of the Controlled Substances Act (Henningfield et al, 2018)

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