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

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.

Adolescent kratom exposure affects cognitive behaviours and brain metabolite profiles in Sprague-Dawley rats

“…In the MWM task, mitragynine was shown to impair spatial learning but not reference memory ( Hassan et al, 2019 ). A recent study also showed that chronic escalating high doses of mitragynine led to the impairment of place learning and its reversal using the IntelliCage ® system ( Iman et al, 2021 ). Electrophysiological study also indicated that mitragynine can cause a disruption in hippocampal synaptic transmission and inhibition of LTP induction ( Hassan et al, 2019 ).…”

IntelliCage: the development and perspectives of a mouse- and user-friendly automated behavioral test system

“…Taken together, the diversity of scientific fields which have profited from the use of IntelliCage underscores the versatility of the system. We present a selection of papers according to clinical criteria in Table 1 and draw attention to useful reviews and discussions of the system using other criteria ( Kiryk et al, 2020 ; Iman et al, 2021a ; Varholick et al, 2021 ).…”

“…Given the high number of divergent IntelliCage papers and topics, we will refrain from discussing them further and we will focus on selected studies showing interesting directions. Readers interested in how the IntelliCage compares to the increasing number of home-cage-based testing systems can find tabulated comparisons ( Kiryk et al, 2020 ; Mingrone et al, 2020 ; Voikar and Gaburro, 2020 ; Iman et al, 2021a ; Coulibaly, 2022 ; Kahnau et al, 2023b ).…”

Goofballing of Opioid and Methamphetamine: The Science Behind the Deadly Cocktail

“…Behavior parameters established using various models of abuse under controlled environmental and drug administration regimens mimic the psychological status of humans in the presence or absence of substances depending on the animal models ( Kumar et al, 2013 ; Kumar et al, 2016 ; Iman et al, 2021 ). Likewise, in opioid dependence animal models, depressive-like behaviors are significant at 1 week after prolonged withdrawal where experiments showed that there was a decreasing level of social interaction and elevation in immobility time which reflects a state of lowered mood or depression-like behavior ( Anraku et al, 2001 ).…”

“…Apart from that, another prominent withdrawal symptom that accompanies abstinence is impulsive behavior, which encapsulate poor inhibitory response control (impulsive action) and impulsive decision making (impulsive choice) where observations suggest that the opioid system plays a significant role in decision making ( Pattij et al, 2009 ). Morphine exposure also increases motor impulsivity in animal models ( Kieres et al, 2004 ; Colin et al, 2012; Moazen et al, 2018 ), as well as deficits in learning and memory ( Iman et al, 2021 ).…”