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.