Mitragynine (Kratom) impairs spatial learning and hippocampal synaptic transmission in rats

Abstract

Background: Mitragynine is the major alkaloid of Mitragyna speciosa (Korth.) or Kratom, a psychoactive plant widely abused in Southeast Asia. While addictive effects of the substance are emerging, adverse cognitive effects of this drug and neuropharmacological actions are insufficiently understood. Aims: In the present study, we investigated the effects of mitragynine on spatial learning and synaptic transmission in the CA1 region of the hippocampus. Methods: Male Sprague Dawley rats received daily (for 12 days) training sessions in the Morris water maze, with each session followed by treatment either with mitragynine (1, 5, or 10 mg/kg; intraperitoneally), morphine (5 mg/kg; intraperitoneally) or a vehicle. In the second experiment, we recorded field excitatory postsynaptic potentials in the hippocampal CA1 area in anesthetized rats and assessed the effects of mitragynine on baseline synaptic transmission, paired-pulse facilitation, and long-term potentiation. Gene expression of major memory-and addiction-related genes was investigated and the effects of mitragynine on Ca 2+ influx was also examined in cultured primary neurons from E16-E18 rats. Results/outcomes: Escape latency results indicate that animals treated with mitragynine displayed a slower rate of acquisition as compared to their control counterparts. Further, mitragynine treatment significantly reduced the amplitude of baseline (i.e. non-potentiated) field excitatory postsynaptic potentials and resulted in a minor suppression of long-term potentiation in CA1. Bdnf and αCaMKII mRNA expressions in the brain were not affected and Ca 2+ influx elicited by glutamate application was inhibited in neurons pre-treated with mitragynine. Conclusions/interpretation: These data suggest that high doses of mitragynine (5 and 10 mg/kg) cause memory deficits, possibly via inhibition of Ca 2+ influx and disruption of hippocampal synaptic transmission and long-term potentiation induction.

Mitragynine Attenuates Morphine Withdrawal Effects in Rats—A Comparison With Methadone and Buprenorphine

“…Here we report that the main psychoactive alkaloid of the kratom plant, mitragynine, mitigates morphine withdrawal symptoms. Although preclinical studies have shown that mitragynine may have an abuse potential and adverse cognitive effects by itself (23,36,43,64), field studies have shown that these effects emerge usually at doses way higher than what humans voluntarily consume (65,66). In addition, we did not find negative effects of mitragynine substitution on hematological, biochemical, and tissue level in this study, which confirms field studies that report mild impairments even after long term chronic use (67,68).…”

“…Purified mitragynine was confirmed by high-performance liquid chromatography (HPLC) and proton nuclear magnetic resonance (1H-NMR) (400 MHz) analysis (35). Mitragynine obtained by this procedure was approximately 98% pure (36).…”

Acute mitragynine administration suppresses cortical oscillatory power and systems theta coherence in rats

“…We did not see a mitragynine-induced change in theta-gamma coupling between the HIP and cortical regions; however, disruption of cortical patterns may independently have potential negative impacts on cognitive processes such as learning and memory. Indeed, both mitragynine and morphine similarly impact on learning and memory processes with both drugs shown to impair both spatial and reversal learning in rodents (Apryani et al, 2010; Brolin et al, 2018; Hassan et al, 2019; Ismail et al, 2017; Lu et al, 2010; Yusoff et al, 2016). However, it is of importance that the present findings do not identify the mechanism by which the observed mitragynine-induced oscillatory changes occurred, which may be entirely independent of MOR activation, and distinct from morphine.…”

“…Similarly, chronic mitragynine administration in rodents has been reported to impair acquisition, consolidation and retrieval of passive avoidance learning (Yusoff et al, 2016), enhance punishment resistance during reward seeking and impair place learning (Ismail et al, 2017), as well as diminish working memory and reduce locomotor activity (Apryani et al, 2010). Mitragynine has also been shown to impair spatial learning in the Morris water maze (Hassan et al, 2019). Additionally, anxiety-like behaviours in rodents have been found to improve with acute mitragynine administration (Hazim et al, 2011, 2014) and antidepressant-like effects associated with mitragynine administration have been demonstrated in a murine model system of depression (Idayu et al, 2011).…”

Kratom instrumentalization for severe pain self-treatment resulting in addiction – A case report of acute and chronic subjective effects

“…It has only weak euphoric effects in the dose range humans voluntarily use ( Singh et al., 2019b ) and is not associated with neurological or psychiatric deficits and addiction development in the vast majority of regular users in Malaysia ( Singh et al., 2015 , 2018a ; 2018b ; Leong Bin Abdullah et al., 2019 ). However, in preclinical studies we showed that its main alkaloid mitragynine can at high doses have reinforcing effects and induce addiction-like behavior with adverse cognitive effects in rodents ( Yusoff et al., 2016 ; Ismail et al., 2017 ; Hassan et al., 2019 ). These effects are partly mediated by an opiate-like mechanism ( Stolt et al., 2014 ; Yusoff et al., 2017 ; Obeng et al., 2020 ), but may also involve other targets in the brain ( Yusoff et al., 2018 ; Hiranita et al., 2019 ).…”