Tenuifolin Attenuates Methamphetamine-Induced Reinstatement in Mice by Regulating Hippocampal Postsynaptic BDNF Signaling.

BACKGROUND

Compulsive relapse (reinstatement) behavior of methamphetamine underlies the difficulty of withdrawal and is associated with abnormal BDNF-mediated synaptic plasticity. However, how to intervene in this aberrant synaptic plasticity to prevent its reinstatement behavior in mice has not fully been studied.

METHODS

The CPP was used to establish a model of methamphetamine-induced reinstatement behavior in C57BL/6 mice. Intraperitoneal injections of TEN were administered during the remission phase after the successful establishment of the CPP model to investigate the therapeutic effects on reinstatement. Immunofluorescence experiments were used to detect c-fos expression in hippocampal CA1 neurons. Electrophysiological methods were used to determine glutamatergic transmission in hippocampal CA1 neural circuits. Western blotting was used to detect BDNF/TrKB and PSD-95 protein expressions. Molecular docking was used to predict TEN molecule-protein binding.

RESULTS

Compared with control mice, METH-treated mice presented increased CPP scores during the reinstatement phase, whereas, compared to METH-treated mice, TEN-treated mice presented significantly lower CPP scores. Immunofluorescence experiments indicated that TEN was able to inhibit the METH-induced increase in c-fos content. In addition, we found that TEN alleviates the METH-triggered increase in glutamatergic transmission in mouse hippocampal CA1 neurons. Importantly, molecular docking studies demonstrated that TEN binds with BDNF, which may be important targets for its biological function. We also demonstrated that interfering with BDNF inhibits the therapeutic effect of TEN on the reinstatement of METH addiction.

CONCLUSION

Our findings suggest that TEN treats METH-induced reinstatement behavior by binding to BDNF, which may provide a novel target for treating relapse in patients addicted to METH.