Hinokinin Decreases Methamphetamine-Induced Hyperlocomotion via the Regulatory Effects on Dopamine Levels

The global abuse of stimulant methamphetamine (METH) imposes a significant social burden. Despite this, effective therapeutic interventions for mitigating the harmful effects associated with METH-induced central nervous system (CNS) stimulation remain elusive. Chamaecyparis obtusa (hinoki), containing hinokinin as its active constituent, has been identified to exhibit CNS depressant properties. Here, we explored the potential of the hinoki extract and hinokinin in modulating METH-induced hyperlocomotion through the regulation of dopaminergic neuronal activity. We discovered that pretreatment with hinokinin significantly attenuates METH-induced locomotor activity, indicative of reduced CNS stimulation. Furthermore, treatment with hinokinin was observed to inhibit the METH-induced elevation in dopamine levels and the concomitant decrease in dopamine transporter (DAT) function within striatal brain slices of mice. In silico analysis coupled with pull-down assays and the dose-response curve substantiated the direct binding of hinokinin to DAT. We propose that hinokinin mitigates METH-induced hyperlocomotion via the inhibition of dopaminergic neurotransmission, with allosteric modulation of DAT playing a critical role in this regulatory mechanism. Collectively, our research suggests the potential of hinokinin to mitigate dopamine-mediated central nervous system excitation.