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. <i>Chamaecyparis obtusa</i> (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.