Abstract: Objective To investigate the effects of methamphetamine(Meth) on the transient outward K⁺ currents and its mechanisms.Methods Hippocampal neurons were harvested from 18-day-old embryonic rats and divided into control and Meth treated group.The currents were recorded with the whole cell patch clamp and the cell damage was detected by the TdT-mediated dUTP nick end labeling(TUNEL) assay.The mRNA expressions of Kv1.4,Kv4.1,Kv4.2,and Kv4.3 were evaluated by reverse transcription-PCR(RT-PCR).Furthermore,the expression of Kv4.2 was detected with western-blot after the treatment of Meth.Results Meth significantly increased the transient outward K⁺ currents(120.1±19.6 pA/pF,P<0.01)compared with the control group(87.4±12.5 pA/pF) and caused neuronal damage(control group:1.00±0.18 vs Meth treated group:7.11±0.95,P<0.01).However,4-aminopyridine(4-AP),the antagonist of the transient currents,substantially retarded the cell damage induced by Meth(4.96±1.32,P<0.01).Moreover,Kv4.2 might be the main contributor in transient currents.With western-blot assay,we observed that Meth up-regulated the Kv4.2 expression and the expressions of Kchip2/3,Kchip4,and CaMK2,which were closely associated with the expression of Kv4.2,were also up-regulated.Conclusion The up-regulation of Kv4.2 might be involved in Meth induced transient outward K⁺ current increments,however,the mechanisms still need to be clarified.