Abstract: AimTo explore the modulation of 5-HT on GABA-activated current (I_GABA) in the membrane of rat dorsal root ganglion (DRG) neurons and its mechanism. MethodsRat DRG neurons were isolated mechanically and enzymatically, on which whole-cell patch clamp recording and repatch technique for intracellular dialysis were performed. ResultsIn the majority of neurons examined (92.0%, 69/75) GABA induced a concentration-dependent inward current. In neurons sensitive to GABA preapplication of 5-HT produced potentiation effect (82.6%, 57/69) on I_GABA. Preapplication of 5-HT at concentrations of 1×10^-6, 1×10^-5, 1×10^-4 and 1×10^-3 mol·L^-1 potentiated I_GABA by (35±8)% (n=8), (47±11)% (n=10), (65±17)% (n=9) and (75±18)% (n=11), respectively. This effect was mimicked by α-methyl-5-HT (1×10^-6 mol·L^-1), a specific 5-HT₂ receptor agonist, and reversed by cyproheptadine, a selective 5-HT₂ receptor antagonist. The potentiation of I_GABA by 5-HT was irrespective to whether the I_5-HT presents or not in a subset of neurons. The concentration-response curves for GABA before and after pretreatment with 5-HT manifested the same threshold value and similar EC₅₀ (2.0×10^-5 and 1.9×10^-5 mol·L^-1, respectively), while the maximal value of I_GABA for the latter was 33.6% higher than that for the former. Intracellular dialysis with GDP-β-S or H-7 abolished the potentiation of I_GABA by 5-HT, while H-9 did not. Conclusion5-HT can potentiate GABA-activated current via PKC-dependent phosphorylation of GABA_A receptor following the activation of 5-HT₂ receptor.