Tetrahydroberberine inhibits acetylcholine-induced K⁺ current in acutely dissociated rat hippocampal CA1 pyramidal neurons

The effects of a novel chemical type of dopamine receptor antagonist, the tetrahydroprotoberberine analogs (THPBs), on acetylcholine (ACh)-induced current were studied in freshly dissociated pyramidal neurons from rat hippocampal CA1 area using the nystatin perforated patch-clamp recording technique. Under voltage clamp conditions, the ACh-induced outward current (I(ACh)) is sensitive to the muscarinic receptor antagonist, atropine and the K⁺ channel blocker, TEA. The reversal potential of I(ACh) (-84.1 ± 0.8 mV) is close to the K⁺ equilibrium potential, indicating that the I(ACh) is mediated by a muscarinic receptor, and is carried mainly by K⁺. Tetrahydroberberine (THB) markedly reduced the I(ACh) while its chemical analogs, l-stepholidine (l-SPD) or l-tetrahydropalmatine (l-THP), had little effect on the I(ACh). The half-maximal inhibitory concentration (IC₅₀) of THB was 1.3 x 10^-5 M for a 10^-5 M ACh-induced I(ACh). THB suppressed the maximum of the ACh concentration-response curve without shifting the Hill coefficient, indicating a non-competitive inhibition. It is concluded that THB non-competitively inhibits the ACh-induced K⁺ current in a concentration-dependent manner, and that this inhibitory effect provides further evidence that THB plays its pharmacological roles in the central nervous system by effects other than through blockade of dopamine receptors.