Inhibition of the 5-HT 1A receptor-mediated inwardly rectifying K + current by dextromethorphan in rat dorsal raphe neurones

Abstract

The effect of dextromethorphan (DM) on the inwardly rectifying K + currents mediated by 5-HT 1A receptors in acutely dissociated dorsal raphe (DR) neurones of rats was studied using nystatin-perforated patch and conventional whole-cell patch recording configurations under voltage-clamp conditions. DM rapidly and reversibly inhibited the K + currents induced by 10 −7 M 5-HT in a concentration-dependent manner with a half-maximum inhibitory concentration of 1.43×10 −5 M. The inhibitory effect of DM was neither voltage- nor use-dependent. DM caused a suppression of the maximum response of the 5-HT concentration–response curve, thus suggesting a non-competitive type of inhibition. In neurones perfused intracellularly with a pipette-solution containing the nonhydrolyzable GTP analog GTPγS, 5-HT activated K + currents in an irreversible manner. DM suppressed the current irreversibly activated by intracellular GTPγS even in the absence of the agonist. DM also inhibited the inwardly rectifying K + currents regulated by α 2-adrenoceptors in freshly isolated rat locus coeruleus neurones. These results suggest that DM may inhibit the G-protein coupled inwardly rectifying K + channels, but not the neurotransmitter receptors, in the central nervous system.