Subunit-dependent inhibition of human neuronal nicotinic acetylcholine receptors and other ligand-gated ion channels by dissociative anesthetics ketamine and dizocilpine

Background The neuronal mechanisms responsible for dissociative anesthesia remain controversial. N-methyl-D-aspartate (NMDA) receptors are inhibited by ketamine and related drugs at concentrations lower than those required for anesthetic effects. Thus, the authors studied whether ligand-gated ion channels other than NMDA receptors might display a sensitivity to ketamine and dizocilpine that is consistent with concentrations required for anesthesia. Methods: Heteromeric human neuronal nicotinic acetylcholine receptors (hnAChR channels alpha(2)beta(2), alpha(2)beta(4), alpha(3)beta(2), alpha(3)beta(4), alpha(4)beta(2) and alpha(4)beta(4)), 5-hydroxytryptamine(3) (5-HT3), alpha(1)beta(2)gamma(2s) gamma-aminobutyric acid type A (GABA(A)) and alpha(1) glycine receptors were expressed in Xenopus oocytes, and effects of ketamine and dizocilpine were studied using the two-electrode voltage-clamp technique. Results: Both ketamine and dizocilpine inhibited hnAChRs in a noncompetitive and voltage-dependent manner. Receptors containing beta(4) subunits were more sensitive to ketamine and dizocilpine than those containing beta(2) subunits, The inhibitor concentration for half-maximal response (IC50) values for ketamine of hnAChRs composed of beta(4) subunits were 9.5-29 mu M, whereas those of beta(2) subunits were 50-92 mu M, Conversely, 5-HT3 receptors were inhibited only by concentrations of ketamine and dizocilpine higher than the anesthetic concentrations. This inhibition was mixed (competitive/noncompetitive). GABA, and glycine receptors were very resistant to dissociative anesthetics, Conclusions: Human nAChRs are inhibited by ketamine and dizocilpine at concentrations possibly achieved In vivo during anesthesia in a subunit-dependent manner, with beta subunits being more critical than alpha subunits, Conversely, 5-HT3, GABA(A), and glycine receptors were relatively insensitive to dissociative anesthetics.