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 b y ketamine and related drugs at concentrations lower than those required fo r anesthetic effects. Thus, the authors studied whether ligand-gated ion ch annels other than NMDA receptors might display a sensitivity to ketamine an d dizocilpine that is consistent with concentrations required for anesthesi a. Methods: Heteromeric human neuronal nicotinic acetylcholine receptors (hnAC hR 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 ket amine and dizocilpine were studied using the two-electrode voltage-clamp te chnique. Results: Both ketamine and dizocilpine inhibited hnAChRs in a noncompetitiv e and voltage-dependent manner. Receptors containing beta(4) subunits were more sensitive to ketamine and dizocilpine than those containing beta(2) su bunits, The inhibitor concentration for half-maximal response (IC50) values for ketamine of hnAChRs composed of beta(4) subunits were 9.5-29 mu M, whe reas those of beta(2) subunits were 50-92 mu M, Conversely, 5-HT3 receptors were inhibited only by concentrations of ketamine and dizocilpine higher t han the anesthetic concentrations. This inhibition was mixed (competitive/n oncompetitive). GABA, and glycine receptors were very resistant to dissocia tive anesthetics, Conclusions: Human nAChRs are inhibited by ketamine and dizocilpine at conc entrations possibly achieved In vivo during anesthesia in a subunit-depende nt manner, with beta subunits being more critical than alpha subunits, Conv ersely, 5-HT3, GABA(A), and glycine receptors were relatively insensitive t o dissociative anesthetics.