Droperidol Inhibits GABAA and Neuronal Nicotinic Receptor Activation

Background: Droperidol is used in neuroleptanesthesia and as an antiemetic. Although its antiemetic effect is thought to be caused by dopaminergic inhibition, the mechanism of droperidol's anesthetic action is unknown. Because [gamma]-aminobutyric acid type A (GABAA) and neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as putative targets of other general anesthetic drugs, the authors tested the ability of droperidol to modulate these receptors.

Methods: [gamma]-Aminobutyric acid type A [alpha]1[beta]1[gamma]2 receptor, [alpha]7 and [alpha]4[beta]2 nAChRs were expressed in Xenopus oocytes and studied with two-electrode voltage clamp recording. The authors tested the ability of droperidol at concentrations from 1 nm to 100 [mu]m to modulate activation of these receptors by their native agonists.

Results: Droperidol inhibited the GABA response by a maximum of 24.7 +/- 3.0%. The IC50 for inhibition was 12.6 +/- 0.47 nm droperidol. At high concentrations, droperidol (100 [mu]m) activates the GABAA receptor in the absence of GABA. Inhibition of the GABA response is significantly greater at hyperpolarized membrane potentials. The activation of the [alpha]7 nAChR is also inhibited by droperidol, with an IC50 of 5.8 +/- 0.53 [mu]m. The Hill coefficient is 0.95 +/- 0.1. Inhibition is noncompetitive, and membrane voltage dependence is insignificant.