Droperidol inhibits GABA(A) 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 alpha1beta1gamma2 receptor, alpha7 and alpha4beta2 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 microm 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 microm) 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 alpha7 nAChR is also inhibited by droperidol, with an IC50 of 5.8 +/- 0.53 microm. The Hill coefficient is 0.95 +/- 0.1. Inhibition is noncompetitive, and membrane voltage dependence is insignificant.


CONCLUSIONS
Droperidol inhibits activation of both the GABAA alpha1beta1gamma2 and alpha7 nAChR. The submaximal GABA inhibition occurs within a concentration range such that it might be responsible for the anxiety, dysphoria, and restlessness that limit the clinical utility of high-dose droperidol anesthesia. Inhibition of the alpha7 nAChR might be responsible for the anesthetic action of droperidol.
Flood
Pamela
P
Department of Anesthesiology, Columbia University, New York, New York 10032, USA. pdf3@columbia.edu
Coates
Kristen M
KM
D000759:Adjuvants, Anesthesia / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004329:Droperidol / Q000494:pharmacology*; D005260:Female; D058787:GABA-A Receptor Antagonists; D009474:Neurons / Q000187:drug effects*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D014982:Xenopus laevis
D000759:Adjuvants, Anesthesia; D058787:GABA-A Receptor Antagonists; D018733:Nicotinic Antagonists; D004329:Droperidol