RT Journal Article SR Electronic T1 Dose-Dependent EEG Effects of Zolpidem Provide Evidence for GABAA Receptor Subtype Selectivity in Vivo JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1251 OP 1257 DO 10.1124/jpet.102.044859 VO 304 IS 3 A1 S. A. G. Visser A1 F. L. C. Wolters A1 P. H. van der Graaf A1 L. A. Peletier A1 M. Danhof YR 2003 UL http://jpet.aspetjournals.org/content/304/3/1251.abstract AB Zolpidem is a nonbenzodiazepine GABAA receptor modulator that binds in vitro with high affinity to GABAA receptors expressing α1 subunits but with relatively low affinity to receptors expressing α2, α3, and α5 subunits. In the present study, it was investigated whether this subtype selectivity could be detected and quantified in vivo. Three doses (1.25, 5, and 25 mg) of zolpidem were administered to rats in an intravenous infusion over 5 min. The time course of the plasma concentrations was determined in conjunction with the change in the β-frequency range of the EEG as pharmacodynamic endpoint. The concentration-effect relationship of the three doses showed a dose-dependent maximum effect and a dose-dependent potency. The data were analyzed for one- or two-site binding using two pharmacodynamic models based on 1) the descriptive model and 2) a novel mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for GABAAreceptor modulators that aims to separates drug- and system-specific properties, thereby allowing the estimation of in vivo affinity and efficacy. The application of two-site models significantly improved the fits compared with one-site models. Furthermore, in contrast to the descriptive model, the mechanism-based PK/PD model yielded dose-independent estimates for affinity (97 ± 40 and 33,100 ± 14,800 ng · ml−1). In conclusion, the mechanism-based PK/PD model is able to describe and explain the observed dose-dependent EEG effects of zolpidem and suggests the subtype selectivity of zolpidem in vivo. The American Society for Pharmacology and Experimental Therapeutics