In vivo estimates of efficacy at 5-HT1A receptors: effects of EEDQ on the ability of agonists to produce lower-lip retraction in rats

Rationale: Maximal responses are often used as a measure of intrinsic activ ity or efficacy, but cannot be directly equated to efficacy. Using irrevers ible antagonists, estimates of efficacy can be obtained that may be less de pendent on specific conditions. Objectives: To characterize the intrinsic a ctivity of serotonin (5-HT)(1A) agonists by examining the effects of an irr eversible antagonist on their ability to produce 5-HT1A receptor-mediated r esponses. Methods: The effects of N-ethoxycarbonyl-2-ethoxy-1.2-dihydroquin oline (EEDQ) on the ability of 5-HT1A agonists to produce lower-lip retract ion (LLR) in rats were studied. Results: In the absence of EEDQ, each 5-HT1 A agonist produced full effects, the rank order of potency being: S 14506 > 8-OH-DPAT > buspirone > ipsapirone. EEDQ decreased the number of 5-HT1A bi nding sites and shifted the dose-response curves (DRCs) of each agonist eit her to the right or, at higher EEDQ doses, to the right and downward. The m anner in which these shifts occurred, however, differed among the compounds . For each agonist, all DRCs obtained after different doses of EEDQ were fi tted to models proposed by Furchgott and Black and Leff, and the results in dicated the following rank order of efficacy: ipsapirone < buspirone = 8-OH -DPAT < S 14506. 5-HT1A agonist-induced LLR appears to be mediated by 5-HT1 A receptors, because the 5-HT1A antagonist, WAY 100635, shifted the agonist DRCs to the right in a parallel and dose-related manner, with pA(2) values ranging from 7.8 to 8.1. Moreover, pretreatment with WAY 100635 protected against the antagonist activity of EEDQ. Conclusions: The results suggest t hat the effects of EEDQ on the ability of 5-HT1A agonists to produce LLR in rats may be useful to obtain estimates of their apparent efficacy at 5-HT1 A receptors.