In vivo estimates of efficacy at 5-HT_1A receptors: effects of EEDQ on the ability of agonists to produce lower-lip retraction in rats

Abstract 

Rationale: Maximal responses are often used as a measure of intrinsic activity or efficacy, but cannot be directly equated to efficacy. Using irreversible antagonists, estimates of efficacy can be obtained that may be less dependent on specific conditions. Objectives: To characterize the intrinsic activity of serotonin (5-HT)_1A agonists by examining the effects of an irreversible antagonist on their ability to produce 5-HT_1A receptor-mediated responses. Methods: The effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on the ability of 5-HT_1A agonists to produce lower-lip retraction (LLR) in rats were studied. Results: In the absence of EEDQ, each 5-HT_1A agonist produced full effects, the rank order of potency being: S 14506 > 8-OH-DPAT > buspirone > ipsapirone. EEDQ decreased the number of 5-HT_1A binding sites and shifted the dose–response curves (DRCs) of each agonist either to the right or, at higher EEDQ doses, to the right and downward. The manner in which these shifts occurred, however, differed among the compounds. For each agonist, all DRCs obtained after different doses of EEDQ were fitted to models proposed by Furchgott and Black and Leff, and the results indicated the following rank order of efficacy: ipsapirone < buspirone ≈ 8-OH-DPAT < S 14506. 5-HT_1A agonist-induced LLR appears to be mediated by 5-HT_1A receptors, because the 5-HT_1A antagonist, WAY 100635, shifted the agonist DRCs to the right in a parallel and dose-related manner, with pA₂ values ranging from 7.8 to 8.1. Moreover, pretreatment with WAY 100635 protected against the antagonist activity of EEDQ. Conclusions: The results suggest that the effects of EEDQ on the ability of 5-HT_1A agonists to produce LLR in rats may be useful to obtain estimates of their apparent efficacy at 5-HT_1A receptors.