Estimation of apparent pA(2) values for WAY 100635 at 5-HT1A receptors regulating 5-hydroxytryptamine release in anaesthetised rats

5-HT1A receptor agonists decrease 5-hydroxytryptamine (5-HT) terminal relea se by activating somatodendritic 5-HT1A autoreceptors. The selective 5-HT1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-p yridinyl)cyclohexanecarboxamide (WAY 100635) inhibits these effects of 5-HT 1A receptor agonists. The present study was aimed at estimating apparent pA (2) values for WAY 100635 to antagonise 5-HT1A receptor agonist-induced dec rease in 5-HT release in rat hippocampus. Extracellular concentrations of 5 -HT were measured in microdialysis samples after administration of cumulati ve doses of 5-HT1A receptor agonists with different intrinsic activity, alo ne or in the presence of increasing doses of WAY 100635. Administration of cumulative doses of (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT ) (0.01-40 mg/kg), 1[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl)pip erazine (S 14506) (0.00063-2.5 mg/kg), or buspirone (0.16-40 mg/kg), dose-d ependently decreased the extracellular concentrations of 5-HT in the ventra l hippocampus. Pre-treatment with WAY 100635 (0.01-0.63 mg/kg) shifted the dose-response curve of each agonist to the right in a dose-dependent manner . WAY 100635 antagonised the effects of all three compounds in a competitiv e manner, with an estimated apparent in vivo pA(2) value of 7.95 (95% confi dence limits: 7.66-8.24). Taken together, the results are evidence that bus pirone, S 14506 and 8-OH-DPAT, administered in cumulative doses, decreased 5-HT release by activating similar 5-HT1A receptors, because a common appar ent pA(2) value was obtained for WAY 100635. The results also show that ord erly microdialysis data can be obtained using cumulative dosing, which enab les one to collect dose-response data rapidly, with fewer animals. (C) 2000 Elsevier Science B.V. All rights reserved.