Numerous studies have demonstrated the stimulatory effect of 5-HT1A receptor agonists, such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on plasma corticotrophin (ACTH) levels in the rat. However, until recently the lack of a selective 5-HT1A receptor antagonist has hampered mechanistic studies in this area. In this study we examined the effects of the selective 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1- piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY100635) on plasma ACTH levels and on the elevation of ACTH induced by the 5-HT1A receptor agonist 8-OH-DPAT in the conscious rat. The basal plasma ACTH level was 41.0 +/- 1.8 pg/ml. 8-OH-DPAT increased ACTH levels at doses of 100 and 300 micrograms/kg with maximum increases of 551 and 546% respectively occurring 10 min post-injection. WAY100635 had no effects per se on plasma ACTH at doses up to 100 micrograms/kg, indicating it has no 5-HT1A receptor agonist properties. WAY100635 dose-dependently blocked the elevation of ACTH induced by 8-OH-DPAT, the minimum effective dose being 10 micrograms/kg. The present results indicate that 8-OH-DPAT elevates plasma ACTH levels by stimulating 5-HT1A receptors, a conclusion that is consistent with the findings of previous studies using non-selective 5-HT1A receptor antagonists such as pindolol.