INHIBITION OF 8-OH-DPAT-INDUCED ELEVATION OF PLASMA CORTICOTROPIN BY THE 5-HT1A RECEPTOR ANTAGONIST WAY100635

Numerous studies have demonstrated the stimulatory effect of 5-HT1A re ceptor agonists, such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH- DPAT), on plasma corticotrophin (ACTH) levels in the rat. However, unt il recently the lack of a selective 5-HT1A receptor antagonist has ham pered mechanistic studies in this area. In this study we examined the effects of the selective 5-HT1A receptor antagonist azinyl]ethyl]N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635) on plasm a ACTH levels and on the elevation of ACTH induced by the 5-HT1A recep tor agonist 8-OH-DPAT in the conscious rat. The basal plasma ACTH leve l was 41.0 +/- 1.8 pg/ml. 8-OH-DPAT increased ACTH levels at doses of 100 and 300 mu g/kg with maximum increases of 551 and 546% respectivel y occurring 10 min post-injection. WAY100635 had no effects per se on plasma ACTH at doses up to 100 mu g/kg, indicating it has no 5-HT1A re ceptor agonist properties. WAY100635 dose-dependently blocked the elev ation of ACTH induced by 8-OH-DPAT, the minimum effective dose being 1 0 mu g/kg. The present results indicate that 8-OH-DPAT elevates plasma ACTH levels by stimulating 5-HT1A receptors, a conclusion that is con sistent with the findings of previous studies using non-selective 5-HT 1A receptor antagonists such as pindolol.