Effects of the selective 5-HT 1A receptor antagonist WAY100135 and its enantiomers on 8-OH-DPAT-induced hyperglycaemia in conscious rats

Abstract

8-Hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT) increases plasma glucose levels in conscious rats probably by stimulation of central 5-HT 1 receptors. We have examined the effects of WAY100135 ( N-tert-butyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2- phenylpropanamide), a selective 5-HT 1A receptor antagonist and its enantiomers on plasma glucose levels and on the hyperglycaemia induced by 8-OH-DPAT. ( R, S)-WAY100135 (minimum effective dose (MED) 3 mg/kg i.v.) and ( S)-WAY100135 (MED 1 mg/kg i.v.) dose-dependently attenuated 8-OH-DPAT-induced hyperglycaemia. In contrast, ( R)-WAY100135 at doses up to 3 mg/kg i.v. was unable to block hyperglycaemia induced by 8-OH-DPAT. When the antagonist were examined for intrinsic effects on plasma glucose levels only ( S)-WAY100135 (3 mg/kg i.v.) caused a significant but transient hyperglycaemia (20% increase). These results are consistent with previous suggestions that ( R, S)-WAY100135 and ( S)-WAY100135 are selective 5-HT 1A receptor antagonist and that 8-OH-DPAT-induced hyperglycaemia is mediated by 5-HT 1A receptors. The antagonist action of WAY100135 is stereoselective, the more potent activity being observed with the ( S) enantiomer.