EFFECTS OF 5-HT1A RECEPTOR ANTAGONISTS ON HIPPOCAMPAL 5-HYDROXYTRYPTAMINE LEVELS - (S)-WAY100135, BUT NOT WAY100635, HAS PARTIAL AGONIST PROPERTIES

In vivo microdialysis measuring 5-hydroxytryptamine (5-HT) levels in t he ventral hippocampus of chloral hydrate-anaesthetised rats was used to characterise further the recently described 5-HT1A receptor antagon ists (S)-WAY100135 (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine- 1-yl)-2-phenylpropanamide) and WAY100635 nyl]ethyl]-N-(2-pyridinyl)cyc lohexanecarboxamide). In addition, binding experiments were performed to determine the affinity of the compounds for 5-HT1A receptors and fo r alpha(1)-adrenoceptors. Both (S)-WAY100135 and WAY100635 exhibited h igh affinity for 5-HT1A receptors and moderate affinity for alpha(1)-a drenoceptors. The effects of(S)-WAY1OD135 (0.63-20 mg/kg) and of WAY10 0635 (0.0025-0.16 mg/kg) on 5-HT levels were examined alone, and in co mbination with the 5-HT1A receptor agonist, (+/-)-8-hydroxy-2-(di-n-pr opylamino)tetralin (8-OH-DPAT). Both compounds dose-dependently revers ed the 8-OH-DPAT-induced decrease in extracellular 5-HT levels with ED (50) values of approximately 3.3 and 0.03 mg/kg, respectively. When gi ven alone, WAY100635 did not alter 5-HT levels. (S)-WAY100135, however , induced, by itself, a transient but significant and dose-dependent d ecrease in 5-HT levels. WAY100635 (0.16 mg/kg) prevented the decrease induced by (S)-WAY100135 (10 mg/kg), but did not reverse the decrease induced by the alpha(1)-adrenoceptor antagonist, prazosin (0.16 mg/kg) . These results are further evidence that (S)-WAY100135 may modulate t he release of 5-HT by acting as a partial agonist at somatodendritic 5 -HT1A receptors. In contrast, WAY100635 acts as a potent and selective 5-HT1A receptor antagonist.