Effects of 5-HT 1A receptor antagonists on hippocampal 5-hydroxytryptamine levels: ( S)-WAY100135, but not WAY100635, has partial agonist properties

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In vivo microdialysis measuring 5-hydroxytryptamine (5-HT) levels in the ventral hippocampus of chloral hydrate-anaesthetised rats was used to characterise further the recently described 5-HT 1A receptor antagonists ( S)-WAY100135 (( S)- N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide) and WAY100635 ( N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridinyl)cyclohexanecarboxamide). In addition, binding experiments were performed to determine the affinity of the compounds for 5-HT 1A receptors and for α 1-adrenoceptors. Both ( S)-WAY100135 and WAY100635 exhibited high affinity for 5-HT 1A receptors and moderate affinity for α 1-adrenoceptors. The effects of ( S)-WAY100135 (0.63–20 mg/kg) and of WAY100635 (0.0025–0.16 mg/kg) on 5-HT levels were examined alone, and in combination with the 5-HT 1A receptor agonist, (±)-8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT). Both compounds dose-dependently reversed 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 given alone, WAY100635 did not alter 5-HT levels. ( S)-WAY100135, however, induced, by itself, a transient but significant and dose-dependent decrease 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 α 1-adrenoceptor antagonist, prazosin (0.16 mg/kg). These results are further evidence that ( S)-WAY100135 may modulate the release of 5-HT by acting as a partial agonist at somatodendritic 5-HT 1A receptors. In contrast, WAY100635 acts as a potent and selective 5-HT 1A receptor antagonist.