title: Effects of 5-HT1A receptor antagonists on hippocampal 5-hydroxytryptamine levels: (S)-WAY100135, but not WAY100635, has partial agonist properties.
abstract: 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-HT1A 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-HT1A receptors and for alpha 1-adrenoceptors. Both (S)-WAY100135 and WAY100635 exhibited high affinity for 5-HT1A receptors and moderate affinity for alpha 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-HT1A 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 ED50 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 alpha 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-HT1A receptors. In contrast, WAY100635 acts as a potent and selective 5-HT1A receptor antagonist.
authors.affiliation: Neurobiology Division II, Centre de Recherche Pierre Fabre, Castres, France.
authors.forename: M B
authors.initials: MB
authors.lastname: Assié
authors.forename: W
authors.initials: W
authors.lastname: Koek
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D006624:Hippocampus / Q000737:chemistry* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C081293:WAY 100135; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D011224:Prazosin