title: Estimation of apparent pA2 values for WAY 100635 at 5-HT1A receptors regulating 5-hydroxytryptamine release in anaesthetised rats.
abstract: 5-HT1A receptor agonists decrease 5-hydroxytryptamine (5-HT) terminal release by activating somatodendritic 5-HT1A autoreceptors. The selective 5-HT1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY 100635) inhibits these effects of 5-HT1A receptor agonists. The present study was aimed at estimating apparent pA2 values for WAY 100635 to antagonise 5-HT1A receptor agonist-induced decrease in 5-HT release in rat hippocampus. Extracellular concentrations of 5-HT were measured in microdialysis samples after administration of cumulative doses of 5-HT1A receptor agonists with different intrinsic activity, alone or in the presence of increasing doses of WAY 100635. Administration of cumulative doses of (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.01-40 mg/kg), 1[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl)pipe razine (S 14506) (0.00063-2.5 mg/kg), or buspirone (0.16-40 mg/kg), dose-dependently decreased the extracellular concentrations of 5-HT in the ventral hippocampus. Pre-treatment with WAY 100635 (0.01-0.63 mg/kg) shifted the dose-response curve of each agonist to the right in a dose-dependent manner. WAY 100635 antagonised the effects of all three compounds in a competitive manner, with an estimated apparent in vivo pA2 value of 7.95 (95% confidence limits: 7.66-8.24). Taken together, the results are evidence that buspirone, S 14506 and 8-OH-DPAT, administered in cumulative doses, decreased 5-HT release by activating similar 5-HT1A receptors, because a common apparent pA2 value was obtained for WAY 100635. The results also show that orderly microdialysis data can be obtained using cumulative dosing, which enables one to collect dose-response data rapidly, with fewer animals.
authors: Neurobiology Division II, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81106 Cedex, Castres, France. marie.bernadette.assie@pierre-fabre.com
authors: M B
authors: MB
authors: Assié
authors: W
authors: W
authors: Koek
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002065:Buspirone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D001549:Benzamides; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C092824:1-((4-fluorobenzoylamino)ethyl)-4-(7-methoxy-1-naphthyl)piperazine hydrochloride; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D002065:Buspirone