Characterization of the serotonin1A receptor antagonist activity of WAY-100135 and spiperone.
The effects of the putative serotonin (5-HT)1A receptor antagonists WAY-100135 (WAY) and spiperone on the neuronal activity recorded from medullary and dorsal raphe 5-HT neurons and the inferior cardiac sympathetic nerve were investigated in chloralose anesthetized cats. We also determined the effectiveness of WAY and spiperone to antagonize the sympathoinhibitory effects of the 5-HT1A agonist 8-hydroxy-(2-di-n-propylamino)tetralin (8-OH DPAT). Intravenous administration of both WAY and spiperone produced a dose-related inhibition of the firing of medullary 5-HT neurons. WAY also inhibited firing of serotonergic neurons in the dorsal raphe nucleus. WAY treatment had no significant effect on inferior cardiac sympathetic nerve discharge (SND), whereas spiperone treatment caused a small, but significant, increase in SND. WAY treatment did not significantly affect 8-OH DPAT-induced inhibition of unit firing. Spiperone, however, did display antagonist activity at the presynaptic autoreceptor site. WAY and spiperone pretreatments resulted in significant rightward shifts in the 8-OH DPAT inhibition of SND dose-response curves and reversed the depressant effects of 8-OH DPAT. These results suggest that WAY and spiperone act as 5-HT1A antagonists postsynaptically, but WAY appears to have more potent agonist efficacy at the 5-HT1A presynaptic autoreceptor site in the cat. However, because all drugs were administered intravenously, conclusions regarding direct effects of WAY and spiperone on 5-HT1A receptors must be made cautiously.
Escandon
N A
NA
Upjohn Company, Kalamazoo, Michigan.
Zimmermann
D C
DC
McCall
R B
RB
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors; D000818:Animals; D002415:Cats; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D012702:Serotonin Antagonists; D013134:Spiperone / Q000494:pharmacology*
D010879:Piperazines; D012702:Serotonin Antagonists; C081293:WAY 100135; D013134:Spiperone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin