Agonist properties of pindolol at h5-HT1A receptors coupled to mitogen-activated protein kinase

At h5-HT1A receptors, stably transfected into Chinese Hamster Ovary Cells ( CHO-hS-HT1A), the selective 5-HT1A receptor agonist, (+)8-hydroxy-dipropyl- amino-tetralin, ((+)8-OH-DPAT), transiently activated mitogen-activated pro tein kinase NAM with a pEC(50) of 8.5. The arylalkylamine, (-)-pindolol, al so behaved as an agonist with a maximal effect of 57% relative to (+)8-OH-D PAT (100%), and with a pEC(50) of 7.2. The selective 5-HT1A receptor antago nist, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohe xane carboxamide (WAY100,635), blocked (+)8-OH-DPAT- and (-)-pindolol-induc ed MAPK activation with pK(B)s of 9.7 and 9.9, respectively, whereas the se lective 5-HT1B receptor antagonist, 1 ' -Methyl-5-[2 ' -methyl-4 '-(5-methy l-1,2,4-oxadiazol-3-yl)biphenyl-4-ylcarbonyl]-2,3,6,7-tetrahydro-5H-spiro[f uro[2,3-f]indole-3,4 ' -piperidine] (SB224,289) was inactive. Pertussis tox in blocked the actions of (+)8-OH-DPAT and (-)-pindolol demonstrating impli cation of G(i)/G(o) proteins. Thus, stimulation of MAPK provides an intrace llular marker and signal for expression of the agonist actions of (-)-pindo lol at h5-HT1A receptors. (C) 2001 Published by Elsevier Science B.V.