Agonist properties of pindolol at h5-HT 1A receptors coupled to mitogen-activated protein kinase

Abstract

At h5-HT 1A receptors, stably transfected into Chinese Hamster Ovary Cells (CHO-h5-HT 1A), the selective 5-HT 1A receptor agonist, (+)8-hydroxy-dipropyl-amino-tetralin, ((+)8-OH-DPAT), transiently activated mitogen-activated protein kinase (MAPK) with a pEC 50 of 8.5. The arylalkylamine, (−)-pindolol, also behaved as an agonist with a maximal effect of 57% relative to (+)8-OH-DPAT (100%), and with a pEC 50 of 7.2. The selective 5-HT 1A receptor antagonist, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}- N-(2-pyridinyl)cyclo-hexane carboxamide (WAY100,635), blocked (+)8-OH-DPAT- and (−)-pindolol-induced MAPK activation with p K Bs of 9.7 and 9.9, respectively, whereas the selective 5-HT 1B receptor antagonist, 1′-Methyl-5-[2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-ylcarbonyl]-2,3,6,7-tetrahydro-5 H-spiro[furo[2,3-f]indole-3,4′-piperidine] (SB224,289) was inactive. Pertussis toxin blocked the actions of (+)8-OH-DPAT and (−)-pindolol demonstrating implication of G i/G o proteins. Thus, stimulation of MAPK provides an intracellular marker and signal for expression of the agonist actions of (−)-pindolol at h5-HT 1A receptors.