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Vol. 291, Issue 1, 374-382, October 1999
Department of Anatomy and Cell Biology, Columbia University, New
York, New York (J.Z., M.D.G., A.L.K.); and Center for Ulcer Research,
UCLA (J.H.W., H.C.W.), Los Angeles, California
The whole-cell patch-clamp technique was used to analyze the effects of
5-hydroxytryptamine (5-HT) and alosetron on cultured myenteric neurons
from newborn guinea pigs. All neurons responded to 5-HT
(EC50 ~ 38.7 µM) with a concentration-dependent
inward current (reversal potential = 7.1 ± 1.7 mV) with a
short latency and rapid decay. Because the 5-HT-induced inward current
was mimicked by 2-methyl-5-hydroxytryptamine (50 µM) and blocked by
ondansetron (5.0 µM) and MDL 72222 (0.05 µM), it was
5-HT3-mediated. Alosetron blocked
(IC50 ~ 0.05 µM; Hill coefficient ~ 1.24)
the 5-HT- and 2-methyl-5-hydroxytryptamine-induced inward currents.
This effect was independent of membrane potential and was not seen when
alosetron was delivered to the inside of cells. Alosetron-sensitive
sites are, thus, accessible only on the ectodomain of the plasmalemma. The effect of alosetron was reversible, but not surmountable. Although
nicotine (100 µM) mimicked the 5-HT-induced inward current, the
response was antagonized by hexamethonium (100 µM), but not by
alosetron, implying its potential to be a selective 5-HT3
antagonist. Hexamethonium did not affect responses to 5-HT. Most
neurons in the cultures were 5-HT-immunoreactive and immunostained with
an antibody raised against 5-HT3 receptors. The
5-HT-selective uptake inhibitor, fluoxetine (30 µM), gradually
reduced the amplitude of the current induced by 5-HT; the residual
response was abolished by alosetron (0.2 µM). The effect of
fluoxetine could have been caused by either the desensitization of
5-HT3 receptors or by a nonspecific 5-HT3
antagonistic effect of fluoxetine. It is concluded that alosetron is a
potent and noncompetitive 5-HT3 antagonist on myenteric neurons.
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