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Journal of Neuroscience, Vol 5, 1769-1780, Copyright © 1985 by Society for Neuroscience
Specific antagonism of enteric neural serotonin receptors by dipeptides of 5-hydroxytryptophan: evidence that serotonin is a mediator of slow synaptic excitation in the myenteric plexus
M Takaki, T Branchek, H Tamir and MD Gershon
Research on the role of serotonin (5-hydroxytryptamine, 5-HT) in the
function of the enteric nervous system has been impeded by the lack of
specific inhibitors of the enteric neural actions of 5-HT. Saturable,
reversible, high affinity enteric binding sites for 3H-5-HT have recently
been characterized and radioautographically located. Affinity for the
3H-5-HT binding site requires an indole ring substituted with a free
hydroxyl group. These 3H-5-HT binding sites have been proposed to be
enteric neural 5-HT receptors. This hypothesis was tested in the current
study by comparing the ability of compounds to inhibit the binding of
3H-5-HT with their electrophysiologically determined actions on myenteric
neurons. 5-Methoxytryptamine did not inhibit the binding of 3H-5-HT to
enteric membranes and neither mimicked nor antagonized the effects of 5-HT
on the membrane potential of myenteric neurons. Two dipeptides of
5-hydroxytryptophan, N-acetyl- and N-hexanoyl-5-
hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP and N-hex-5-HTP- DP)
inhibited the binding of 3H-5-HT (K1 = 0.25 microM for 5-HTP-DP and 1.19
microM for N-hex-5-HTP-DP). 5-HTP-DP applied by pressure microejection or
superfusion (10 microM) antagonized the slow postsynaptic depolarization of
myenteric neurons evoked by microejection of 5-HT. 5-HTP-DP also blocked
the 5-HT-induced presynaptic reduction in amplitude of nicotinic fast
synaptic potentials; however, 5-HTP-DP itself did not affect these
responses. Moreover, 5-HTP-DP also failed to affect responses of myenteric
neurons to microejected substance P, their muscarinic response to
acetylcholine, or antidromic action potentials. In contrast, both
dipeptides blocked the slow synaptic potentials seen in type II/AH neurons
following stimulation of fiber tracts in interganglionic connectives. These
data support the hypotheses that enteric 3H-5-HT binding sites are enteric
neural 5-HT receptors, that dipeptides of 5- hydroxytryptophan are specific
antagonists at these receptors, and that 5-HT is one of the mediators of
slow synaptic potentials in the myenteric plexus.
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