Physiological responses of guinea-pig myenteric neurons secondary to the release of endogenous serotonin by tryptamine

Abstract

Intracellular recordings showed that administration of pulses of tryptamine mimicked one of the actions of serotonin (a slow depolarization associated with an increased input resistance) on type II/AH neurons of the myenteric plexus. After superfusion at high concentration tryptamine initially acted like serotonin, but then blocked the action of serotonin on these cells. Measurements of the release of preloaded [ 3H]serotonin or [ 3H]norepinephrine revealed that tryptamine is a potent releaser of these labeled amines; this release is Ca 2+ independent but temperature dependent. Moreover, incubation with tryptamine depleted the myenteric plexus of endogenous serotonin. Since tryptamine has previously been demonstrated not to inhibit the binding of [ 3H]serotonin to its enteric neural receptor we framed the hypothesis that the serotonin-releasing action of tryptamine is responsible for its ability to mimic serotonin when given in pulses or to desensitize serotonin receptors through the prolonged release of serotonin when it is superfused. This hypothesis was tested by examining the action of tryptamine on the serotonin-mediated slow excitatory postsynaptic potentials evoked in type II/AH neurons by fiber tract stimulation. Tryptamine superfusion antagonized these slow potentials as predicted. Moreover, after a long time when endogenous serotonin was depleted, the response of type II/AH neurons to exogenous serotonin recovered but the slow synaptic potential did not. The action of tryptamine on this neuron was relatively specific. When the slow synaptic potential and serotonin responses were blocked by tryptamine the type II/AH neurons still responded to acetylcholine. Fast excitatory postsynaptic potentials were not affected by tryptamine. Furthermore, other types of neurons (I/S) and other neuronal responses to serotonin (such as a fast depolarization with decreased input resistance or presynaptic inhibition of acetylcholine release) were not blocked by tryptamine. Finally, radioautographic studies revealed a neural uptake of tryptamine in the chemically sympathectomized myenteric plexus; however, the distribution of tryptamine in the plexus was different from that of serotonin and was not blocked by excess non-radioactive serotonin. Therefore tryptamine does not enter myenteric neurons via the specific serotonin uptake mechanism; however, zimelidine, found to be a selective inhibitor of the enteric uptake of serotonin, antagonized the release of serotonin by tryptamine and attenuated the effect of tryptamine on responses to serotonin. It was hypothesized that zimelidine might inhibit the outward transport of serotonin, displaced by tryptamine from synaptic vesicles. It is concluded that tryptamine releases physiologically active serotonin. Tryptamine should therefore prove to be a useful tool for studying actions of serotonin. Moreover, interactions with serotonergic (and noradrenergic) neurons will have to be considered in the future in interpreting experiments on the action of tryptamine.