Receptor-mediated regulation of 5-hydroxytryptamine metabolism: current knowledge and open questions.

As demonstrated for the catecholamine system several receptor-mediated mechanisms appear to be involved in the regulation of serotonergic transmission, though regulatory processes of serotonergic transmission are less well investigated as compared with the catecholamine system. One of the main homeostatic mechanisms appears to be neuronal feedback mediated by postsynaptic 5-HT receptors. The constituents of the neuronal feedback loop are unknown at present. In addition to neuronal feedback, an autoreceptor-mediated feedback appears to exist. According to their localization, 5-HT autoreceptors can be subdivided into somatodendritic and presynaptic autoreceptors. Stimulation of somatodendritic 5-HT receptors leads to inhibition of the firing rate, and stimulation of presynaptic autoreceptors in vitro to inhibition of impulse-induced release of 5-HT. Further to 5-HT receptors, other transmitter receptors appear to exist on presynaptic nerve terminals which may either inhibit or facilitate 5-HT release. The physiological significance of all these presynaptic receptors remains to be shown. The evaluation of feedback mechanisms controlling 5-HT neurons is hampered by the fact that no selective central 5-HT antagonists are available at present. There is an urgent need for selective receptor antagonists for 5-HT autoreceptors as well as postsynaptic receptors. Binding studies have revealed at least two subtypes of 5-HT receptors, 5-HT1 and 5-HT2 receptors. Selective 5-HT1 and 5-HT2 agonists and antagonists are needed in order to characterize these receptors subtypes and to find their functional correlates.