PRESYNAPTIC 5-HT AUTORECEPTORS AND HETERORECEPTORS IN THE HUMAN CENTRAL AND PERIPHERAL NERVOUS-SYSTEM

In view of the potential pathophysiological and therapeutic implicatio ns, presynaptic 5-HT auto- and heteroreceptors have been identified an d characterized in isolated human tissues and their functional role ha s been determined. Such investigations have been carried out in differ ent laboratories including that of the authors. Basic evidence for the involvement of inhibitory 5-HT receptors in modulation of 5-HT releas e in the cerebral cortex was obtained in slices: exogenous 5-HT inhibi ted 5-HT release in a manner susceptible to blockade by methiothepin, which given alone facilitated 5-HT release, probably by preventing end ogenous 5-HT from activating the inhibitory receptors. The latter rece ptors are located on the 5-HT nerve terminals themselves, since 5-HT ( and sumatriptan) also inhibited 5-HT release from cortical synaptosome s. Their pharmacological properties conform to those of the 5-HT1D cla ss. Subclassification (5-HT1D alpha or 5-HT1D beta) has been tried wit h ketanserin which has an at least 60 times higher affinity for 5-HT1D alpha (pk(i) = 7.1) than 5-HT1D beta receptors. Since ketanserin (0.3 2 mu M) did not affect the concentration-response curve for 5-carboxam idotryptamine (5-CT), the presynaptic 5-HT autoreceptor may belong to the 5-HT1D beta rather than the 5-HT1D alpha subtype. The sympathetic nerve terminals of the human saphenous vein are endowed with inhibitor y 5-HT heteroreceptors, as indicated by the potency ratio of several 5 -HT receptor agonists in inhibiting noradrenaline release in strips of this blood vessels and by the ability of methiothepin, but not of ket anserin 0.3 mu M, to act as an antagonist. Noradrenergic nerves in the dura mater, which probably innervate its microvasculature, may also b e endowed with inhibitory 5-HT receptors, since 5-HT inhibited noradre naline release from this tissue. In strips of atrial appendages, 5-HT receptor agonists (e.g. 5-HT, 5-CT and sumatriptan) inhibited noradren aline release at potencies which are correlated with their k(i) values at 5-HT1D alpha and 5-HT1D beta receptors. Since this inhibitory effe ct was antagonized by ketanserin (0.3 but not 0.03 mu M) and methiothe pin, the presynaptic 5-HT receptor in this tissue may belong to the 5- HT1D alpha subtype. However, this conclusion needs further confirmatio n by experiments with more potent and subtype-selective antagonists of 5-HT1D alpha and 5-HT1D beta receptors.