Presynaptic 5-HT auto- and heteroreceptors in the human central and peripheral nervous system.

In view of the potential pathophysiological and therapeutic implications, presynaptic 5-HT auto- and heteroreceptors have been identified and characterized in isolated human tissues and their functional role has been determined. Such investigations have been carried out in different laboratories including that of the authors. Basic evidence for the involvement of inhibitory 5-HT receptors in modulation of 5-HT release in the cerebral cortex was obtained in slices: exogenous 5-HT inhibited 5-HT release in a manner susceptible to blockade by methiothepin, which given alone facilitated 5-HT release, probably by preventing endogenous 5-HT from activating the inhibitory receptors. The latter receptors are located on the 5-HT nerve terminals themselves, since 5-HT (and sumatriptan) also inhibited 5-HT release from cortical synaptosomes. Their pharmacological properties conform to those of the 5-HT1D class. Subclassification (5-HT1D alpha or 5-HT1D beta) has been tried with ketanserin which has an at least 60 times higher affinity for 5-HT1D alpha (pki = 7.1) than 5-HT1D beta receptors. Since ketanserin (0.32 microM) did not affect the concentration-response curve for 5-carboxamidotryptamine (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 inhibitory 5-HT1D beta 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 ketanserin 0.3 microM, to act as an antagonist. Noradrenergic nerves in the dura mater, which probably innervate its microvasculature, may also be endowed with inhibitory 5-HT receptors, since 5-HT inhibited noradrenaline release from this tissue. In strips of atrial appendages, 5-HT receptor agonists (e.g. 5-HT, 5-CT and sumatriptan) inhibited noradrenaline release at potencies which are correlated with their ki values at 5-HT1D alpha and 5-HT1D beta receptors. Since this inhibitory effect was antagonized by ketanserin (0.3 but not 0.03 microM) and methiothepin, the presynaptic 5-HT receptor in this tissue may belong to the 5-HT1D alpha subtype. However, this conclusion needs further confirmation by experiments with more potent and subtype-selective antagonists of 5-HT1D alpha and 5-HT1D beta receptors.