Langer et al. reply

This important field of modulation of transmitter release is one of growing physiological and pharmacological importance. The earliest observations date back to the late 1960s ([36xLoffelholz, K. and Muscholl, E. Naunyn-Schmiedeberg's Arch. Pharmacol. 1969; 265: 1–15Crossref | PubMed | Scopus (102)See all References[36]) and Raiteri's group has made important contributions in this area[37xRaiteri, M., Maura, G., and Versace, P. J. Pharmacol. Exp. Ther. 1983; 224: 679–684PubMedSee all References, 38xPittaluga, A. and Raiteri, M. Eur. J. Pharmacol. 1990; 191: 231–234Crossref | PubMed | Scopus (88)See all References, 39xBonanno, G., Gemignani, A., Fedele, E., Fontana, G., and Raiteri, M. J. Pharmacol. Exp. Ther. 1991; 259: 1153–1159PubMedSee all References, 40xMaura, G. and Raiteri, M. Eur. J. Pharmacol. 1986; 129: 333–337Crossref | PubMed | Scopus (165)See all References].The example of sumatriptan, an agonist at presynaptic 5-HT1D heteroreceptors, inhibiting the release of neuropeptides like substance P and calcitonin gene-regulated peptide (CGRP), which are involved in neurogenic inflammation[41xArvieu, L. et al. NeuroReport. 1996; 7: 1973–1976Crossref | PubMedSee all References[41], is an excellent choice as an example of an effective, marketed drug acting as an agonist on presynaptic release modulating heteroreceptors. However, sumatriptan also has postsynaptic effects on vascular smooth muscle.Many publications show convincingly the existence of terminal presynaptic 5-HT1D inhibitory autoreceptors on 5-HT nerve terminals[42xEl-Mansari, M. and Blier, P. Br. J. Pharmacol. 1996; 118: 681–689Crossref | PubMedSee all References, 43xMaura, G. et al. J. Neurochem. 1993; 60: 1179–1182Crossref | PubMedSee all References, 44xWilkinson, L.O. et al. Neuropharmacology. 1993; 32: 205–208Crossref | PubMed | Scopus (7)See all References, 45xO'Connor, J.J. and Kruk, Z.L. Br. J. Pharmacol. 1992; 106: 524–532Crossref | PubMedSee all References, 46xSleight, A.J., Cervenka, A., and Peroutka, S.J. Neuropharmacology. 1990; 29: 511–513Crossref | PubMed | Scopus (51)See all References], which modulate 5-HT release through a negative feed-back mechanism similar to that described for noradrenaline, dopamine, acetylcholine and GABA. Why accept the presence of presynaptic release- modulating heteroreceptors and at the same time challenge the presynaptic 5-HT1D terminal autoreceptor that regulates 5-HT release?In conclusion, the presence of presynaptic, release-modulating heteroreceptors and autoreceptors is supported by a wealth of experimental evidence. Significant therapeutic advances have been made on the basis of the concept of presynaptic heteroreceptors in the treatment of migraine (cf. sumatriptan), presynaptic hetero- and autoreceptors in the treatment of depression (cf. mirtazapine), and presynaptic autoreceptors in the treatment of schizophrenia (cf. amisulpride). Given the physiological, and presumably pathological, importance of presynaptic modulation of neurotransmitter release and the large variety of hetero- and autoreceptors presently known, the number of thera- peutic applications that rely on this concept is likely to increase significantly. In other words: `presynaptic receptors, perhaps more hetero than auto, but both alive and kicking'.