Serotonin discovery and stepwise disclosure of 5-HT receptor complexity over four decades. Part II. Some...

About 40% of the papers within the scientific oeuvre of Manfred Göthert (1939-2019) were dedicated to serotonin (5-hydroxytryptamine, 5-HT). He was not only the witness of the gradual definition of the fourteen 5-HT receptor subtypes but also was involved directly by identifying 5-HT_1B, 5-HT_1D and 5-HT₃ receptors. Moreover, he identified presynaptic 5-HT receptors on central and/or peripheral serotoninergic, noradrenergic and/or cholinergic neurones. Two inhibitory (5-HT_1B, 5-HT_1D) and two facilitatory (5-HT₃, 5-HT₄) receptors were found, the 5-HT_1B receptor representing a possible target for antidepressant drugs. Ten years earlier than electrophysiologists, he identified ligand-gated receptors like the 5-HT₃ and the nicotinic acetylcholine (nACh) receptor as targets of halothane. Simultaneously with, but independent of, other authors he found that ethanol allosterically inhibits N-methyl-D-aspartate (NMDA) receptors, which are affected at an even lower concentration than 5-HT₃ and nACh receptors. The latter two receptors were shown to be subject to allosteric inhibition also by cannabinoids via a mechanism unrelated to cannabinoid CB₁ or CB₂ receptors; cannabinoid inhibition of 5-HT₃ receptors may represent a new target for the treatment of neuropathic pain.