AGONIST RESPONSES OF NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTORS ARE POTENTIATED BY A NOVEL CLASS OF ALLOSTERICALLY ACTING LIGANDS

Similar to the gamma-aminobutyric acid(A) receptor and the N-methyl-D- aspartate subtype of glutamate receptor, neuronal nicotinic acetylchol ine receptors are subject to positive modulatory control by allosteric ally acting ligands. Exogenous ligands such as galanthamine and the ne urotransmitter 5-hydroxytryptamine, when applied in submicromolar conc entrations with nicotinic agonists, significantly increase the frequen cy of opening of nicotinic receptor channels and potentiate agonist-ac tivated currents. Because these effects have been shown to be blocked by the monoclonal antibody FK1, they are mediated by binding sites tha t are located on alpha subunits of nicotinic receptors and distinct fr om those for acetylcholine and acetylcholine-competitive ligands. At h igher concentrations, the potentiating effect of these ligands decreas es and is eventually overcome by an inhibition of the agonist-induced response. The sensitizing actions of galanthamine, 5-hydroxytryptamine , and related compounds, at submicromolar concentrations, may reflect the existence of cross-talk between adjacent neuroreceptors and synaps es in the central nervous system and thus suggests the formation of tr ansiently active chemical networks in the vertebrate brain.