Modulation of the function of presynaptic α7 and non-α7 nicotinic receptors by the tryptophan metabolites, 5-hydroxyindole and kynurenate in mouse brain

Background and purpose: Two metabolites of tryptophan, 5-hydroxyindole and kynurenic acid (kynurenate) affect the function of alpha 7 nicotinic acetylcholine receptors (nAChRs), as measured by electrophysiological and Ca2+ fluorescence techniques. To better understand the modulations by 5-hydroxyindole and kynurenate of the function of nAChR subtypes, we compared the effects of 5-hydroxyindole and kynurenate on the release of various transmitters evoked by nAChR activation. Experimental approach: The function of alpha 7nAChRs located on glutamatergic terminals was investigated by monitoring the release of [H-3]D-aspartate or of endogenous glutamate from neocortical synaptosomes. We also comparatively considered non-alpha 7 release-enhancing nAChRs localized on hippocampal noradrenergic or cholinergic terminals, as well as on striatal dopaminergic terminals. Key results: Epibatidine or nicotine, inactive on their own on basal release, enhanced [H-3]D-aspartate and glutamate efflux in presence of 5-hydroxyindole. The release evoked by nicotine plus 5-hydroxyindole was abolished by methyllycaconitine or alpha-bungarotoxin. Presynaptic nAChRs mediating the release of [H-3] noradrenaline ([H-3]NA), [H-3]dopamine ([H-3]DA), or [H-3]ACh were inhibited by 5-OHi. The alpha 7nAChR-mediated release of [H-3]D-aspartate was reduced by kynurenate at concentrations unable to affect the non-alpha 7 receptor-mediated release of tritiated NA, DA or ACh. Conclusions and Implications: (i) 5-hydroxyindole permits selective activation of alpha 7nAChRs mediating glutamate release; (ii) kynurenate down-regulates the permissive role of 5-hydroxyindole on alpha 7nAChR activation; (iii) the non-alpha 7nAChRs mediating release of NA, DA or ACh can be inhibited by 5-hydroxyindole, but not by kynurenate. These findings suggest up the possibility of developing novel drugs able to modulate selectively the cholinergic-glutamatergic transmission.