Modulation of the function of presynaptic alpha7 and non-alpha7 nicotinic receptors by the tryptophan metabolites, 5-hydroxyindole and kynurenate in mouse brain.
OBJECTIVE
Two metabolites of tryptophan, 5-hydroxyindole and kynurenic acid (kynurenate) affect the function of alpha7 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.


METHODS
The function of alpha7nAChRs located on glutamatergic terminals was investigated by monitoring the release of [3H]D-aspartate or of endogenous glutamate from neocortical synaptosomes. We also comparatively considered non-alpha7 release-enhancing nAChRs localized on hippocampal noradrenergic or cholinergic terminals, as well as on striatal dopaminergic terminals.


RESULTS
Epibatidine or nicotine, inactive on their own on basal release, enhanced [3H]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 [3H]noradrenaline ([3H]NA), [3H]dopamine ([3H]DA), or [3H]ACh were inhibited by 5-OHi. The alpha7nAChR-mediated release of [3H]D-aspartate was reduced by kynurenate at concentrations unable to affect the non-alpha7 receptor-mediated release of tritiated NA, DA or ACh.


CONCLUSIONS
(i) 5-hydroxyindole permits selective activation of alpha7nAChRs mediating glutamate release; (ii) kynurenate down-regulates the permissive role of 5-hydroxyindole on alpha7nAChR activation; (iii) the non-alpha7nAChRs 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.
Grilli
M
M
Section of Pharmacology and Toxicology, Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Raiteri
L
L
Patti
L
L
Parodi
M
M
Robino
F
F
Raiteri
M
M
Marchi
M
M
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D007211:Indoles / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000494:pharmacology*; D051379:Mice; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000502:physiology; D011978:Receptors, Nicotinic / Q000502:physiology*
D007211:Indoles; D011978:Receptors, Nicotinic; C026785:5-hydroxyindole; D007736:Kynurenic Acid