title: Direct evidence that release-stimulating alpha7* nicotinic cholinergic receptors are localized on human and rat brain glutamatergic axon terminals.
abstract: The existence on glutamatergic nerve endings of nicotinic acetylcholine receptors (nAChRs) mediating enhancement of glutamate release has often been suggested but not demonstrated directly. Here, we study the effects of nAChR agonists on [3 H]-d-aspartate ([3 H]-d-ASP) release from synaptosomes superfused in conditions known to prevent indirect effects. Nicotinic receptor agonists, while unable to modify the basal [3 H]-d-ASP release from human neocortex or rat striatal synaptosomes, enhanced the Ca2+ -dependent exocytotic release evoked by K+ (12 mm) depolarization. Their rank order of potency were anatoxin-a > epibatidine > nicotine > ACh (+ atropine). The anatoxin-a effect, both in human and rat synaptosomes, was antagonized by mecamylamine, alpha-bungarotoxin or methyllycaconitine. The basal release of [3 H]ACh from human cortical synaptosomes was increased by (-)-nicotine (EC50 = 1.16 +/- 0.33 microm) or by ACh plus atropine (EC50 = 2.0 +/- 0.04 microm). The effect of ACh plus atropine was insensitive to alpha-bungarotoxin, methyllycaconitine or alpha-conotoxin MII, whereas it was totally antagonized by mecamylamine or dihydro-beta-erythroidine. To conclude, glutamatergic axon terminals in human neocortex and in rat striatum possess alpha7* nicotinic heteroreceptors mediating enhancement of glutamate release. Release-enhancing cholinergic autoreceptors in human neocortex are nAChRs with a pharmacological profile compatible with the alpha4beta2 subunit combination.
authors.affiliation: Sezione di Farmacologia e Tossicologia, Dipartimento di Medicina Sperimentale, Università di Genova, Genoa, Italy. marchi@pharmatox.unige.it
authors.forename: Mario
authors.initials: M
authors.lastname: Marchi
authors.forename: Francesca
authors.initials: F
authors.lastname: Risso
authors.forename: Concetta
authors.initials: C
authors.lastname: Viola
authors.forename: Paolo
authors.initials: P
authors.lastname: Cavazzani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Raiteri
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001427:Bacterial Toxins / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D000087522:Cyanobacteria Toxins; D005089:Exocytosis / Q000187:drug effects; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D008387:Marine Toxins / Q000494:pharmacology; D052998:Microcystins; D008875:Middle Aged; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D014326:Tropanes; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001427:Bacterial Toxins; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D000087522:Cyanobacteria Toxins; D008387:Marine Toxins; D052998:Microcystins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D014326:Tropanes; D064569:alpha7 Nicotinic Acetylcholine Receptor; D001224:Aspartic Acid; D018698:Glutamic Acid; C509783:anatoxin a