title: Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus.
abstract: Glutamate neurotransmission was recently implicated in the action of stress and in antidepressant mechanisms. We report that chronic (not acute) treatment with three antidepressants with different primary mechanisms (fluoxetine, reboxetine, and desipramine) markedly reduced depolarization-evoked release of glutamate, stimulated by 15 or 25 mm KCl, but not release of GABA. Endogenous glutamate and GABA release was measured in superfused synaptosomes, freshly prepared from hippocampus of drug-treated rats. Interestingly, treatment with the three drugs only barely changed the release of glutamate (and of GABA) induced by ionomycin. In synaptic membranes of chronically treated rats we found a marked reduction in the protein-protein interaction between syntaxin 1 and Thr286-phosphorylated alphaCaM kinase II (alpha-calcium/calmodulin-dependent protein kinase II) (an interaction previously proposed to promote neurotransmitter release) and a marked increase in the interaction between syntaxin 1 and Munc-18 (an interaction proposed to reduce neurotransmitter release). Furthermore, we found a selective reduction in the expression level of the three proteins forming the core SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex. These findings suggest that antidepressants work by stabilizing glutamate neurotransmission in the hippocampus and that they may represent a useful tool for the study of relationship between functional and molecular processes in nerve terminals.
authors.affiliation: Section of Pharmacology and Toxicology, Department of Experimental Medicine, and Center of Excellence for Biomedical Research, University of Genoa, 16148 Genoa, Italy.
authors.forename: Giambattista
authors.initials: G
authors.lastname: Bonanno
authors.forename: Roberto
authors.initials: R
authors.lastname: Giambelli
authors.forename: Luca
authors.initials: L
authors.lastname: Raiteri
authors.forename: Ettore
authors.initials: E
authors.lastname: Tiraboschi
authors.forename: Simona
authors.initials: S
authors.lastname: Zappettini
authors.forename: Laura
authors.initials: L
authors.lastname: Musazzi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Raiteri
authors.forename: Giorgio
authors.initials: G
authors.lastname: Racagni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Popoli
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D047468:Immunoprecipitation / Q000379:methods; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D051938:Munc18 Proteins / Q000378:metabolism; D010766:Phosphorylation; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050600:SNARE Proteins / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D050827:Syntaxin 1 / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D007476:Ionophores; D051938:Munc18 Proteins; D050600:SNARE Proteins; D050827:Syntaxin 1; D013912:Threonine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D015759:Ionomycin; D011189:Potassium Chloride; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517675:Camk2a protein, rat; D002118:Calcium