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The Journal of Neuroscience, March 30, 2005, 25(13):3270-3279; doi:10.1523/JNEUROSCI.5033-04.2005

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Cellular/Molecular
Chronic Antidepressants Reduce Depolarization-Evoked Glutamate Release and Protein Interactions Favoring Formation of SNARE Complex in Hippocampus

Giambattista Bonanno,¹ Roberto Giambelli,^2 * Luca Raiteri,^1 * Ettore Tiraboschi,³ Simona Zappettini,¹ Laura Musazzi,³ Maurizio Raiteri,¹ Giorgio Racagni,^2,3 and Maurizio Popoli³

¹Section of Pharmacology and Toxicology, Department of Experimental Medicine, and Center of Excellence for Biomedical Research, University of Genoa, 16148 Genoa, Italy, ²Genetics Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy, and ³Center of Neuropharmacology, Department of Pharmacological Sciences, and Center of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy

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 CaM kinase II (-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.

Key words: release; glutamate; GABA; antidepressant; CaMKII; SNARE protein; neuroplasticity

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Received Dec 10, 2004; revised February 2, 2005; accepted February 4, 2005.

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