title: Antidepressant activity of fluoxetine in the zinc deficiency model in rats involves the NMDA receptor complex.
abstract: The zinc deficiency animal model of depression has been proposed; however, it has not been validated in a detailed manner. We have recently shown that depression-like behavior induced by dietary zinc restriction is associated with up-regulation of hippocampal N-methyl-d-aspartate receptor (NMDAR). Here we examined the effects of chronic administration of a selective serotonin reuptake inhibitor, fluoxetine (FLX), on behavioral and biochemical alterations (within NMDAR signaling pathway) induced by zinc deficiency. Male Sprague Dawley rats were fed a zinc adequate diet (ZnA, 50mg Zn/kg) or a zinc deficient diet (ZnD, 3mg Zn/kg) for 4 weeks. Then, FLX treatment (10mg/kg, i.p.) begun. Following 2 weeks of FLX administration the behavior of the rats was examined in the forced swim test (FST) and the spontaneous locomotor activity test. Twenty four hours later tissue was harvested. The proteins of NMDAR (GluN1, GluN2A and GluN2B) or AMPAR (GluA1) subunits, p-CREB and BDNF in the hippocampus (Western blot) and serum zinc level (TXRF) were examined. Depression-like behavior induced by ZnD in the FST was sensitive to chronic treatment with FLX. ZnD increased levels of GluN1, GluN2A, GluN2B and decreased pS485-GluA1, p-CREB and BDNF proteins. Administration of FLX counteracted the zinc restriction-induced changes in serum zinc level and hippocampal GluN1, GluN2A, GluN2B and p-CREB but not BDNF or pS845-GluA1 protein levels. This finding adds new evidence to the predictive validity of the proposed zinc deficiency model of depression. Antidepressant-like activity of FLX in the zinc deficiency model is associated with NMDAR complex.
authors.affiliation: Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland. Electronic address: doboszew@if-pan.krakow.pl.
authors.forename: Urszula
authors.initials: U
authors.lastname: Doboszewska
authors.affiliation: Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
authors.forename: Bernadeta
authors.initials: B
authors.lastname: Szewczyk
authors.affiliation: Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Sowa-Kućma
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Młyniec
authors.affiliation: Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rafało
authors.affiliation: Faculty of Physics and Applied Computer Sciences, AGH University of Science and Technology, Mickiewicza 30, PL 30-059 Kraków, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Ostachowicz
authors.affiliation: Faculty of Physics and Applied Computer Sciences, AGH University of Science and Technology, Mickiewicza 30, PL 30-059 Kraków, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Lankosz
authors.affiliation: Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland; Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage* / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000008:administration & dosage* / Q000627:therapeutic use; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010766:Phosphorylation; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D015032:Zinc / Q000172:deficiency*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D005473:Fluoxetine; D021122:Protein Subunits; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D017367:Selective Serotonin Reuptake Inhibitors; D015032:Zinc
keywords: Fluoxetine; Forced swim test; NMDA receptor; Rats; Zinc deficiency