Sequential changes in BDNF mRNA expression and synaptic levels of AMPA receptor subunits in rat hippocampus after chronic antidepressant treatment.
Increased expression of brain-derived neurotrophic factor (BDNF) appears to be involved in the mechanism of action of antidepressant drugs. It has also been proposed that potentiation of the AMPA receptor (AMPAR) function may be useful in the treatment of depression. Here we looked for the time course of the effect of different doses of two antidepressants, desipramine (DMI) and paroxetine (PAR), which differentially affect monoamine reuptake, on BDNF mRNA expression in hippocampal subfields (CA1, CA3 and dentate gyrus) and levels of AMPAR subunits in total and membrane-enriched extracts from rat hippocampus. Acute antidepressant treatment changed neither BDNF mRNA expression nor AMPAR subunit levels. In chronic treatments, rats were treated daily with the antidepressants for 7-21 days. PAR produced a time- and dose-dependent increase of BDNF expression in the three hippocampal subfields examined. On the contrary, the effect of DMI on BDNF mRNA was neither dose- nor time-dependent. In rats receiving the same chronic antidepressant treatments, PAR produced a dose-dependent increase of GluR1 and GluR2/3 levels in the membrane fraction after a 3-week treatment, and not at earlier times. DMI increased the membrane levels of AMPAR subunits after a 3-week treatment with the lower dose tested. However, a higher dose, 15 mg/kg, did not produce any change in AMPAR subunits and reduced membrane levels of alpha-tubulin and PSD-95, possibly indicating a disorganization of membrane scaffolding proteins. The results suggest that paroxetine, but not desipramine, enhances synaptic plasticity in the hippocampus by increasing BDNF mRNA expression, which determines a later AMPAR subunit trafficking to synaptic membranes.
Martínez-Turrillas
Rebeca
R
Department of Pharmacology, School of Medicine, University of Navarra, Apartado 177, 31080 Pamplona, Spain.
Del Río
Joaquín
J
Frechilla
Diana
D
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001345:Autoradiography; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D003891:Desipramine / Q000494:pharmacology; D000076122:Disks Large Homolog 4 Protein; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D017374:Paroxetine / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D019208:Brain-Derived Neurotrophic Factor; D003891:Desipramine; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017374:Paroxetine; D012333:RNA, Messenger; D018091:Receptors, AMPA; D017367:Selective Serotonin Reuptake Inhibitors; D014404:Tubulin; C501449:Dlg4 protein, rat; C104722:glutamate receptor ionotropic, AMPA 2