Effects of anti-depressant treatments on FADD and p-FADD protein in rat brain cortex: enhanced anti-apoptotic p-FADD/FADD ratio after chronic desipramine and fluoxetine administration.
Fas-associated death domain (FADD) is an adaptor of death receptors that can also induce anti-apoptotic actions through its phosphorylated form (p-FADD). Activation of monoamine receptors, indirect targets of classic anti-depressant drugs (ADs), reduced FADD and increased p-FADD and p-FADD/FADD ratio in brain.



To ascertain whether ADs, which indirectly regulate monoamine receptors, modulate FADD protein forms to promote anti-apoptotic actions.



The effects of selected norepinephrine transporter (NET), serotonin transporter (SERT), monoamine oxidase (MAO) inhibitors, atypical ADs, and electroconvulsive shock (ECS) or behavioral procedures (forced swim test, FST) on FADD forms and pro-survival FADD-like interleukin-1β-converting enzyme-inhibitory protein (FLIP-L) and phosphoprotein enriched in astrocytes of 15 kDa (p-PEA-15) contents were assessed in rat brain cortex by western blot analysis.



Acute NET (e.g., nisoxetine) but not SERT (e.g., fluoxetine) inhibitors decreased cortical FADD (up to 37 %) and increased p-FADD/FADD ratio (up to 1.9-fold). Nisoxetine effects were prevented by α2-antagonist RX-821002, suggesting the involvement of presynaptic α2-autoreceptors. Immobility time in the FST correlated with increases of pro-apoptotic FADD and decreases of anti-apoptotic p-FADD. The MAO-A/B inhibitor phenelzine decreased FADD (up to 33 %) and increased p-FADD (up to 65 %) and p-FADD/FADD (up to 2.4-fold). Other MAO inhibitors (clorgyline, Ro 41-1049, rasagiline), atypical ADs (ketamine and mirtazapine), or ECS did not modulate cortical FADD. Chronic (14 days) desipramine and fluoxetine, but not phenelzine, increased p-FADD (up to 59 %), p-FADD/FADD ratio (up to 1.8-fold), and pro-survival p-PEA-15 (up to 46 %) in rat brain cortex.



Multifunctional FADD protein, through an increased p-FADD/FADD ratio, could participate in the mechanisms of anti-apoptotic actions induced by ADs.
Neurobiology of Drug Abuse Group, IUNICS/IdISPa, University of the Balearic Islands, Cra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain. j.garcia@uib.es.|Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), ISCIII, Madrid, Spain. j.garcia@uib.es.
M Julia
MJ
García-Fuster
Laboratory of Neuropharmacology, IUNICS/IdISPa, University of the Balearic Islands, Palma de Mallorca, Spain.|Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), ISCIII, Madrid, Spain.
Jesús A
JA
García-Sevilla
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D017209:Apoptosis; D017660:Autoreceptors / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003010:Clorgyline / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology*; D004597:Electroshock; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein / Q000187:drug effects* / Q000378:metabolism; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology*; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives / Q000494:pharmacology; D000078785:Mirtazapine; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D010624:Phenelzine / Q000494:pharmacology; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D000928:Antidepressive Agents; D017660:Autoreceptors; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018691:Excitatory Amino Acid Antagonists; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; C482440:Sert1 protein, rat; C493226:Slc6a2 protein, rat; D013844:Thiazoles; C031967:rasagiline; D005473:Fluoxetine; C011386:nisoxetine; D008803:Mianserin; C063456:Ro 41-1049; D007649:Ketamine; D000078785:Mirtazapine; C058525:2-methoxyidazoxan; D003010:Clorgyline; D010624:Phenelzine; D003891:Desipramine; D019329:Idazoxan
Anti-depressant drugs; Electroconvulsive shock; FADD and p-FADD; Forced swim test; Neuroplasticity; Neuroprotection