Journal
NEUROSCIENCE
Volume 161, Issue 1, Pages 23-38Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2009.03.028
Keywords
opiate addiction; postmortem human brain; p-Ser194 FADD; MAP kinases; PEA-15; Akt kinase; neuroplasticity
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Funding
- MICINN and FEDER, Madrid, Spain [SAF2008-01311]
- Plan Nacional sobre Drogas, MSC, Madrid [20071032]
- Red Tematica de Investigacion Cooperativa en Salud [RD06/001/003]
- Gobierno Vasco [IT-199-07]
- Centro de Investigacion Biomedica en Red sobre Salud Mental (CIBERSAM) [CB07/09/0008]
- MEC (Madrid)
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Fas-associated protein with death domain (FADD) is a multifunctional protein that can induce both apoptotic and non-apoptotic actions. Recently, FADD was found down-regulated in the prefrontal cortex of opiate abusers, which suggested an attenuation of Fas death signals in human addicts. Phosphorylation of FADD (Ser194) has been reported to regulate its non-apoptotic activity, which might include the induction of neuroplastic effects in the brain. This postmortem brain study examined the status of phosphorylated (p)-Ser194 FADD and signaling pathways involved in neuroplasticity in the prefrontal cortex (BA 9) of short-term (ST) and long-term (LT) heroin or methadone abusers. In these subjects, the content of monomeric p-FADD was significantly increased when compared with that in age-, gender-, and postmortem delay-matched controls (all addicts: 65%, n=26; ST abuse: 51%; n=11; LT abuse: 75%, n=15). Oligomeric p-FADD forms were modestly increased (11%-23%). At the subcellular level, opiate addiction upregulated the expression of monomeric p-FADD in the nucleus (110%) and that of p-oligomers in the cytosol (66%). In LT opiate addicts (but not ST abusers), a pronounced downregulation of p-extracellular signal-regulated kinase (ERK)1/2 (52%) and p-c-Jun NH2-terminal protein kinase (JNK)1/2 (51%), but not p-p38 mitogen-activated protein kinase (MAPK), was quantified in the prefrontal cortex (total homogenate and subcellular compartments). Similarly, the signaling pathway mediated by p-phosphoprotein enriched in astrocytes of 15 kDa (PEA-15) protein and its phosphorylating kinase p-Akt1 was also downregulated in cortical homogenate (43% and 41%, respectively) and cytosolic preparations of chronic opiate addicts. The results indicate that opiate addiction in humans is associated with an altered balance between p-Ser194 FADD (increased) and total FADD (decreased) in brain, which may favor its neuroplastic actions. The interaction between p-FADD (upregulated) and neuronal pathways (downregulated) could play a relevant role in mediating specific forms of structural and behavioral neuroplasticity. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.
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