Regulation of the extrinsic and intrinsic apoptotic pathways in the prefrontal cortex of short- and long-term human opiate abusers

Détails

ID Serval
serval:BIB_11A316C04978
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Regulation of the extrinsic and intrinsic apoptotic pathways in the prefrontal cortex of short- and long-term human opiate abusers
Périodique
Neuroscience
Auteur(s)
García-Fuster M.J., Ramos-Miguel A., Rivero G., La Harpe R., Meana J.J., García-Sevilla J.A.
ISSN
0306-4522
Statut éditorial
Publié
Date de publication
11/2008
Peer-reviewed
Oui
Volume
157
Numéro
1
Pages
105-119
Langue
anglais
Résumé
Opiate addiction is a chronic medical disorder characterized by drug tolerance and dependence, behavioral sensitization, vulnerability to compulsive relapse, and high mortality. In laboratory animals, the potential effect of opiate drugs to induce cell death by apoptosis is a controversial topic. This postmortem human brain study examined the status of the extrinsic and intrinsic apoptotic pathways in the prefrontal cortex of a large group of well-characterized heroin or methadone abusers. In these subjects (n=36), the immunocontent of apoptosis-1 protein (Fas) death receptor did not differ from that in age-, gender-, and postmortem delay-matched controls. In contrast, Fas-associated protein with death domain (FADD), the mediator of the death signal, was significantly decreased in the same brain samples (all addicts: 30%, n=36; short-term abuse (ST): 31%, n=15; long-term abuse (LT): 29%, n=21). The initiator caspase-8 was not altered, but FLIPL (Fas-associated protein with death domain-like interleukin-1β-converting enzyme-inhibitory protein), a dominant inhibitor of caspase-8, was increased in LT addicts (19%). In the intrinsic pathway, the pro-apoptotic mitochondrial proteins Bax (Bcl-2-associated X protein) and AIF (apoptosis-inducing factor) remained unchanged, but cytochrome c was decreased (all addicts: 25%; ST: 31%; LT: 20%) and anti-apoptotic B-cell leukemia 2 (Bcl-2) increased in LT addicts (24%). The content of executioner caspase-3 and the pattern of cleavage of the nuclear enzyme poly-(ADP-ribose)-polymerase-1 (PARP-1) were similar in opiate addicts and control subjects. Taken together, the data revealed that the extrinsic and intrinsic canonical apoptotic pathways are not abnormally activated in the prefrontal cortex of opiate abusers. Instead, the chronic modulation of some of their components (downregulation of FADD and cytochrome c; upregulation of FLIPL and Bcl-2) suggests the induction of non-apoptotic actions by opiate drugs related to phenomena of synaptic plasticity in the brain. These neurochemical adaptations could play a major role in the development of opiate tolerance, sensitization and relapse in human addicts.
Pubmed
Web of science
Création de la notice
15/06/2018 10:16
Dernière modification de la notice
20/08/2019 13:39
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