programa - XIV Congreso Nacional de la Sociedad Española de ...

Reunión Científica Red de Trastornos Adictivos-CIBERSAMSalamanca 27 y 28 de septiembre de 2011O3. MOLECULAR ADAPTATIONS OF APOPTOTIC PATHWAYS AND SIGNALING PARTNERS IN THECEREBRAL CORTEX OF HUMAN COCAINE ADDICTSM. Álvaro-Bartolomé 1 , R. La Harpe 2 , L. F. Callado 3, 4 , J. J. Meana 3, 4 , J. A. Garcia-Sevilla 11Laboratorio de Neurofarmacología, IUNICS, Universidad de las Islas Baleares y RETICS-RTA2Centre Universitaire Romand de Médecine Légale–Site Genève, Faculté de Médecine, Université de Genève3Departamento de Farmacología, Universidad del País Vasco (UPV/EHU), Leioa, Bizkaia4CIBER de Salud Mental (CIBERSAM), ISCIII, MadridIntroduction: Cocaine induces apoptotic effects in cultured cells and in the developing brain, but the aberrantactivation of cell death in the adult brain remains inconclusive, especially in humans. This postmortem humanbrain study examined the status of canonical apoptotic pathways, signaling partners, and the cleavage ofpoly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, in the prefrontal cortex (PFC) cocaineabusers.Hypothesis: Cocaine addiction results in abnormal activation of apoptotic pathways in human brain.Methods: Specimens of prefrontal cortex (PFC/BA9) were collected from 10 cocaine addicts (6M/4F; 37±4 yr;27±7 PMD) and 10 healthy matched-controls (6M/4F; 40±4 yr; 25±5 PMD). A history of cocaine abuse was madewith the presence of cocaine and/or benzoylecgonine (the main active metabolite) in blood and/or hair samples.Cocaine abusers had no recent history of opiate abuse as revealed by absence of opiate drugs in blood and hairsamples. The target proteins were quantified by Western immunoblot analyses.Results: Fas receptor aggregates and Fas-associated death domain (FADD) adaptor were reduced (26% and66%, respectively) as well as the content of mitochondrial cytochrome c (61%). In the same brain samples, theproteolytic cleavage of PARP-1 was increased (39%). Nuclear PARP-1 degradation, possibly a consequence ofincreased mitochondrial oxidative stress, involved the activation of apoptosis-inducing factor (AIF) and not that ofcaspase-3.Conclusions: Cocaine addiction is not associated with upregulation of relevant pro-apoptotic molecules of thecanonical pathways that could suggest greater rates of cell death in the PFC/BA9. In fact, the observeddownregulation of Fas–FADD receptor complex and mitochondrial cytochrome c, together with normal caspase-3activity, suggest the induction of contra-regulatory mechanisms to minimize the consequences on cell death of anincreased degradation of nuclear PARP-1, possibly mediated by AIF, in brains of cocaine addicts.Supported by SAF2008-01311 (MICINN/FEDER) and RD06/001/003 (RETICS-RTA, ISCIII, MICINN/FEDER).Página 12 de 41