title: Molecular adaptations of apoptotic pathways and signaling partners in the cerebral cortex of human cocaine addicts and cocaine-treated rats.
abstract: Cocaine induces apoptotic effects in cultured cells and in the developing brain, but the aberrant activation of cell death in the adult brain remains inconclusive, especially in humans. This postmortem human brain study examined the status of canonical apoptotic pathways, signaling partners, and the cleavage of poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, in prefrontal cortex (PFC) of a small but well-characterized cohort of cocaine abusers (n=10). For comparison, the chosen targets were also quantified in the cerebral cortex of cocaine-treated rats. In the PFC of cocaine abusers, FS7-associated cell surface antigen (Fas) receptor aggregates and Fas-associated death domain (FADD) adaptor were reduced (-26% and -66%, respectively) as well as the content of mitochondrial cytochrome c (-61%). In the same brain samples of cocaine abusers, the proteolytic cleavage of PARP-1 was increased (+39%). Nuclear PARP-1 degradation, possibly a consequence of increased mitochondrial oxidative stress, involved the activation of apoptosis-inducing factor (AIF) and not that of caspase-3. In the PFC of cocaine abusers, several signaling molecules associated with cocaine/dopamine and/or apoptotic pathways were not significantly altered, with the exception of anti-apoptotic truncated DARPP-32 (t-DARPP), a truncated isoform of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), whose content was decreased (-28%). Chronic exposure to cocaine in rats, including withdrawal for 3 days, did not alter Fas-FADD receptor complex, cytochrome c, caspase-3/fragments, AIF, PARP-1 cleavage, and associated signaling in the cerebral cortex. Chronic cocaine and abstinence, however, increased the content of t-DARPP (+39% and +47%) in rat brain cortex. The major findings indicate that cocaine addiction in humans is not associated with abnormal activation of extrinsic and intrinsic apoptotic pathways in PFC. The downregulation of Fas-FADD receptor complex and cytochrome c could reflect the induction of contraregulatory adaptations or non-apoptotic (neuroplastic) actions induced by the psychostimulant. The enhanced degradation of nuclear PARP-1, a hallmark of apoptosis, indicates the possibility of aberrant cell death.
authors.affiliation: Laboratorio de Neurofarmacología, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears (UIB) and Red Temática de Investigación Cooperativa en Salud (RETICS-RTA), Cra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Alvaro-Bartolomé
authors.forename: R
authors.initials: R
authors.lastname: La Harpe
authors.forename: L F
authors.initials: LF
authors.lastname: Callado
authors.forename: J J
authors.initials: JJ
authors.lastname: Meana
authors.forename: J A
authors.initials: JA
authors.lastname: García-Sevilla
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D053200:Fas-Associated Death Domain Protein; D019014:fas Receptor; C499320:PARP1 protein, human; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D003042:Cocaine