Molecular adaptations of apoptotic pathways and signaling partners in the cerebral cortex of human cocaine addicts and cocaine-treated rats

doi:10.1016/j.neuroscience.2011.08.074

Neuroscience

Volume 196, 24 November 2011, Pages 1-15

https://doi.org/10.1016/j.neuroscience.2011.08.074 Get rights and content

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.

Highlights

▶Pro-apoptotic Fas–FADD receptor complex is downregulated in brains of cocaine addicts. ▶Pro-apoptotic mitochondrial cytochrome c is reduced in brains of cocaine addicts. ▶Anti-apoptotic t-DARPP, truncated DARPP-32, is reduced in brains of cocaine addicts. ▶Nuclear PARP-1, a sensor of DNA damage, is increased in brains of cocaine addicts. ▶Chronic cocaine in rats only increased t-DARPP content in the cerebral cortex.

Section snippets

Postmortem brain samples of cocaine abusers and healthy controls

Specimens of PFC, middle frontal gyrus, Brodmann's area 9 (BA9) from cocaine abusers and healthy controls were obtained at autopsies performed in the Centre Universitaire Romand de Médecine Légale–Site Genève, University of Geneva, Switzerland, following the established legal and ethical procedures. The bodies had been stored in a refrigerator at 4 °C until autopsy. The right part of the PFC/BA9 was selected for examination to keep in line with previous postmortem studies on the molecular

Regulation of the extrinsic apoptotic pathway in brains of cocaine abusers

In the PFC/BA9 of long-term cocaine abusers, the content of Fas aggregates was reduced (−26%) when compared to that quantified in age-, gender-, and PMD-matched control subjects (Fig. 1A). Monomeric and glycosylated Fas forms were unchanged (Fig. 1A). The receptor adaptor FADD was markedly downregulated (−66%) in the same brain samples of cocaine addicts (Fig. 1B). Consistent with these findings, Fas aggregates and FADD were decreased in key subcellular compartments of a representative cocaine

Discussion

The results indicate that cocaine addiction in humans is not associated with upregulation of major components of the extrinsic and intrinsic apoptotic machineries in the PFC/BA9. On the contrary, the marked downregulation of Fas–FADD receptor complex and cytochrome c could reflect the induction of contraregulatory adaptations or non-apoptotic (neuroplastic) actions induced by the chronic use of the psychostimulant through dopaminergic (even though the PFC/BA9 receives little dopamine input)

Conclusion

In conclusion, cocaine addiction in humans is not associated with upregulation of major components of the extrinsic and intrinsic apoptotic machineries in the PFC/BA9. In fact, the observed downregulation of Fas–FADD receptor complex and mitochondrial cytochrome c suggest the induction of contraregulatory adaptations or non-apoptotic actions induced by the psychostimulant. In brains of cocaine addicts, however, the enhanced degradation of nuclear PARP-1, a hallmark of apoptosis, indicates the

Acknowledgments

This study was supported by grants SAF2008-01311 (MICINN/FEDER, Madrid, Spain) and 2007I032 (Plan Nacional sobre Drogas, MSC, Madrid) to J.A.G.-S. This research was also funded by Red Temática de Investigación Cooperativa en Salud (RETICS, Instituto de Salud Carlos III, MICINN/FEDER, Madrid): Red de Trastornos Adictivos, RD06/0001/0003 (J.A.G.-S.), and Centro de Investigación Biomédica en Red sobre Salud Mental (CIBERSAM, Instituto de Salud Carlos III, MICINN/FEDER, Madrid) (J.J.M.). M.A.-B.

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Cellular and Molecular NeuroscienceResearch PaperMolecular adaptations of apoptotic pathways and signaling partners in the cerebral cortex of human cocaine addicts and cocaine-treated rats

Abstract

Highlights

Section snippets

Postmortem brain samples of cocaine abusers and healthy controls

Regulation of the extrinsic apoptotic pathway in brains of cocaine abusers

Discussion

Conclusion

Acknowledgments

J Biol Chem

Toxicology

Brain Res Rev

Neuropharmacology

Brain Res Mol Brain Res

Neuron

Eur J Pharmacol

Neuropharmacology

Neuroscience

Brain Res

Med Hypotheses

Prog Neurobiol

Prog Neurobiol

Neuropharmacology

Neurotoxicol Teratol

Biol Psychiatry

Brain Res Mol Brain Res

Eur Neuropsychopharmacol

Neuroscience

J Stroke Cerebrovasc Dis

Exp Neurol

A review of the effects of prenatal cocaine exposure among school-aged children

Pediatrics

Molecular ordering of the initial signaling events of CD95

Mol Cell Biol

Regulation of Fas receptor/Fas-associated protein with death domain apoptotic complex and associated signalling systems by cannabinoid receptors in the mouse brain

Br J Pharmacol

Diagnostic and statistical manual of mental disorders

Mitochondrial and nuclear cross talk in cell death: parthanatos

Ann N Y Acad Sci

t-Darpp promotes cancer cell survival by up-regulation of Bcl2 through Akt-dependent mechanism

Cancer Res

Novel 2-substituted cocaine analogs: uptake and ligand binding studies at dopamine, serotonin and norepinephrine transport sites in the rat brain

J Pharmacol Exp Ther

Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5

Nature

Chronic morphine induces up-regulation of the pro-apoptotic Fas receptor and down-regulation of the anti-apoptotic Bcl-2 oncoprotein in rat brain

Br J Pharmacol

Hair as a biological indicator of drug use, drug abuse or chronic exposure to environmental toxicants

Int J Toxicol

Cortical and sub-cortical effects in primate models of cocaine use: implications for addiction and the increased risk of psychiatric illness

Neurotox Res

The neuropathology of drug abuse

Neuropath Appl Neurobiol

PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration

Cell Commun Signal

JNK signaling in apoptosis

Oncogene

Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP

Cancer Res

Increased density of guanine nucleotide-binding proteins in the postmortem brains of heroin addicts

Arch Gen Psychiatry

Downregulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats: relation to neurofilament phosphorylation

Neuropsychopharmacology

Mitochondrial membrane permeabilization in neuronal injury

Nat Rev Neurosci

Cellular and Molecular Neuroscience
Research Paper
Molecular adaptations of apoptotic pathways and signaling partners in the cerebral cortex of human cocaine addicts and cocaine-treated rats