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A Comprehensive View of the Neurotoxicity Mechanisms of Cocaine and Ethanol

Abstract

Substance use disorder is an emerging problem concerning to human health, causing severe side effects, including neurotoxicity. The use of illegal drugs and the misuse of prescription or over-the-counter drugs are growing in this century, being one of the major public health problems. Ethanol and cocaine are one of the most frequently used drugs and, according to the National Institute on Drug Abuse, their concurrent consumption is one of the major causes for emergency hospital room visits. These molecules act in the brain through different mechanisms, altering the nervous system function. Researchers have focused the attention not just in the mechanism of action of these drugs, but also in the mechanism by which they damage the nervous tissue (neurotoxicity). Therefore, the goal of the present review is to provide a global perspective about the mechanisms of the neurotoxicity of cocaine and ethanol.

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References

  • Aggrawal A (1995) Cocaine: Gift from the Gods. Narcotic drugs. National Book Trust, New Delhi, pp 52–53

    Google Scholar 

  • Ahlskog JE (2007) Beating a dead horse: dopamine and Parkinson disease. Neurology 69:1701–1711

    PubMed  CAS  Article  Google Scholar 

  • Ahn SM, Kim SW, Choe ES (2007) Cocaine increases immunoglobulin heavy chain binding protein and caspase-12 expression in the rat dorsal striatum. Psychopharmacology 195:407–414

    PubMed  CAS  Article  Google Scholar 

  • Albanese AP (2012) Management of alcohol abuse. Clin Liver Dis 16:737–762

    PubMed  Article  Google Scholar 

  • Alfonso-Loeches S, Pascual-Lucas M, Blanco AM, Sanchez-Vera I, Guerri C (2010) Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J Neurosci 30:8285–8295

    PubMed  CAS  Article  Google Scholar 

  • Andrews P (1997) Cocaethylene toxicity. J Addict Dis 16:75–84

    PubMed  CAS  Article  Google Scholar 

  • Ang E, Chen J, Zagouras P, Magna H, Holland J, Schaeffer E, Nestler EJ (2001) Induction of nuclear factor-kappaB in nucleus accumbens by chronic cocaine administration. J Neurochem 79:221–224

    PubMed  CAS  Article  Google Scholar 

  • Apantaku-Olajide T, Darker CD, Smyth BP (2013) Onset of cocaine use: associated alcohol intoxication and psychosocial characteristics among adolescents in substance abuse treatment. J Addict Med 7:183–188

    PubMed  CAS  Article  Google Scholar 

  • Baeuerle PA, Baltimore D (1996) NF-κB: ten years after. Cell 87:13–20

    PubMed  CAS  Article  Google Scholar 

  • Bailey SM, Cunningham CC (1998) Acute and chronic ethanol increases reactive oxygen species generation and decreases viability in fresh, isolated rat hepatocytes. Hepatology 28:1318–1326

    PubMed  CAS  Article  Google Scholar 

  • Banerjee K, Munshi S, Sen O, Pramanik V, Roy MT, Chakrabarti S (2014) Dopamine cytotoxicity involves both oxidative and nonoxidative pathways in SH-SY5Y cells: potential role of alpha-synuclein overexpression and proteasomal inhibition in the etiopathogenesis of Parkinson’s disease. Parkinsons Dis 2014:1–12

    Article  CAS  Google Scholar 

  • Beal MF (2001) Experimental models of Parkinson’s disease. Nat Rev Neurosci 2:325–334

    PubMed  CAS  Article  Google Scholar 

  • Binet F, Chiasson S, Girard D (2010) Evidence that endoplasmic reticulum (ER) stress and caspase-4 activation occur in human neutrophils. Biochem Biophys Res Commun 391:18–23

    PubMed  CAS  Article  Google Scholar 

  • Blanco AM, Vallés SL, Pascual M, Guerri C (2005) Involvement of TLR4/type I IL-1 receptor signaling in the induction of inflammatory mediators and cell death induced by ethanol in cultured astrocytes. J Immunol 175:6893–6899

    PubMed  CAS  Article  Google Scholar 

  • Bodmer M, Enzler F, Liakoni E, Bruggisser M, Liechti ME (2014) Acute cocaine-related health problems in patients presenting to an urban emergency department in Switzerland: a case series. BMC Res Notes 7:1–7

    Article  Google Scholar 

  • Borja-Oliveira CR (2014) Alcohol-medication interactions: the acetaldehyde syndrome. J Pharmacovigil 2:1000145

    Google Scholar 

  • Bradberry CW, Nobiletti JB, Elsworth JD, Murphy B, Jatlow P, Roth RH (1993) Cocaine and cocaethylene: microdialysis comparison of brain drug levels and effects on dopamine and serotonin. J Neurochem 60:429–435

    Article  Google Scholar 

  • Brassai A, Suvanjeiev RG, Bán EG, Lakatos M (2015) Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity. Brain Res Bull 112:1–6

    PubMed  CAS  Article  Google Scholar 

  • Brunelle JK, Letai A (2009) Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci 122:437–441

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Butterworth RF, Kril JJ, Harper CG (1993) Thiamine-dependent enzyme changes in the brains of alcoholics: relationship to the Wernicke–Korsakoff syndrome. Alcohol Clin Exp Res 17:1084–1088

    PubMed  CAS  Article  Google Scholar 

  • Cadet JL, Brannock C (1998) Free radicals and the pathobiology of brain dopamine systems. Neurochem Int 32:117–131

    PubMed  CAS  Article  Google Scholar 

  • Cagienard F, Schulzki T, Reinhart WH (2014) Cocaine in high concentrations inhibits platelet aggregation in vitro. Clin Hemorheol Microcirc 57:385–394

    PubMed  CAS  Google Scholar 

  • Cao SS, Kaufman RJ (2012) Unfolded protein response. Curr Biol 22:R622–R626

    PubMed  CAS  Article  Google Scholar 

  • Caudle WM, Richardson JR, Wang MZ, Taylor TN, Guillot TS, McCormack AL, Colebrooke RE, di Monte DA, Emson PC, Miller GW (2007) Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration. J Neurosci 27:8138–8148

    PubMed  CAS  Article  Google Scholar 

  • Chaung WW, Jacob A, Ji Y, Wang P (2008) Suppression of PGC-1α by ethanol: implications of its role in alcohol induced liver injury. Int J Clin Exp Med 1:161–170

    PubMed  CAS  PubMed Central  Google Scholar 

  • Choe ES, Ahn SM, Yang JH, Go BS, Wang JQ (2011) Linking cocaine to endoplasmic reticulum in striatal neurons: role of glutamate receptors. Basal Ganglia 1:59–63

    PubMed  PubMed Central  Google Scholar 

  • Corsini GU, Zuddas A, Bonuccelli U, Schinelli S, Kopin IJ (1987) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice is enhanced by ethanol or acetaldehyde. Life Sci 40:827–832

    PubMed  CAS  Article  Google Scholar 

  • Costa BM, Yao H, Yang L, Buch S (2013) Role of endoplasmic reticulum (ER) stress in cocaine-induced microglial cell death. J Neuroimmune Pharmacol 8:705–714

    PubMed  PubMed Central  Article  Google Scholar 

  • Coutts DJ, Harrison NL (2015) Acetaldehyde, not ethanol, impairs myelin formation and viability in primary mouse oligodendrocytes. Alcohol Clin Exp Res 39:455–462

    PubMed  CAS  Article  Google Scholar 

  • Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D (2006) Transcriptional repression of PGC-1α by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127:59–69

    PubMed  CAS  Article  Google Scholar 

  • Cunha-Oliveira T, Rego AC, Morgadinho MT, Macedo T, Oliveira CR (2006) Differential cytotoxic responses of PC12 cells chronically exposed to psychostimulants or to hydrogen peroxide. Toxicology 217:54–62

    PubMed  CAS  Article  Google Scholar 

  • Cunha-Oliveira T, Rego AC, Oliveira CR (2008) Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs. Brain Res Rev 58:192–208

    PubMed  CAS  Article  Google Scholar 

  • Cunha-Oliveira T, Silva L, Silva AM, Moreno AJ, Oliveira CR, Santos MS (2013) Mitochondrial complex I dysfunction induced by cocaine and cocaine plus morphine in brain and liver mitochondria. Toxicol Lett 219:298–306

    PubMed  CAS  Article  Google Scholar 

  • Dai Q, Zhang J, Pruett SB (2005) Ethanol alters cellular activation and CD14 partitioning in lipid rafts. Biochem Biophys Res Commun 332:37–42

    PubMed  CAS  Article  Google Scholar 

  • Dawson P, Moffatt JD (2012) Cardiovascular toxicity of novel psychoactive drugs: lessons from the past. Prog Neuropsychopharmacol Biol Psychiatry 39:244–252

    PubMed  CAS  Article  Google Scholar 

  • de la Monte SM, Kril JJ (2014) Human alcohol-related neuropathology. Acta Neuropathol 127:71–90

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Dean RA, Bosron WF, Zachman FM, Zhang J, Brzezinski MR (1997) Effects of ethanol on cocaine metabolism and disposition in the rat. NIDA Res Monogr 173:35–47

    PubMed  CAS  Google Scholar 

  • Devlin RJ, Henry JA (2008) Clinical review: major consequences of illicit drug consumption. Crit Care 12:202

    PubMed  PubMed Central  Article  Google Scholar 

  • Dey S, Mactutus CF, Booze RM, Snow DM (2007) Cocaine exposure in vitro induces apoptosis in fetal locus coeruleus neurons by altering the Bax/Bcl-2 ratio and through caspase-3 apoptotic signaling. Neuroscience 144:509–521

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Dhillon NK, Williams R, Peng F, Tsai YJ, Dhillon S, Nicolay B, Gadgil M, Kumar A, Buch SJ (2007) Cocaine-mediated enhancement of virus replication in macrophages: implications for human immunodeficiency virus-associated dementia. J Neurovirol 13:483–495

    PubMed  CAS  Article  Google Scholar 

  • Dietrich JB, Mangeol A, Revel MO, Burgun C, Aunis D, Zwiller J (2005) Acute or repeated cocaine administration generates reactive oxygen species and induces antioxidant enzyme activity in dopaminergic rat brain structures. Neuropharmacology 48:965–974

    PubMed  CAS  Article  Google Scholar 

  • Duty S, Jenner P (2011) Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br J Pharmacol 164:1357–1391

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Echevarria DJ, Toms CN, Jouandot DJ (2011) Alcohol-induced behavior change in zebrafish models. Rev Neurosci 22:85–93

    PubMed  CAS  Google Scholar 

  • EMCDDA (2012) Annual report on the state of the drugs problem in Europe. http://www.emcdda.europa.eu/publications/annual-report/2012. Accessed 4 June 2015

  • Enoksson M, Robertson JD, Gogvadze V, Bu P, Kropotov A, Zhivotovsky B, Orrenius S (2004) Caspase-2 permeabilizes the outer mitochondrial membrane and disrupts the binding of cytochrome c to anionic phospholipids. J Biol Chem 279:49575–49578

    PubMed  CAS  Article  Google Scholar 

  • Ersche KD, Jones PS, Williams GB, Robbins TW, Bullmore ET (2013) Cocaine dependence: a fast-track for brain ageing? Mol Psychiatry 18:134–135

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Finck BN, Kelly DP (2006) PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest 116:615–622

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Fleckenstein AE, Volz TJ, Hanson GR (2009) Psychostimulant-induced alterations in vesicular monoamine transporter-2 function: neurotoxic and therapeutic implications. Neuropharmacology 56:133–138

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Friedman WJ (2001) Cytokines regulate expression of the type I interleukin-1 receptor in rat hippocampal neurons and glia. Exp Neurol 168:23–31

    PubMed  CAS  Article  Google Scholar 

  • Galluzzi L, Morselli E, Kepp O, Vitale I, Rigoni A, Vacchelli E, Michaud M, Zischka H, Castedo M, Kroemer G (2010) Mitochondrial gateways to cancer. Mol Asp Med 31:1–20

    CAS  Article  Google Scholar 

  • Gandhi S, Vaarmann A, Yao Z, Duchen MR, Wood NW, Abramov AY (2012) Dopamine induced neurodegeneration in a PINK1 model of Parkinson’s disease. PLoS ONE 7:e37564

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Gaziano JM, Buring JE, Breslow JL, Goldhaber SZ, Rosner B, VanDenburgh M, Willett W, Hennekens CH (1993) Moderate alcohol intake, increased levels of high-density lipoprotein and its sub-fractions, and decreased risk of myocardial infarction. N Engl J Med 329:1829–1834

    PubMed  CAS  Article  Google Scholar 

  • Ghosh A, Roy A, Liu X, Kordower JH, Mufson EJ, Hartley DM, Ghosh S, Mosley RL, Gendelman HE, Pahan K (2007) Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 104:18754–18759

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Ghribi O, Herman MM, Spaulding NK, Savory J (2002) Lithium inhibits aluminum-induced apoptosis in rabbit hippocampus, by preventing cytochrome c translocation, Bcl-2 decrease, Bax elevation and caspase-3 activation. J Neurochem 82:137–145

    PubMed  CAS  Article  Google Scholar 

  • Giovannini MG, Scali C, Prosperi A, Belluci G, Pepeu G, Casamenti F (2003) Experimental brain inflammation and neurodegeneration as model of Alzheimer’s disease: protective effects of selective COX-2 inhibitors. Int J Immunopathol Pharmacol 16:31–40

    PubMed  CAS  Google Scholar 

  • Gluck MR, Zeevalk GD (2004) Inhibition of brain mitochondrial respiration by dopamine and its metabolites: implications for Parkinson’s disease and catecholamine-associated diseases. J Neurochem 91:788–795

    PubMed  CAS  Article  Google Scholar 

  • González-Hernández T, Barroso-Chinea P, De La Cruz Muros I, Del Mar Pérez-Delgado M, Rodríguez M (2004) Expression of dopamine and vesicular monoamine transporters and differential vulnerability of mesostriatal dopaminergic neurons. J Comp Neurol 479:198–215

    PubMed  Article  CAS  Google Scholar 

  • Gowrishankar R, Hahn MK, Blakely RD (2014) Good riddance to dopamine: roles for the dopamine transporter in synaptic function and dopamine-associated brain disorders. Neurochem Int 73:42–48

    PubMed  CAS  Article  Google Scholar 

  • Grewal SI, Moazed D (2003) Heterochromatin and epigenetic control of gene expression. Science 301:798–802

    PubMed  CAS  Article  Google Scholar 

  • Gveric D, Kaltschmidt C, Cuzner L, Newcombe J (1998) Transcription factor NFkB and inhibitor IkB are localized in macrophages in active Multiple Sclerosis lesions. J Neuropathol Exp Neurol 57:168–178

    PubMed  CAS  Article  Google Scholar 

  • Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk −/− mice reveals a role for translational control in secretory cell survival. Mol Cell 7:1153–1163

    PubMed  CAS  Article  Google Scholar 

  • Harper C (2009) The neuropathology of alcohol-related brain damage. Alcohol Alcohol 44:136–140

    PubMed  CAS  Article  Google Scholar 

  • Harris DS, Everhart ET, Mendelson J, Jones RT (2003) The pharmacology of cocaethylene in humans following cocaine and ethanol administration. Drug Alcohol Depend 72:169–182

    PubMed  CAS  Article  Google Scholar 

  • Hayden MS, Ghosh S (2008) Shared principles in NF-kappaB signaling. Cell 132:344–362

    PubMed  CAS  Article  Google Scholar 

  • Hearn WL, Rose S, Wagner J, Ciarleglio A, Mash DC (1991a) Cocaethylene is more potent than cocaine in mediating lethality. Pharmacol Biochem Behav 39:531–533

    PubMed  CAS  Article  Google Scholar 

  • Hearn WL, Flynn DD, Hime GW, Rose S, Cofino JC, Mantero-Atienza E, Wetli CV, Mash DC (1991b) Cocaethylene: a unique cocaine metabolite displays high affinity for the dopamine transporter. J Neurochem 56:698–701

    PubMed  CAS  Article  Google Scholar 

  • Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP (2003) The role of glial reaction and inflammation in Parkinson’s disease. Ann NY Acad Sci 991:214–228

    PubMed  CAS  Article  Google Scholar 

  • Horowitz JM, DiPirro JM, Kristal MB, Torres G (1997) Dopaminergic and glutamatergic mechanisms mediate the induction of FOS-like protein by cocaethylene. Brain Res Bull 42:393–398

    PubMed  CAS  Article  Google Scholar 

  • Hou H, Wang C, Jia S, Hu S, Tian M (2014) Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings. Neurosci Bull 30:765–776

    PubMed  CAS  Article  Google Scholar 

  • Huang WY, Vallés S, Qwarnstrom EE (2001) Translocation of the IL-1 receptor to focal adhesions is regulated through the C-terminal end of the cytoplasmic domain. Cell Biol Int 25:309–317

    PubMed  CAS  Article  Google Scholar 

  • Ivester P, Lide MJ, Cunningham CC (1995) Effect of chronic ethanol consumption on the energy state and structural stability of periportal and perivenous hepatocytes. Arch Biochem Biophys 322:14–21

    PubMed  CAS  Article  Google Scholar 

  • Iyer RN, Nobiletti JB, Jatlow PI, Bradberry CW (1995) Cocaine and cocaethylene: effects on extracellular dopamine in the primate. Psychopharmacology 120:150–155

    PubMed  CAS  Article  Google Scholar 

  • Jatlow P, McCance EF, Bradberry CW, Elsworth JD, Taylor JR, Roth RH (1996) Alcohol plus cocaine: the whole is more than the sum of its parts. Ther Drug Monit 18:460–464

    PubMed  CAS  Article  Google Scholar 

  • John GR, Lee SC, Brosnan CF (2003) Cytokines: powerful regulators of glial cell activation. Neuroscientist 9:10–22

    PubMed  CAS  Article  Google Scholar 

  • John GR, Lee SC, Song X, Rivieccio M, Brosnan CF (2005) IL-1-regulated responses in astrocytes: relevance to injury and recovery. Glia 49:161–176

    PubMed  Article  Google Scholar 

  • Jung ME, Metzger DB (2015) Aberrant histone acetylation promotes mitochondrial respiratory suppression in the brain of alcoholic rats. J Pharmacol Exp Ther 352:258–266

    PubMed  CAS  Article  Google Scholar 

  • Kim TE, Lee EJ, Young JB, Shin DJ, Kim JH (2014) Wernicke encephalopathy and ethanol-related syndromes. Semin Ultrasound CT MR 35:85–96

    PubMed  Article  Google Scholar 

  • Ko HW, Park KY, Kim H, Han PL, Kim YU, Gwag BJ, Choi EJ (1998) Ca2+-mediated activation of c-Jun N-terminal kinase and nuclear factor kappa B by NMDA in cortical cell cultures. J Neurochem 71:1390–1395

    PubMed  CAS  Article  Google Scholar 

  • Kunitoh S, Imaoka S, Hiroi T, Yabusaki Y, Monna T, Funae Y (1997) Acetaldehyde as well as ethanol is metabolized by human CYP2E1. J Pharmacol Exp Ther 280:527–532

    PubMed  CAS  Google Scholar 

  • Lan YL, Zhao J, Li S (2014) Estrogen receptors’ neuroprotective effect against glutamate-induced neurotoxicity. Neurol Sci 35:1657–1662

    PubMed  Article  Google Scholar 

  • Lau A, Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Pflug Arch 460:525–542

    CAS  Article  Google Scholar 

  • Le Foll B, Diaz J, Sokoloff P (2005) A single cocaine exposure increases BDNF and D3 receptor expression: implications for drug-conditioning. NeuroReport 16:175–178

    PubMed  Article  Google Scholar 

  • Lee YW, Hennig B, Yao J, Toborek M (2001) Methamphetamine induces AP-1 and NF-kappaB binding and transactivation in human brain endothelial cells. J Neurosci Res 66:583–591

    PubMed  CAS  Article  Google Scholar 

  • León-Velarde F, Huicho L, Monge C (1992) Effects of cocaine on oxygen consumption and mitochondrial respiration in normoxic and hypoxic mice. Life Sci 50:213–218

    PubMed  Article  Google Scholar 

  • Lepsch LB, Munhoz CD, Kawamoto EM, Yshii LM, Lima LS, Curi-Boaventura MF, Salgado TM, Curi R, Planeta CS, Scavone C (2009) Cocaine induces cell death and activates the transcription nuclear factor kappa-b in pc12 cells. Mol Brain 2:1–15

    Article  CAS  Google Scholar 

  • Li F, Tsien JZ (2009) Memory and the NMDA receptors. N Engl J Med 361:302–303

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Li J, Guo Y, Schroeder FA, Youngs RM, Schmidt TW, Ferris C, Konradi C, Akbarian S (2004) Dopamine D2-like antagonists induce chromatin remodeling in striatal neurons through cyclic AMP-protein kinase A and NMDA receptor signaling. J Neurochem 90:1117–1131

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Lieber CS (1998) Hepatic and other medical disorders of alcoholism: from pathogenesis to treatment. J Stud Alcohol 59:9–25

    PubMed  CAS  Article  Google Scholar 

  • Lin TY, Huang WJ, Wu CC, Lu CW, Wang SJ (2014) Acacetin inhibits glutamate release and prevents kainic acid-induced neurotoxicity in rats. PLoS ONE 9:e88644

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Lipton JW, Gyawali S, Borys ED, Koprich JB, Ptaszny M, McGuire SO (2003) Prenatal cocaine administration increases glutathione and alpha-tocopherol oxidation in fetal rat brain. Brain Res Dev Brain Res 147:77–84

    PubMed  CAS  Article  Google Scholar 

  • Litosch I (2002) Novel mechanisms for feedback regulation of phospholipase C-beta activity. IUBMB Life 54:253–260

    PubMed  CAS  Article  Google Scholar 

  • Liu Z, Liu Y, Gao R, Li H, Dunn T, Wu P, Smith RG, Sarkar PS, Fang X (2014) Ethanol suppresses PGC-1α expression by interfering with the cAMP-CREB pathway in neuronal cells. PLoS ONE 9:e104247

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Ma Y, Hendershot LM (2004) ER chaperone functions during normal and stress conditions. J Chem Neuroanat 28:51–65

    PubMed  CAS  Article  Google Scholar 

  • Macedo DS, de Vasconcelos SM, dos Santos RS, Aguiar LM, Lima VT, Viana GS, de Sousa FC (2005) Cocaine alters catalase activity in prefrontal cortex and striatum of mice. Neurosci Lett 387:53–56

    PubMed  CAS  Article  Google Scholar 

  • Marini AM, Jiang X, Wu X, Tian F, Zhu D, Okagaki P, Lipsky RH (2004) Role of brain-derived neurotrophic factor and NF-kappaB in neuronal plasticity and survival: from genes to phenotype. Restor Neurol Neurosci 22:121–130

    PubMed  CAS  Google Scholar 

  • Mark S, Gold MD (1993) The neurobiology of cocaine. cocaine. Springer, New York, pp 37–79

    Google Scholar 

  • Martin PR, Singleton CK, Hiller-Sturmhofel S (2003) The role of thiamine deficiency in alcoholic brain disease. Alcohol Res Health 27:134–142

    PubMed  Google Scholar 

  • Martin BJ, Naughton BJ, Thirtamara-Rajamani K, Yoon DJ, Han DD, Devries AC, Gu HH (2011) Dopamine transporter inhibition is necessary for cocaine-induced increases in dendritic spine density in the nucleus accumbens. Synapse 65:490–496

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Masaki T, Mochizuki H, Matsushita S, Yokoyama A, Kamakura K, Higuchi S (2004) Association of aldehyde dehydrogenase-2 polymorphism with alcoholic polyneuropathy in humans. Neurosci Lett 363:288–290

    PubMed  CAS  Article  Google Scholar 

  • Mastrogiacomo F, Bergeron C, Kish SJ (1993) Brain alpha-ketoglutarate dehydrogenase complex activity in Alzheimer’s disease. J Neurochem 61:2007–2014

    PubMed  CAS  Article  Google Scholar 

  • Mattson MP, Meffert MK (2006) Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ 13:852–860

    PubMed  CAS  Article  Google Scholar 

  • Matus S, Castillo K, Hetz C (2012) Hormesis: protecting neurons against cellular stress in Parkinson disease. Autophagy 8:997–1001

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Maze I, Nestler EJ (2011) The epigenetic landscape of addiction. Ann NY Acad Sci 1216:99–113

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • McCance-Katz EF, Price LH, McDougle CJ, Kosten TR, Black JE, Jatlow PI (1993) Concurrent cocaine-ethanol ingestion in humans: pharmacology, physiology, behavior and the role of cocaethylene. Psychopharmacology 11:39–46

    Article  Google Scholar 

  • McCarthy DM, Zhang X, Darnell SB, Sangrey GR, Yanagawa Y, Sadri-Vakili G, Bhide PG (2011) Cocaine alters BDNF expression and neuronal migration in the embryonic mouse forebrain. J Neurosci 31:13400–13411

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Mermelstein PG (2009) Membrane-localised oestrogen receptor alpha and beta influence neuronal activity through activation of metabotropic glutamate receptors. J Neuroendocrinol 21:257–262

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Messing RO (2014) Alcohol and the nervous system. Aminoff’s neurology and general medicine, 5th edn. Academic Press, San Diego, pp 713–724

    Chapter  Google Scholar 

  • Morris JA, Dorner AJ, Edwards CA, Hendershot LM, Kaufman RJ (1997) Immunoglobulin binding protein (BiP) function is required to protect cells from endoplasmic reticulum stress but is not required for the secretion of selective proteins. J Biol Chem 272:4327–4334

    PubMed  CAS  Article  Google Scholar 

  • Muriach M, López-Pedrajas R, Barcia JM, Sanchez-Villarejo MV, Almansa I, Romero FJ (2010) Cocaine causes memory and learning impairments in rats: involvement of nuclear factor kappa B and oxidative stress, and prevention by topiramate. J Neurochem 114:675–684

    PubMed  CAS  Article  Google Scholar 

  • National Institute on Drug Abuse (2011) http://www.drugabuse.gov/. Accessed 5 February 2015

  • Nnadi CU, Mimiko OA, McCurtis HL, Cadet JL (2005) Neuropsychiatric effects of cocaine use disorders. J Natl Med Assoc 97:1504–1515

    PubMed  PubMed Central  Google Scholar 

  • Northcutt AL, Hutchinson MR, Wang X, Baratta MV, Hiranita T, Cochran TA, Pomrenze MB, Galer EL, Kopajtic TA, Li CM, Amat J, Larson G, Cooper DC, Huang Y, O’Neill CE, Yin H, Zahniser NR, Katz JL, Rice KC, Maier SF, Bachtell RK, Watkins LR (2015) DAT isn’t all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling. Mol Psychiatry. doi:10.1038/mp.2014.177

    PubMed  Google Scholar 

  • Numa R, Kohen R, Poltyrev T, Yaka R (2008) Tempol diminishes cocaine-induced oxidative damage and attenuates the development and expression of behavioral sensitization. Neuroscience 155:649–658

    PubMed  CAS  Article  Google Scholar 

  • O’Neill L (2000) The Toll/interleukin-1 receptor domain: a molecular switch for inflammation and host defence. Biochem Soc Trans 28:557–563

    PubMed  Article  Google Scholar 

  • Olney JW, Tenkova T, Dikranian K, Muglia LJ, Jermakowicz WJ, D’Sa C, Roth KA (2002) Ethanol-induced caspase-3 activation in the in vivo developing mouse brain. Neurobiol Dis 9:205–219

    PubMed  CAS  Article  Google Scholar 

  • Pascual M, Blanco AM, Cauli O, Miñarro J, Guerri C (2007) Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats. Eur J Neurosci 25:541–550

    PubMed  Article  Google Scholar 

  • Pascual M, Boix J, Felipo V, Guerri C (2009) Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat. J Neurochem 108:920–931

    PubMed  CAS  Article  Google Scholar 

  • Patel M, Modig F, Magnusson M, Fransson PA (2010) Alcohol intoxication at 0.06 and 0.10% blood alcohol concentration changes segmental body movement coordination. Exp Brain Res 202:431–443

    PubMed  CAS  Article  Google Scholar 

  • Peragallo J, Biousse V, Newman NJ (2013) Ocular manifestations of drug and alcohol abuse. Curr Opin Ophthalmol 24:566–573

    PubMed  PubMed Central  Article  Google Scholar 

  • Pereira DM, Valentão P, Correia-da-Silva G, Teixeira N, Andrade PB (2015) Translating endoplasmic reticulum biology into the clinic: a role for ER-targeted natural products? Nat Prod Rep. doi:10.1039/c4np00102h

    Google Scholar 

  • Plush T, Shakespeare W, Jacobs D, Ladi L, Sethi S, Gasperino J (2015) Cocaine-induced agitated delirium: a case report and review. J Intensive Care Med 30:49–57

    PubMed  Article  Google Scholar 

  • Poon HF, Abdullah L, Mullan MA, Mullan MJ, Crawford FC (2007) Cocaine-induced oxidative stress precedes cell death in human neuronal progenitor cells. Neurochem Int 50:69–73

    PubMed  CAS  Article  Google Scholar 

  • Qin W, Haroutunian V, Katsel P, Cardozo CP, Ho L, Buxbaum JD, Pasinetti GM (2009) PGC-1α expression decreases in the Alzheimer disease brain as a function of dementia. Arch Neurol 66:352–361

    PubMed  PubMed Central  Article  Google Scholar 

  • Ravina B, Marek K, Eberly S, Oakes D, Kurlan R, Ascherio A, Beal F, Beck J, Flagg E, Galpern WR, Harman J, Lang AE, Schwarzschild M, Tanner C, Shoulson I (2012) Dopamine transporter imaging is associated with long-term outcomes in Parkinson’s disease. Mov Disord 27:1392–1397

    PubMed  Article  Google Scholar 

  • Ribeiro FM, Devries RA, Hamilton A, Guimarães IM, Cregan SP, Pires RG, Ferguson SS (2014) Metabotropic glutamate receptor 5 knockout promotes motor and biochemical alterations in a mouse model of Huntington’s disease. Hum Mol Genet 23:2030–2042

    PubMed  CAS  Article  Google Scholar 

  • Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ (1999) Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ 319:1523–1528

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Rindi G, Imarisio L, Patrini C (1986) Effects of acute and chronic ethanol administration on regional thiamin pyrophosphokinase activity of the rat brain. Biochem Pharmacol 35:3903–3908

    PubMed  CAS  Article  Google Scholar 

  • Ron D (2002) Translational control in the endoplasmic reticulum stress response. J Clin Invest 110:1383–1388

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Russo SJ, Wilkinson MB, Mazei-Robison MS, Dietz DM, Maze I, Krishnan V, Renthal W, Graham A, Birnbaum SG, Green TA, Robison B, Lesselyong A, Perrotti LI, Bolaños CA, Kumar A, Clark MS, Neumaier JF, Neve RL, Bhakar AL, Barker PA, Nestler EJ (2009) Nuclear factor kappa B signaling regulates neuronal morphology and cocaine reward. J Neurosci 29:3529–3537

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Schmidt HD, McGinty JF, West AE, Sadri-Vakili G (2013) Epigenetics and psychostimulant addiction. Cold Spring Harb Perspect Med 3:a012047

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M (1999) NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat Med 5:554–559

    PubMed  CAS  Article  Google Scholar 

  • Schroeder FA, Penta KL, Matevossian A, Jones SR, Konradi C, Tapper AR, Akbarian S (2008) Drug-induced activation of dopamine D(1) receptor signaling and inhibition of class I/II histone deacetylase induce chromatin remodeling in reward circuitry and modulate cocaine-related behaviors. Neuropsychopharmacology 33:2981–2992

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Schweizer S, Meisel A, Märschenz S (2013) Epigenetic mechanisms in cerebral ischemia. J Cereb Blood Flow Metab 33:1335–1346

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Sechi GP, Serra A (2007) Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol 6:442–455

    PubMed  CAS  Article  Google Scholar 

  • Sharma HS, Menon P, Lafuente JV, Muresanu DF, Tian ZR, Patnaik R, Sharma A (2014) Development of in vivo drug-induced neurotoxicity models. Expert Opin Drug Metab Toxicol 10:1637–1661

    PubMed  Article  CAS  Google Scholar 

  • Shen Y, Schlessinger K, Zhu X, Meffre E, Quimby F, Levy DE, Darnell JE (2004) Essential role of STAT3 in postnatal survival and growth revealed by mice lacking STAT3 serine 727 phosphorylation. Mol Cell Biol 24:407–419

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Shimoke K, Utsumi T, Kishi S, Nishimura M, Sasaya H, Kudo M, Ikeuchi T (2004) Prevention of endoplasmic reticulum stress induced cell death by brain-derived neurotrophic factor in cultured cerebral cortical neurons. Brain Res 1028:105–111

    PubMed  CAS  Article  Google Scholar 

  • Shin EH, Bian S, Shim YB, Rahman MA, Chung KT, Kim JY, Wang JQ, Choe ES (2007) Cocaine increases endoplasmic reticulum stress protein expression in striatal neurons. Neuroscience 145:621–630

    PubMed  CAS  Article  Google Scholar 

  • Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, Troconso JC, Dawson VL, Dawson TM (2011) PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease. Cell 144:689–702

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Siddiqui WA, Ahad A, Ahsan H (2015) The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update. Arch Toxicol 89:289–317

    PubMed  CAS  Article  Google Scholar 

  • Signorini-Allibe N, Gonthier B, Lamarche F, Eysseric H, Barret L (2005) Chronic consumption of ethanol leads to substantial cell damage in cultured rat astrocytes in conditions promoting acetaldehyde accumulation. Alcohol Alcohol 40:163–171

    PubMed  CAS  Article  Google Scholar 

  • Siniscalchi A, Bonci A, Mercuri NB, De Siena A, De Sarro G, Malferrari G, Diana M, Gallelli L (2015) Cocaine dependence and stroke: pathogenesis and management. Curr Neurovasc Res 12:163–172

    PubMed  CAS  Article  Google Scholar 

  • Sordo L, Indave BI, Barrio G, Degenhardt L, de la Fuente L, Bravo MJ (2014) Cocaine use and risk of stroke: a systematic review. Drug Alcohol Depend 142:1–13

    PubMed  CAS  Article  Google Scholar 

  • Stephenson FA (2001) Subunit characterization of NMDA receptors. Curr Drug Targets 2:233–239

    PubMed  CAS  Article  Google Scholar 

  • St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127:397–408

    PubMed  CAS  Article  Google Scholar 

  • Surendran S, Rajasankar S (2010) Parkinson’s disease: oxidative stress and therapeutic approaches. Neurol Sci 31:531–540

    PubMed  Article  Google Scholar 

  • Takeuchi M, Saito T (2005) Cytotoxicity of acetaldehyde-derived advanced glycation end-products (AA-AGE) in alcoholic-induced neuronal degeneration. Alcohol Clin Exp Res 29:220S–224S

    PubMed  CAS  Article  Google Scholar 

  • Tallarida CS, Bires K, Avershal J, Tallarida RJ, Seo S, Rawls SM (2014) Ethanol and cocaine: environmental place conditioning, stereotypy, and synergism in planarians. Alcohol 48:579–586

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Tarragon E, Baliño P, Aragon CM (2014) Centrally formed acetaldehyde mediates ethanol-induced brain PKA activation. Neurosci Lett 580:68–73

    PubMed  CAS  Article  Google Scholar 

  • Thomas K, Davies A (2005) Neurotrophins: a ticket to ride for BDNF. Curr Biol 15:R262–R264

    PubMed  CAS  Article  Google Scholar 

  • Tiwari V, Chopra K (2013) Resveratrol abrogates alcoholinduced cognitive deficits by attenuating oxidative-nitrosative stress and inflammatory cascade in the adult rat brain. Neurochem Int 62:861–869

    PubMed  CAS  Article  Google Scholar 

  • Todd Wilk MD (2008) Manual of adolescent substance abuse treatment. American Psychiatric Publishing, Virginia, pp 44–45

    Google Scholar 

  • Vidhya A, Renjugopal V, Indira M (2013) Impact of thiamine supplementation in the reversal of ethanol induced toxicity in rats. Indian J Physiol Pharmacol 57:406–417

    PubMed  CAS  Google Scholar 

  • Volkow ND, Kim SW, Wang GJ, Alexoff D, Logan J, Muench L, Shea C, Telang F, Fowler JS, Wong C, Benveniste H, Tomasi D (2013) Acute alcohol intoxication decreases glucose metabolism but increases acetate uptake in the human brain. Neuroimage 64:277–283

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  • Yoon H, Kim DS, Lee GH, Kim KW, Kim HR, Chae HJ (2011a) Apoptosis induced by manganese on neuronal SK-N-MC cell line: endoplasmic reticulum (ER) stress and mitochondria dysfunction. Environ Health Toxicol 26:e2011017

    PubMed  PubMed Central  Article  Google Scholar 

  • Yoon H, Lee GH, Kim DS, Kim KW, Kim HR, Chae HJ (2011b) The effects of 3, 4 or 5 amino salicylic acids on manganese-induced neuronal death: ER stress and mitochondrial complexes. Toxicol In Vitro 25:1259–1268

    PubMed  CAS  Article  Google Scholar 

  • Ziedonis DM, Kosten TR (1991) Pharmacotherapy improves treatment outcome in depressed cocaine addicts. J Psycoactive Drugs 23:417–425

    CAS  Article  Google Scholar 

  • Zimatkin SM, Pronko SP, Vasiliou V, Gonzalez FJ, Deitrich RA (2006) Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol Clin Exp Res 30:1500–1505

    PubMed  CAS  Article  Google Scholar 

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Acknowledgments

The authors are grateful for the European Union (FEDER funds through COMPETE) and National Funds (FCT, Fundação para a Ciência e Tecnologia) through project UID/QUI/50006/2013 and for financial support from the European Union (FEDER funds) under the framework of QREN through Project NORTE-07-0124-FEDER-000069. R. Pereira is grateful to i3DU program for PhD fellowship.

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Correspondence to Patrícia Valentão.

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Pereira, R.B., Andrade, P.B. & Valentão, P. A Comprehensive View of the Neurotoxicity Mechanisms of Cocaine and Ethanol. Neurotox Res 28, 253–267 (2015). https://doi.org/10.1007/s12640-015-9536-x

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  • DOI: https://doi.org/10.1007/s12640-015-9536-x

Keywords

  • Cocaine
  • Ethanol
  • Mechanisms
  • Neurotoxicity