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Brazilian Journal of Medical and Biological Research

On-line version ISSN 1414-431X

Braz J Med Biol Res vol.46 no.11 Ribeirão Preto Nov. 2013  Epub Oct 15, 2013

http://dx.doi.org/10.1590/1414-431X20133379 

REVIEWS

Influence of the dopaminergic system, CREB, and transcription factor-κB on cocaine neurotoxicity

C.S. Planeta2 

L.B. Lepsch1 

R. Alves1 

C. Scavone1 

1Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brasil

2Laboratório de Neuropsicofarmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP, Brasil

ABSTRACT

Cocaine is a widely used drug and its abuse is associated with physical, psychiatric and social problems. Abnormalities in newborns have been demonstrated to be due to the toxic effects of cocaine during fetal development. The mechanism by which cocaine causes neurological damage is complex and involves interactions of the drug with several neurotransmitter systems, such as the increase of extracellular levels of dopamine and free radicals, and modulation of transcription factors. The aim of this review was to evaluate the importance of the dopaminergic system and the participation of inflammatory signaling in cocaine neurotoxicity. Our study showed that cocaine activates the transcription factors NF-κB and CREB, which regulate genes involved in cellular death. GBR 12909 (an inhibitor of dopamine reuptake), lidocaine (a local anesthetic), and dopamine did not activate NF-κB in the same way as cocaine. However, the attenuation of NF-κB activity after the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, suggests that the activation of NF-κB by cocaine is, at least partially, due to activation of D1 receptors. NF-κB seems to have a protective role in these cells because its inhibition increased cellular death caused by cocaine. The increase in BDNF (brain-derived neurotrophic factor) mRNA can also be related to the protective role of both CREB and NF-κB transcription factors. An understanding of the mechanisms by which cocaine induces cell death in the brain will contribute to the development of new therapies for drug abusers, which can help to slow down the progress of degenerative processes.

Key words: Cocaine; Apoptosis; NF-κB; CREB; BDNF; Neurotoxicity

Introduction

Drug abuse and addiction constitute a public health problem of great importance: both affect many people and cause a wide variety of consequences to society. Cocaine is an abused drug with a high prevalence worldwide. According to the United Nations Office on Drugs and Crime (UNODC, 2011 <http://www.unodc.org/documents/data-and-analysis/WDR2011/World_Drug_Report_2011_ebook.pdf>), although cocaine use has declined, it is still one of the most abused drugs in the USA. Cocaine inhibits the dopamine transporter (DAT) in neuron terminals, causing an increase in extracellular dopamine levels. Activation of dopamine transmission in the mesocorticolimbic system is a common characteristic of all addictive drugs. This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC). Repeated exposure to cocaine leads to neuroadaptations in the mesocorticolimbic system that are associated with the development of addiction (1,2). Addiction is a chronic relapsing disease (3) and its treatment is the most expensive of the neuropsychiatric disorders (4), mainly owing to the costs of health care, productivity loss, and crime (UNODC, 2011).

Cocaine Toxicity

Cocaine users seek the effects of euphoria (feeling of well-being), self-confidence, and increased alertness. However, cocaine abuse can also lead to adverse effects such as anxiety, paranoia, self-centered behavior, dysphoria, and delusions (5). Moreover, many studies have demonstrated a variety of toxic effects of cocaine in humans (5-8) and animals (9,10). A study of 332 cocaine users in São Paulo found that one-fifth had severe seizures and death resulting from its chronic use (11). It has also been demonstrated that the use of high doses of cocaine is associated with violent behavior, including murder and suicide (12). The stimulant effects of cocaine can lead to a rapid increase in its intensity due to a sensitization process related to drug craving and increased intake, leading to the use of increasing concentrations of the drug by chronic users (13). There are reports that cocaine causes cardiovascular, neuromuscular, and central nervous system toxicity, and complications such as infections, kidney and lung injury, liver toxicity, and reproductive disorders (14). The occurrence of epilepsy and psychiatric and neurological deficits is also related to the use of this drug (15). Cocaine can affect cellular morphology or function, including: inhibition of neurite extension (extensions of the cell bodies of neurons) (16), changes in the function and morphology of mitochondria (17), reduced dilation of the endoplasmic reticulum (18), and abnormal lysosomal proteolysis (19). Cognitive disorders such as learning and memory deficits are reported in most chronic users of cocaine (20-22) and in children of dependent mothers (23-25). Prenatal exposure to cocaine (26,27) may affect fetal development because cocaine is able to cross the placenta (28) and accumulate in the fetus (29,30). The consequences - for developing neurons - of in utero exposure to psychostimulants are regarded as a major area of interest. It is estimated that approximately 30,000-160,000 newborns are exposed to cocaine in utero per year (Mathias, 1995 <http://archives.drugabuse.gov/NIDA_Notes/NNVol10N1/NIDASurvey.html>). However, the consequences of prenatal cocaine use and the mechanism of action by which this drug exerts its effects have not been widely investigated. It has been reported that newborns exposed to cocaine in utero tend to have low birth weight, decreased head circumference, systemic hypertension, tachycardia (31,32), and deficits in cognitive development (33,34). The cognitive abnormalities detected in the first year of life appear to contribute to learning and attention disabilities at school age (35). The changes associated with intrauterine exposure to cocaine may be related to molecular adaptations or to anatomical changes in specific brain regions, such as the anterior cingulate cortex, prefrontal cortex, and middle frontal areas that regulate cognitive and emotional development (25).

In vitro studies investigating the effects of cocaine in cell culture neuroglioblastomas (36), PC12 cells (37), cortical neurons of fetal mice (38), and neuronal precursor cells (39) have reported changes in the growth and differentiation of neurons and in the activation of cell death pathways. In addition, it has been reported in animal studies that prenatal exposure to cocaine causes morphological brain abnormalities and cognitive deficits after birth (34,40). Taken together, these data suggest that cocaine can cause a variety of adverse effects on neuronal development.

Cocaine effects on CREB and NF-κB

The induction by cocaine of the immediate expression of genes involved in apoptotic cascades has been reported by several researchers and it is believed that this effect is mediated primarily by the stimulation of D1 receptors (41,42). Thus, it is suggested that cocaine causes changes in gene transcription that can be associated with some long-lasting functional changes (43). CREB is a transcription factor that can be phosphorylated by several protein kinases. CREB proteins comprise a family that binds to a particular sequence of DNA, called the cAMP response element (CRE) (44). Activation of CREB involves several steps; the phosphorylation of serine 133 (45) and the recruitment of CREB-binding protein (CBP) are crucial (46,47). CREB plays an important role in mediating the effects of cAMP and neurotransmitters that act on gene expression via the cAMP pathway. Some of the genes that contain CRE sites express Fos, proencephalin, somatostatin, tyrosine hydroxylase, α1-Na, Κ-ATPase, and vasoactive intestinal peptide (48,49). The activation of the cAMP pathway is regulated by the dopaminergic system, so the transcription factor CREB seems to be involved in the effects of chronic administration of psychostimulants (50).

NF-κB plays an important role in regulating the inflammatory response and cell death (51). NF-κB is a transcription factor found in a variety of cell types, including neurons and microglia (52). NF-κB can be activated by pro-inflammatory stimuli such as: pathogen-derived lipopolysaccharide (LPS); cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-1 β (IL-1β); and reactive oxygen species (53-55).

NF-κB proteins comprise members of the Rel/NF-κB family, forming homo- and heterodimers through a combination of the p65 (or RelA), p50, p52, c-Rel, or RelB subunits. It is constitutively expressed in the cytoplasm where it is bound to IκB, a protein that masks the nuclear localization signal of NF-κB, thereby retaining it in the cytoplasm (56). Inducers of NF-κB act through intracellular signaling cascades that activate the IκB kinases (IΚΚs), which phosphorylate two specific N-terminal serines of IκBα, resulting in IκBα polyubiquitination and degradation in the 26S proteasome (57).

When IκBα is degraded, NF-κB migrates to the nucleus and modulates the transcription of target genes involved in cell death. Evidence obtained in our laboratory showed, by electrophoretic mobility shift assay, that 1.0 mM cocaine induced activation of NF-κB in PC12 cells after 6 h of incubation (58). The activation of the p50/p65 subunit of NF-κB by cocaine is linked to the activation of the D1 dopamine receptor (58). Cocaine concentrations used in our study were similar to those previously used by others in different cell types (59,60). Cocaine-induced NF-κB activation was also observed in macrophages (61), human brain endothelial cells (62), and PC12 cells (63). In addition, in vivo studies in mice showed that chronic administration of cocaine induced NF-κB activation in NAc (64). It is important to note that high constitutive NF-κB activity mediates resistance to oxidative stress in neuronal cells (65) and in agents that inhibit NF-κB activation-induced apoptosis in response to several neurotoxins (66,67). In fact, in our study, the inhibition of NF-κB significantly increased cell death accelerated by cocaine treatment, suggesting that this transcription factor plays a protective role in cocaine-treated PC12 cells (58). In addition, Lee et al. (62) showed an anti-apoptotic effect of NF-κB in PC12 cell death induced by auto-oxidized dopamine. Taken together, the results showed that concentrations of cocaine comparable to the concentration that has been reported in plasma levels (0.3 μM to 1 mM) of subjects who use this drug (60,68) can induce changes in transcription factors that are important to the inflammatory response and innate immune response (69) and to cell death and the cell protection response.

Cell Death and Cocaine

Cell death can occur by two distinct mechanisms: necrosis and apoptosis. Necrosis, also called pathological or accidental cell death, occurs when cells are exposed to an extreme variation of their physiological conditions (such as hyperthermia and hypoxia) with consequent damage of the membrane, leading to cell death. Apoptosis, unlike necrosis, is a selective and regulated process important for embryogenesis, development, and the depletion of infected cells. However, a change in the process of apoptosis can lead to the development of some neurodegenerative diseases such as stroke, Alzheimer's disease, and Parkinson's disease (70).

Given the diversity of situations that can cause neuronal death by apoptosis, it is not surprising that several components of signal transduction have been described that participate in this process. Among them is the loss of growth factors with neurotrophic activity such as neuronal growth factor (71), which can be caused by an increased release of cytokines such as TNF-α (72), the excitotoxicity caused by an excessive increase in the concentration of excitatory amino acids such as glutamate (73), or by the increased oxidative stress and modulation of transcription factors such as NF-κB (74).

In nervous tissue, apoptosis and necrosis may coexist or occur sequentially, with the mode of cell death being influenced by the intensity and duration of harmful stimuli and also by the energy state of the cell (75). One way to induce apoptosis is by the release of mitochondrial cytochrome c and the subsequent activation of caspases 3, 6, and 7 (76).

In addition to the caspase-dependent apoptotic process, caspase-independent events may also occur (77). One of the most studied proteins involved in apoptosis is caspase-independent apoptosis-inducing factor, which, when released from mitochondria, translocates to the nucleus, where it induces DNA fragmentation independent of caspases. The proteins that form part of the Bcl-2 family (Bax, Bak, Bcl-XL, Bcl-2, and others) regulate programmed cell death, the integrity of the mitochondria, and cytochrome c release (78). By acting on mitochondria, these proteins have an important role in determining death and cell survival (79). The Bax protein is considered pro-apoptotic and the Bcl-2 protein anti-apoptotic (60). The expression of Bcl-2 is increased in neurons that survived ischemic strokes, and a reduction in this protein exacerbates neuronal death (80). The expression of Bcl-2 can be induced by several promoters that bind to its regulatory region, including CREB (81). Thus, the Bcl-2/Bax balance is crucial to the regulation of cell death.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in neuronal protection. The intracellular signaling of BDNF occurs by the binding of neurotrophin to its receptor TrκB and by the activation of protein tyrosine kinases in the cytoplasm (82). BDNF is regulated by many factors, including transcription factors such as NF-κB and CREB. These, too, are indirectly regulated by the expression of the receptor TrκB, which requires the presence of secondary events such as increased cAMP or Ca2+ to be efficiently inserted in the plasma membrane, thereby being able to transduce the signal triggered by the binding of BDNF (83).

Several reports suggest that cell death by apoptosis plays an important role in the induction of neuronal loss caused by cocaine and other psychostimulants (84,85). It has been shown that cocaine activates the mitochondrial apoptotic pathway, decreasing the levels of mitochondrial cytochrome c and activating caspases 3 and 9 in cultured neuronal cortex (59). In myocardial cells, cocaine inhibits a complex of the respiratory chain of mitochondria (68) and decreases the mitochondrial membrane potential and ATP levels in cardiomyocytes (86). Finally, the results of microarray experiments (87) suggest that mitochondrial function and energy metabolism are affected in the brains of cocaine human abusers.

We confirmed that cocaine treatment induced PC12 cell death by apoptosis and that necrosis was associated with mitochondrial dysfunction, increased LDH release, activation of caspase 3, decreased Bcl-2 expression, and increased α-spectrin cleavage. In our experiments, we found an increase in BDNF mRNA levels 6 h after treatment with cocaine, indicating a transitory rise in this neurotrophin. BDNF regulates the differentiation and apoptosis of neurons and glial cells (88), and the increase in BDNF may be considered as a line of defense against the apoptosis process caused - in our model - by cocaine. In fact, the increase in BDNF mRNA levels could be linked to the activation of NF-κB and CREB (89). The protective role of NF-κB in cocaine treatment of PC12 cells may be associated with the expression of anti-apoptotic genes, such as BDNF. However, the compensatory mechanisms for cell death induced by cocaine are ineffective at terminating the apoptosis process later (Figure 1). It is interesting to note that methamphetamine and 3,4-methylenedioxymethamphetamine can also induce apoptosis in the same way as cocaine, but cocaine seems to be less toxic (84). This may be due to the induction of protective systems (e.g., NF-κB and BDNF) by cocaine. Therefore, the activation of both transcription factors may represent a compensatory mechanism to limit cell death associated with cocaine drug abuse.

Figure 1 Schematic representation of the neurotoxic action of cocaine in PC12 cells. The treatment of PC12 cells with cocaine can alter the Bax/Bcl-2 ratio, reducing the Bcl2 levels, which could lead to activation of caspase 3 and the triggering of the cell death process seen after 24 h of treatment. On the other hand, to protect the cell from cocaine toxicity, both NF-κB and CREB are activated at 6 h. The activation of these transcription factors could lead to transcription of anti-apoptotic genes, such as brain-derived neurotrophic factor (BDNF), that act to reverse the process of cell death. 

Although we have considered the induction of apoptosis related to mitochondrial dysfunction as the prime pathway involved in cocaine neurotoxicity, it is important to consider other alternative pathways that can also play an important role in this process, such as the NADPH oxidase pathway. In fact, cocaine is associated with severe oxidative stress in cardiomyocytes involving the production of reactive oxygen species, leading to MAPΚ activation and an apoptosis process that is mediated by NOX2 (90).

An understanding of the mechanisms by which cocaine induces cell death in the brain will contribute to the development of new therapies designed to slow the progress of neurodegenerative processes in drug abusers.

Cocaine can cause damage to the newborn children of pregnant women who use cocaine during the pregnancy. As the migration behavior of neurons ultimately determines their connectivity, synaptic potential, and success of neurotransmission, cocaine may produce behavioral and anatomical alterations as a result of maternal cocaine use during pregnancy by acting on neuronal guidance. An understanding of the mechanisms by which cocaine leads to motivational alterations in offspring may ultimately pave the way for the development of strategies for educational intervention programs and/or potential pharmacological treatments.

Acknowledgements

Research supported by FAPESP (#2006/50105-0 to C. Scavone) and partially supported by the University of São Paulo (Grant #2011.1.9333.1.3, NAPNA). L.B. Lepsch was supported by student research fellowships from FAPESP and CAPES. R. Alves is supported by CAPES (PRODOC). C. Scavone and C.S. Planeta are recipients of research fellowship from CNPq.

References

1. Wise RA, Bozarth MA. A psychomotor stimulant theory of addiction. Psychol Rev 1987; 94: 469-492, doi: 10.1037/0033-295X.94.4.469. [ Links ]

2. Robinson TE, Becker JB. Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 1986; 396: 157-198, doi: 10.1016/0165-0173(86)90002-0. [ Links ]

3. Leshner AI. Addiction is a brain disease, and it matters. Science 1997; 278: 45-47, doi: 10.1126/science.278.5335.45. [ Links ]

4. Uhl GR, Grow RW. The burden of complex genetics in brain disorders. Arch Gen Psychiatry 2004; 61: 223-229, doi: 10.1001/archpsyc.61.3.223. [ Links ]

5. Nnadi CU, Mimiko OA, McCurtis HL, Cadet JL. Neuropsychiatric effects of cocaine use disorders. J Natl Med Assoc 2005; 97: 1504-1515. [ Links ]

6. Mittleman RE, Wetli CV. Death caused by recreational cocaine use. An update. JAMA 1984; 252: 1889-1893, doi: 10.1001/jama.1984.03350140035021. [ Links ]

7. Cregler LL, Mark H. Medical complications of cocaine abuse. N Engl J Med 1986; 315: 1495-1500, doi: 10.1056/NEJM198612043152327. [ Links ]

8. Bates CK. Medical risks of cocaine use. West J Med 1988; 148: 440-444. [ Links ]

9. Wilson MC, Holbrook JM. Intravenous cocaine lethality in the rat. Pharmacol Res Commun 1978; 10: 243-256, doi: 10.1016/S0031-6989(78)80018-6. [ Links ]

10. Bozarth MA, Wise RA. Toxicity associated with long-term intravenous heroin and cocaine self-administration in the rat. JAMA 1985; 254: 81-83, doi: 10.1001/jama.1985.03360010087032. [ Links ]

11. Ferri CP, Dunn J, Gossop M, Laranjeira R. Factors associated with adverse reactions to cocaine among a sample of long-term, high-dose users in São Paulo, Brazil. Addict Behav 2004; 29: 365-374, doi: 10.1016/j.addbeh.2003.08.029. [ Links ]

12. Karch SB. Diphenhydramine toxicity: comparisons of postmortem findings in diphenhydramine-, cocaine-, and heroin-related deaths. Am J Forensic Med Pathol 1998; 19: 143-147, doi: 10.1097/00000433-199806000-00008. [ Links ]

13. Karch SB, Stephens BS. When is cocaine the cause of death? Am J Forensic Med Pathol 1991; 12: 1-2, doi: 10.1097/00000433-199103000-00001. [ Links ]

14. Glauser J, Queen JR. An overview of non-cardiac cocaine toxicity. J Emerg Med 2007; 32: 181-186, doi: 10.1016/j.jemermed.2006.05.044. [ Links ]

15. Dhuna A, Pascual-Leone A, Langendorf F. Chronic, habitual cocaine abuse and kindling-induced epilepsy: a case report. Epilepsia 1991; 32: 890-894, doi: 10.1111/j.1528-1157.1991.tb05547.x. [ Links ]

16. Marshall W. Size control in dynamic organelles. Trends Cell Biol 2002; 12: 414-419, doi: 10.1016/S0962-8924(02)02341-3. [ Links ]

17. Yuan C, Acosta D Jr. Cocaine-induced mitochondrial dysfunction in primary cultures of rat cardiomyocytes. Toxicology 1996; 112: 1-10, doi: 10.1016/0300-483X(96)03341-0. [ Links ]

18. Powers JF, Alroy J, Shuster L. Hepatic morphologic and biochemical changes induced by subacute cocaine administration in mice. Toxicol Pathol 1992; 20: 61-70, doi: 10.1177/019262339202000108. [ Links ]

19. Carpenter G, Cohen S.125I-labeled human epidermal growth factor. Binding, internalization, and degradation in human fibroblasts. J Cell Biol 1976; 71: 159-171, doi: 10.1083/jcb.71.1.159. [ Links ]

20. Ardila A, Rosselli M, Strumwasser S. Neuropsychological deficits in chronic cocaine abusers. Int J Neurosci 1991; 57: 73-79, doi: 10.3109/00207459109150348. [ Links ]

21. O'Malley S, Adamse M, Heaton RK, Gawin FH. Neuropsychological impairment in chronic cocaine abusers. Am J Drug Alcohol Abuse 1992; 18: 131-144, doi: 10.3109/00952999208992826. [ Links ]

22. Mittenberg W, Motta S. Effects of chronic cocaine abuse on memory and learning. Arch Clin Neuropsychol 1993; 8: 477-483. [ Links ]

23. Mayes LC. Genetics of childhood disorders: LV. Prenatal drug exposure. J Am Acad Child Adolesc Psychiatry 2003; 42: 1258-1261, doi: 10.1097/00004583-200310000-00019. [ Links ]

24. Arendt RE, Short EJ, Singer LT, Minnes S, Hewitt J, Flynn S, et al. Children prenatally exposed to cocaine: developmental outcomes and environmental risks at seven years of age. J Dev Behav Pediatr 2004; 25: 83-90, doi: 10.1097/00004703-200404000-00002. [ Links ]

25. Thompson BL, Levitt P, Stanwood GD. Prenatal cocaine exposure specifically alters spontaneous alternation behavior. Behav Brain Res 2005; 164: 107-116, doi: 10.1016/j.bbr.2005.06.010. [ Links ]

26. Chasnoff IJ, Griffith DR. Cocaine: clinical studies of pregnancy and the newborn. Ann N Y Acad Sci 1989; 562: 260-266, doi: 10.1111/j.1749-6632.1989.tb21024.x. [ Links ]

27. Dow-Edwards DL. Long-term neurochemical and neurobehavioral consequences of cocaine use during pregnancy. Ann N Y Acad Sci 1989; 562: 280-289, doi: 10.1111/j.1749-6632.1989.tb21026.x. [ Links ]

28. Schenker S, Yang Y, Johnson RF, Downing JW, Schenken RS, Henderson GI, et al. The transfer of cocaine and its metabolites across the term human placenta. Clin Pharmacol Ther 1993; 53: 329-339, doi: 10.1038/clpt.1993.29. [ Links ]

29. Wiggins RC, Rolsten C, Ruiz B, Davis CM. Pharmacokinetics of cocaine: basic studies of route, dosage, pregnancy and lactation. Neurotoxicology 1989; 10: 367-381. [ Links ]

30. Szeto HH. Kinetics of drug transfer to the fetus. Clin Obstet Gynecol 1993; 36: 246-254, doi: 10.1097/00003081-199306000-00006. [ Links ]

31. Handler A, Kistin N, Davis F, Ferre C. Cocaine use during pregnancy: perinatal outcomes. Am J Epidemiol 1991; 133: 818-825. [ Links ]

32. Silvestri JM, Long JM, Weese-Mayer DE, Barkov GA. Effect of prenatal cocaine on respiration, heart rate, and sudden infant death syndrome. Pediatr Pulmonol 1991; 11: 328-334, doi: 10.1002/ppul.1950110409. [ Links ]

33. Lester BM, Tronick EZ, LaGasse L, Seifer R, Bauer CR, Shankaran S, et al. The maternal lifestyle study: effects of substance exposure during pregnancy on neurodevelopmental outcome in 1-month-old infants. Pediatrics 2002; 110: 1182-1192, doi: 10.1542/peds.110.6.1182. [ Links ]

34. Harvey JA. Cocaine effects on the developing brain: current status. Neurosci Biobehav Rev 2004; 27: 751-764, doi: 10.1016/j.neubiorev.2003.11.006. [ Links ]

35. Singer LT, Minnes S, Short E, Arendt R, Farkas K, Lewis B, et al. Cognitive outcomes of preschool children with prenatal cocaine exposure. JAMA 2004; 291: 2448-2456, doi: 10.1001/jama.291.20.2448. [ Links ]

36. Johnson JE Jr, Weissman AD. Cocaine produces fine structural nuclear alterations in cultured neuroglioblastoma cells. Brain Res Bull 1988; 20: 39-47, doi: 10.1016/0361-9230(88)90007-X. [ Links ]

37. Zachor D, Cherkes JK, Fay CT, Ocrant I. Cocaine differentially inhibits neuronal differentiation and proliferationin vitro. J Clin Invest 1994; 93: 1179-1185, doi: 10.1172/JCI117071. [ Links ]

38. Nassogne MC, Louahed J, Evrard P, Courtoy PJ. Cocaine induces apoptosis in cortical neurons of fetal mice. J Neurochem 1997; 68: 2442-2450, doi: 10.1046/j.1471-4159.1997.68062442.x. [ Links ]

39. Hu S, Cheeran MC, Sheng WS, Ni HT, Lokensgard JR, Peterson PK. Cocaine alters proliferation, migration, and differentiation of human fetal brain-derived neural precursor cells. J Pharmacol Exp Ther 2006; 318: 1280-1286, doi: 10.1124/jpet.106.103853. [ Links ]

40. Mayes LC. Developing brain andin utero cocaine exposure: effects on neural ontogeny. Dev Psychopathol 1999; 11: 685-714, doi: 10.1017/S0954579499002278. [ Links ]

41. Hope B, Kosofsky B, Hyman SE, Nestler EJ. Regulation of immediate early gene expression and AP-1 binding in the rat nucleus accumbens by chronic cocaine. Proc Natl Acad Sci U S A 1992; 89: 5764-5768, doi: 10.1073/pnas.89.13.5764. [ Links ]

42. Ennulat DJ, Babb S, Cohen BM. Persistent reduction of immediate early gene mRNA in rat forebrain following single or multiple doses of cocaine. Brain Res Mol Brain Res 1994; 26: 106-112, doi: 10.1016/0169-328X(94)90080-9. [ Links ]

43. Mackler SA, Eberwine JH. The molecular biology of addictive drugs. Mol Neurobiol 1991; 5: 45-58, doi: 10.1007/BF02935612. [ Links ]

44. Montminy MR, Bilezikjian LM. Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature 1987; 328: 175-178, doi: 10.1038/328175a0. [ Links ]

45. Shaywitz AJ, Greenberg ME. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 1999; 68: 821-861, doi: 10.1146/annurev.biochem.68.1.821. [ Links ]

46. Chrivia JC, Kwok RP, Lamb N, Hagiwara M, Montminy MR, Goodman RH. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 1993; 365: 855-859, doi: 10.1038/365855a0. [ Links ]

47. Cardinaux JR, Notis JC, Zhang Q, Vo N, Craig JC, Fass DM, et al. Recruitment of CREB binding protein is sufficient for CREB-mediated gene activation. Mol Cell Biol 2000; 20: 1546-1552, doi: 10.1128/MCB.20.5.1546-1552.2000. [ Links ]

48. Nestler EJ, Hope BT, Widnell KL. Drug addiction: a model for the molecular basis of neural plasticity. Neuron 1993; 11: 995-1006, doi: 10.1016/0896-6273(93)90213-B. [ Links ]

49. Kobayashi M, Kawakami K. ATF-1CREB heterodimer is involved in constitutive expression of the housekeeping Na,K-ATPase alpha 1 subunit gene. Nucleic Acids Res 1995; 23: 2848-2855, doi: 10.1093/nar/23.15.2848. [ Links ]

50. Nestler EJ, Aghajanian GK. Molecular and cellular basis of addiction. Science 1997; 278: 58-63, doi: 10.1126/science.278.5335.58. [ Links ]

51. Barkett M, Gilmore TD. Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene 1999; 18: 6910-6924, doi: 10.1038/sj.onc.1203238. [ Links ]

52. Kaltschmidt C, Kaltschmidt B, Neumann H, Wekerle H, Baeuerle PA. Constitutive NF-kappa B activity in neurons. Mol Cell Biol 1994; 14: 3981-3992. [ Links ]

53. Hoffmann A, Baltimore D. Circuitry of nuclear factor kappaB signaling. Immunol Rev 2006; 210: 171-186, doi: 10.1111/j.0105-2896.2006.00375.x. [ Links ]

54. Munhoz CD, Lepsch LB, Kawamoto EM, Malta MB, Lima LS, Avellar MC, et al. Chronic unpredictable stress exacerbates lipopolysaccharide-induced activation of nuclear factor-kappaB in the frontal cortex and hippocampus via glucocorticoid secretion. J Neurosci 2006; 26: 3813-3820, doi: 10.1523/JNEUROSCI.4398-05.2006. [ Links ]

55. Mattson MP, Meffert MK. Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ 2006; 13: 852-860, doi: 10.1038/sj.cdd.4401837. [ Links ]

56. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998; 16: 225-260, doi: 10.1146/annurev.immunol.16.1.225. [ Links ]

57. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002; 109 (Suppl): S81-S96, doi: 10.1016/S0092-8674(02)00703-1. [ Links ]

58. Lepsch LB, Munhoz CD, Kawamoto EM, Yshii LM, Lima LS, Curi-Boaventura MF, et al. Cocaine induces cell death and activates the transcription nuclear factor kappa-B in PC12 cells. Mol Brain 2009; 2: 3-9, doi: 10.1186/1756-6606-2-3. [ Links ]

59. Cunha-Oliveira T, Rego AC, Morgadinho MT, Macedo T, Oliveira CR. Differential cytotoxic responses of PC12 cells chronically exposed to psychostimulants or to hydrogen peroxide. Toxicology 2006; 217: 54-62, doi: 10.1016/j.tox.2005.08.022. [ Links ]

60. Dey S, Mactutus CF, Booze RM, Snow DM. Cocaine exposurein vitro induces apoptosis in fetal locus coeruleus neurons by altering the Bax/Bcl-2 ratio and through caspase-3 apoptotic signaling. Neuroscience 2007; 144: 509-521, doi: 10.1016/j.neuroscience.2006.09.047. [ Links ]

61. Dhillon NK, Williams R, Peng F, Tsai YJ, Dhillon S, Nicolay B, et al. Cocaine-mediated enhancement of virus replication in macrophages: implications for human immunodeficiency virus-associated dementia. J Neurovirol 2007; 13: 483-495, doi: 10.1080/13550280701528684. [ Links ]

62. Lee YW, Hennig B, Yao J, Toborek M. Methamphetamine induces AP-1 and NF-kappaB binding and transactivation in human brain endothelial cells. J Neurosci Res 2001; 66: 583-591, doi: 10.1002/jnr.1248. [ Links ]

63. Imam SZ, Duhart HM, Skinner JT, Ali SF. Cocaine induces a differential dose-dependent alteration in the expression profile of immediate early genes, transcription factors, and caspases in PC12 cells: a possible mechanism of neurotoxic damage in cocaine addiction. Ann N Y Acad Sci 2005; 1053: 482-490, doi: 10.1196/annals.1344.042. [ Links ]

64. Ang E, Chen J, Zagouras P, Magna H, Holland J, Schaeffer E, et al. Induction of nuclear factor-kappaB in nucleus accumbens by chronic cocaine administration. J Neurochem 2001; 79: 221-224, doi: 10.1046/j.1471-4159.2001.00563.x. [ Links ]

65. Lezoualc'h F, Sagara Y, Holsboer F, Behl C. High constitutive NF-kappaB activity mediates resistance to oxidative stress in neuronal cells. J Neurosci 1998; 18: 3224-3232. [ Links ]

66. Barger SW, Horster D, Furukawa K, Goodman Y, Krieglstein J, Mattson MP. Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc Natl Acad Sci U S A 1995; 92: 9328-9332, doi: 10.1073/pnas.92.20.9328. [ Links ]

67. Mattson MP, Culmsee C, Yu ZF. Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res 2000; 301: 173-187, doi: 10.1007/s004419900154. [ Links ]

68. Yuan C, Acosta D Jr. Effect of cocaine on mitochondrial electron transport chain evaluated in primary cultures of neonatal rat myocardial cells and in isolated mitochondrial preparations. Drug Chem Toxicol 2000; 23: 339-348, doi: 10.1081/DCT-100100119. [ Links ]

69. Clark KH, Wiley CA, Bradberry CW. Psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection. Neurotox Res 2013; 23: 174-188, doi: 10.1007/s12640-012-9334-7. [ Links ]

70. Mancuso M, Coppede F, Murri L, Siciliano G. Mitochondrial cascade hypothesis of Alzheimer's disease: myth or reality? Antioxid Redox Signal 2007; 9: 1631-1646, doi: 10.1089/ars.2007.1761. [ Links ]

71. Sartorius U, Schmitz I, Krammer PH. Molecular mechanisms of death-receptor-mediated apoptosis. Chembiochem 2001; 2: 20-29, doi: 10.1002/1439-7633(20010105)2:1<20::AID-CBIC20>3.0.CO;2-X. [ Links ]

72. Orlinick JR, Chao MV. TNF-related ligands and their receptors. Cell Signal 1998; 10: 543-551, doi: 10.1016/S0898-6568(98)00018-7. [ Links ]

73. Michaelis EK. Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog Neurobiol 1998; 54: 369-415, doi: 10.1016/S0301-0082(97)00055-5. [ Links ]

74. Haddad JJ. Oxygen-sensitive pro-inflammatory cytokines, apoptosis signaling and redox-responsive transcription factors in development and pathophysiology. Cytokines Cell Mol Ther 2002; 7: 1-14, doi: 10.1080/13684730216401. [ Links ]

75. Hutchins JB, Barger SW. Why neurons die: cell death in the nervous system. Anat Rec 1998; 253: 79-90, doi: 10.1002/(SICI)1097-0185(199806)253:3<79::AID-AR4>3.0.CO;2-9. [ Links ]

76. Jemmerson R, Dubinsky JM, Brustovetsky N. Cytochrome C release from CNS mitochondria and potential for clinical intervention in apoptosis-mediated CNS diseases. Antioxid Redox Signal 2005; 7: 1158-1172, doi: 10.1089/ars.2005.7.1158. [ Links ]

77. Kroemer G, Martin SJ. Caspase-independent cell death. Nat Med 2005; 11: 725-730, doi: 10.1038/nm1263. [ Links ]

78. Tsujimoto Y. Prevention of neuronal cell death by Bcl-2. Results Probl Cell Differ 1998; 24: 137-155, doi: 10.1007/978-3-540-69185-3_7. [ Links ]

79. Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev 1999; 13: 1899-1911, doi: 10.1101/gad.13.15.1899. [ Links ]

80. Chen J, Simon RP, Nagayama T, Zhu R, Loeffert JE, Watkins SC, et al. Suppression of endogenous bcl-2 expression by antisense treatment exacerbates ischemic neuronal death. J Cereb Blood Flow Metab 2000; 20: 1033-1039, doi: 10.1097/00004647-200007000-00002. [ Links ]

81. Riccio A, Ahn S, Davenport CM, Blendy JA, Ginty DD. Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 1999; 286: 2358-2361, doi: 10.1126/science.286.5448.2358. [ Links ]

82. Mattson MP. Contributions of mitochondrial alterations, resulting from bad genes and a hostile environment, to the pathogenesis of Alzheimer's disease. Int Rev Neurobiol 2002; 53: 387-409, doi: 10.1016/S0074-7742(02)53014-2. [ Links ]

83. Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001; 24: 677-736, doi: 10.1146/annurev.neuro.24.1.677. [ Links ]

84. Cunha-Oliveira T, Rego AC, Oliveira CR. Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs. Brain Res Rev 2008; 58: 192-208, doi: 10.1016/j.brainresrev.2008.03.002. [ Links ]

85. Cunha-Oliveira T, Silva L, Silva AM, Moreno AJ, Oliveira CR, Santos MS. Mitochondrial complex I dysfunction induced by cocaine and cocaine plus morphine in brain and liver mitochondria. Toxicol Lett 2013; 219: 298-306, doi: 10.1016/j.toxlet.2013.03.025. [ Links ]

86. Xiao Y, He J, Gilbert RD, Zhang L. Cocaine induces apoptosis in fetal myocardial cells through a mitochondria-dependent pathway. J Pharmacol Exp Ther 2000; 292: 8-14. [ Links ]

87. Lehrmann E, Oyler J, Vawter MP, Hyde TM, Kolachana B, Kleinman JE, et al. Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J 2003; 3: 27-40, doi: 10.1038/sj.tpj.6500146. [ Links ]

88. Thomas K, Davies A. Neurotrophins: a ticket to ride for BDNF. Curr Biol 2005; 15: R262-R264, doi: 10.1016/j.cub.2005.03.023. [ Links ]

89. Marini AM, Jiang X, Wu X, Tian F, Zhu D, Okagaki P, et al. Role of brain-derived neurotrophic factor and NF-kappaB in neuronal plasticity and survival: From genes to phenotype. Restor Neurol Neurosci 2004; 22: 121-130. [ Links ]

90. Fan L, Sawbridge D, George V, Teng L, Bailey A, Kitchen I, et al. Chronic cocaine-induced cardiac oxidative stress and mitogen-activated protein kinase activation: the role of Nox2 oxidase. J Pharmacol Exp Ther 2009; 328: 99-106, doi: 10.1124/jpet.108.145201. [ Links ]

First published online October 15, 2013.

Received: July 21, 2013; Accepted: August 19, 2013

Correspondence: C. Scavone, Departamento de Farmacologia, Instituto de Ciências Biomédicas, USP, Av. Prof. Lineu Prestes, 1524, Sala 338, 05508-900 São Paulo, SP, Brasil. +55-11-3091-7325. E-mail:cristoforo.scavone@gmail.com

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