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Neurotox Res

DOI 10.1007/s12640-015-9536-x

REVIEW

A Comprehensive View of the Neurotoxicity Mechanisms


of Cocaine and Ethanol
Renato B. Pereira1 Paula B. Andrade1 Patrcia Valentao1

Received: 24 April 2015 / Revised: 9 June 2015 / Accepted: 16 June 2015


Springer Science+Business Media New York 2015

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.

Keywords Cocaine  Ethanol  Mechanisms 


Neurotoxicity

Introduction
Drug addiction is a growing social and public health
problem. Substance use disorder affects normal brain
function, leading to alterations in memory, behaviour and
& Patrcia Valentao
valentao@ff.up.pt
1

REQUIMTE/LAQV, Laboratorio de Farmacognosia,


Departamento de Qumica, Faculdade de Farmacia,
Universidade do Porto, Rua de Jorge Viterbo Ferreira, n8 228,
4050-313 Porto, Portugal

neuronal physiology. Cocaine and ethanol are one of the


most frequently used drugs (up to 90 % of cocaine users
report co-administering ethanol) (Tallarida et al. 2014) and,
according to the National Institute on Drug Abuse (2011),
their concurrent consumption is one of the major causes for
emergency hospital room visits.
Cocaine (or benzoylmethylecgonine) is a widely used
drug and its use disorder is associated with physical and
psychiatric problems. According to the Annual report on
the state of the drugs problem in Europe, cocaine has
been used at least once in a lifetime by 4.6 % of the
general population (EMCDDA 2012). This drug is a
tropane alkaloid derived from the leaves of Erythroxylum
coca Lam. (Aggrawal 1995). It is a stimulant, an appetite
suppressant and a nonspecific voltage gated sodium
channel blocker, which, in turn, causes it to produce
anaesthesia at low doses (Dawson and Moffatt 2012).
This drug generally occurs as a white powder, but it can
be found as solid crystals called crack. Crack is the
most addicted form of cocaine, which is processed to
make a rock crystal (also called freebase cocaine) that
can be smoked. The crystals are heated to produce
vapours that are absorbed into the blood-stream through
the lungs (Todd Wilk 2008). Cocaine users seek the
effects of euphoria (feeling of well-being), self-confidence
and increased alertness. However, cocaine use disorder
can also cause adverse effects. Findings from animal and
clinical studies have shown that the chronic use of
cocaine can produce serious neuropathies. In humans,
neuropsychiatric complications, such as depression, suicidal ideation, paranoia, kleptomania and catatonia, occur
in approximately 60 % of cocaine users. The first clinical
signs of cocaine toxicity are usually palpitations, epistaxis, sweating, headache, anxiety, tremors, muscle spasm
and hyperventilation (Nnadi et al. 2005). Cocaine use

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Neurotox Res

disorder can lead to seizures, optic neuropathy, cerebral


infarction, subarachnoid and intracerebral haemorrhage,
multifocal cerebral ischemia, cerebral atrophy and
myocardial infarction triggering to global brain ischemia
and edema (Bodmer et al. 2014; Cagienard et al. 2014;
Peragallo et al. 2013; Schweizer et al. 2013; Sharma et al.
2014; Sordo et al. 2014).
Ethanol is one of the psychoactive substances most
broadly consumed by society. According to the Global
status report on alcohol and health 2014 from the World
Health Organisation (WHO), the harmful use of alcohol
causes approximately 3.3 million deaths every year (or
5.9 % of all deaths worldwide), 4 % of which being caused
by neuropsychiatric disorders. Alcoholism or alcohol use
disorder leads to serious health disorders, damaging the
liver, pancreas and brain (Albanese 2012). It is estimated
that 5075 % of long-term alcoholics exhibit cognitive
impairment and structural brain damage (Harper 2009). Due
to its low molecular weight and water solubility, ethanol is
distributed by practically all tissues, being able to cross the
bloodbrain barrier and reach the central nervous system
(CNS), having a neurotoxic effect (Messing 2014). Ethanol
intoxication results in neuronal death, impaired balance,
behaviour alterations and changes in body movement coordination (Echevarria et al. 2011; Patel et al. 2010). Moreover, ethanol may induce variable acute or chronic
neurologic abnormalities, such as Wernicke encephalopathy
(WE), direct toxic effects on the brain, MarchiafavaBignami disease, osmotic demyelination syndrome, chronic
hepatic encephalopathy and acute alcohol withdrawal syndrome (Kim et al. 2014). On the other hand, the moderate
consumption (1025 g/day) revealed to have beneficial
health properties, namely to decrease the risk of coronary
heart disease (Rimm et al. 1999), to increase the levels of
high-density lipoprotein and to decrease the risk of
myocardial infarction (Gaziano et al. 1993).
Researchers have focused the attention not only in the
mechanism of action of these two drugs, but also in the
mechanism by which they damage the nervous tissue,
inducing neurotoxicity. Therefore, this review will provide
a global perspective of the mechanisms underlying cocaine
and ethanol-induced neurotoxicity, addressing their action
in different biological pathways.
Cocaine
Acute cocaine exposure can affect CNS, causing mydriasis,
headache, bruxism, nausea, vomiting, vertigo, non-intentional tremor, pseudo-hallucinations and, in severe cases,
can lead to coma and to the loss of vital functions (Plush
et al. 2015). On the other hand, long-term usage can yield
significant detrimental effects on the brain, increasing the
neurodegeneration speed. A research developed at the

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University of Cambridge using brains of 120 people


between the ages of 18 and 50, suggested that chronic use
of cocaine lead to a loss of grey matter at a significantly
faster rate than healthy individuals, which can be a sign of
premature ageing (Ersche et al. 2013). Moreover, some
researchers believe that cocaine usage can contribute to
blood vessel damage within the brain, which can lead to
increased susceptibility to experiencing a stroke, particularly in young people (Siniscalchi et al. 2015).
The mechanism by which cocaine causes neurological
damage is complex and involves interactions of the drug
with several neurotransmitter systems, by the increase of
extracellular levels of dopamine and free radicals, and
modulation of transcription factors.
Dopamine Toxicity Caused by Cocaine Addiction
Dopamine (DA) is synthesised from the amino acid tyrosine, through the action of tyrosine hydroxylase, a pivotal
enzyme in the synthesis of this catecholamine. This first
step leads to the formation of 3,4-dihydroxyphenylalanine
(DOPA). DA has its origin in the decarboxylation of
DOPA. After that, it is stored in the vesicles of presynaptic
terminals, to be released in the synaptic slot after a neuronal stimulus (Ziedonis and Kosten 1991). DA is inactivated by oxidation (catalyzed by the enzyme monoamine
oxidaseMAO) and methylation (catalyzed by catecholO-methyltransferaseCOMT), giving two major metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and
homovanillic acid, respectively.
Chronic use of cocaine appears to lead to dysregulation
of brain dopaminergic system (Hou et al. 2014). Several
studies have shown that DA at high concentrations may
participate in neurodegenerative processes, such as in
Parkinsons disease (Ahlskog 2007; Ravina et al. 2012).
Although cocaine is able to inhibit the reuptake of DA,
noradrenaline and serotonin, its powerful effect is believed
to ensue from its actions on the dopamine transporter
(DAT) in neuron terminals, causing an increase of the
concentration and of the intensity of action of DA at the
postsynaptic receptors (Fig. 1) (Gowrishankar et al. 2014;
Martin et al. 2011). A recent study developed by Northcutt
and colleagues demonstrated that cocaine can interact with
Toll-like receptor 4 (TLR4) on microglial cells, to initiate
central innate immune signalling. They also showed that a
disruption of cocaine signalling at TLR4 suppresses
cocaine-induced extracellular DA in the nucleus accumbens (NAc), being TLR4 a new target to treat cocaineinduced brain damage (Northcutt et al. 2015). In addition to
the action in DAT and TLR4, cocaine also interacts with
the vesicular monoamine transporter 2 (VMAT-2) (Fig. 1),
favouring the storage of catecholamines inside synaptic
vesicles (Fleckenstein et al. 2009). This action triggers an

Neurotox Res
Fig. 1 Mechanism by which
cocaine induces oxidative stress,
altering the levels of
extracellular dopamine. Glu
glutamate, ARG arginine, CIT
citrulline, TQ toxic quinones

increase of the quantity of DA packed in each vesicle


before its release, leading to a shift in the ratio of cytoplasmic to vesicular DA. This effect on the VMAT-2
contributes to a further increase of synaptic DA, upon a
depolarizing stimulus (Fleckenstein et al. 2009).
Excessive concentrations of DA can be neurotoxic and
catecholamines have been shown to cause neuronal death
in tissue cultures (Gandhi et al. 2012). DA toxicity is
believed to be due to the formation of reactive oxygen
species (ROS) resulting from its metabolism (by autooxidation or MAO action), leading to oxidative stress
(Banerjee et al. 2014) and posteriorly to apoptosis. As
referred above, MAO catalyses the conversion of DA to
DOPAC and hydrogen peroxide (H2O2), which, via
HaberWeiss/Fenton reaction, can react with transition
metal ions, to give the highly toxic hydroxyl radical
(OH) (Caudle et al. 2007; Gonzalez-Hernandez et al.
2004). On the other hand, DA auto-oxidation may occur
in the extracellular medium, leading to the generation of
superoxide (O2 ) and toxic quinones (Banerjee et al.
2014). Furthermore, O2 reacts with nitric oxide, a product of arginine oxidation by neuronal nitric oxide synthase (nNOS), forming the highly toxic peroxynitrite
(ONOO-) (Cadet and Brannock 1998). Muriach et al.

(2010) demonstrated that nNOS activity in the hippocampus increases after a daily intraperitoneal injection
of cocaine at a dose of 15 mg/kg, during 20 days, triggering the formation of more oxidation products. These
products may damage lipids, proteins and DNA, affecting
cell survival (Surendran and Rajasankar 2010). Other
studies also demonstrated that cocaine exposure induced a
decrease of catalase activity (Macedo et al. 2005), as well
as an increase of superoxide dismutase and glutathione
peroxidase (GPx) activities (Dietrich et al. 2005) in the
cortex and in the striatum. On the other hand, GPx
activity was also revealed to decrease in the hippocampus
of cocaine-treated rats (Muriach et al. 2010). The levels
of antioxidants, such as reduced glutathione (GSH) or
reduced vitamin E, have been shown to be decreased
upon cocaine exposure (Lipton et al. 2003; Poon et al.
2007).
Another product of the auto-oxidation of DA is 6-hydroxydopamine, a toxic metabolite that is transported via
the DA uptake carrier into the presynaptic neuron, causing
the axon terminal to degenerate (Duty and Jenner 2011).
This neurotoxin is widely used to investigate the pathogenesis of Parkinsons disease, both in vivo and in vitro
(Beal 2001). Moreover, the increase of DA in the synaptic

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cleft, caused by high consumption of cocaine, activates the


sympathetic nervous system, having effects like vasoconstriction of cerebral blood vessels, increased heart rate and
blood pressure (Mark and Gold 1993). Other problems
originating by the massive release of catecholamines are
respiratory failure, by central depression, and stroke, due to
high blood pressure, in addition to hyperthermia (Siniscalchi et al. 2015; Ziedonis and Kosten 1991). Furthermore, cocaine-induced neurotoxicity may be also mediated
by uncontrolled release of glutamate (Glu) provoked by
ischemic episodes. This triggers an over-activation of Glu
receptors, leading to an excessive excitation of neurons and
to an increase of intracellular Ca2?, which stimulates
endoplasmic reticulum (ER) stress and may induce neuronal death (Lau and Tymianski 2010; Shin et al. 2007).
Cocaine Effects on ER Stress
ER is involved in the synthesis of proteins and lipids, in
cellular detoxification and intracellular transport (Choe
et al. 2011). Cocaine administration increases extracellular
levels of Glu in dorsal striatum that alter calcium homeostasis, inducing ER stress, by two different routes.
(a)

Acting in ionotropic N-methyl-D-aspartate receptors


(NMDARs)

NMDARs are essential to mediate the effect of cocaine


on ER stress and are involved in the control of synaptic
plasticity and memory function (Li and Tsien 2009). These
receptors are activated when Glu binds them, enabling the
influx of Na? and small amounts of Ca2? in the neuron and
the efflux of K?. NMDAR is widely expressed in striatal
projection neurons (Fig. 2) (Stephenson 2001) and can be a
target for the development of drugs to combat Alzheimers
disease.
(b)

Acting in group I glutamate metabotropic receptors


(I mGluRs)

Group I mGluRs (mGluR1 and mGluR5) are involved in


plasticity processes, neurodegeneration and neuroprotection. These receptors are coupled to Gq/G11 proteins and,
once stimulated by a high increase of Glu provoked by
cocaine, lead to the activation of phospholipase C (PLC)
that will hydrolyse phosphoinositides, generating inositol
1,4,5-trisphosphate (IP3) and diacyl-glycerol (DAG). DAG
remains in the plasma membrane and acts in recruiting
protein kinase C (PKC) that phosphorylates NMDARs,
thus potentiating their activity. IP3 diffuses into the cytoplasm and is associated with receptors present in ER
membrane. The activation of these receptors by IP3 leads to
the release of Ca2? from intracellular stores into the
cytoplasm, where it participates in the activation of PKC
and other proteins (Fig. 2) (Litosch 2002). The activation

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of I mGluRs appears to be required for cocaine-stimulated


induction of ER stress proteins (Shin et al. 2007).
Hereupon, both receptors can raise intracellular Ca2?
concentrations triggering ER stress. The accumulation of
unfolded or misfolded proteins in the lumen of ER initiates
the ER stress response, also known as the unfolded protein
response (UPR) that is present in all mammalian species
(Pereira et al. 2015). Once activated, if UPR cannot resolve
the protein-folding defect, restoring the cell normal function, it takes the cell to apoptosis. The main ER membrane
proteins involved in the induction of UPR are inositolrequiring enzyme-1a (Ire1a), PKR-like endoplasmic
reticulum kinase (PERK) and activating transcription factor 6 (ATF6) (Pereira et al. 2015; Shen et al. 2004). At the
basal state, these proteins are inhibited through the linkage
of chaperone binding immunoglobulin protein (BiP), protecting the cells against ER stress. Some studies associated
malfunction of this response with cell death, contributing to
stroke, inflammatory disease and neurodegenerative diseases (Cao and Kaufman 2012; Matus et al. 2012).
PERK (eIF2a3 K) is an enzyme that, once dissociated
from BiP, dimerizes and induces the activation of its kinase
domain by auto phosphorylation. PERK target protein is
the eukaryotic translation initiation factor 2-alpha subunit
(eIF2a) (Ma and Hendershot 2004). PERK activation in the
UPR leads to a generalised inhibition of mRNA translation
and, consequently, to a reduction of the contribution of
protein in the ER. Under these conditions, the translation of
mRNAs that encode proteins playing a key role in stress
adaptation, such us activating transcription factor 4
(ATF4), is more advantageous (Harding et al. 2001). PERK
also promotes the cellular surveillance by phosphorylation
of nuclear factor erythroid 2-related factor 2 (Nrf2), which
leads to an increase of translations, giving proteins with an
important role in antioxidant response (Ma 2013). However, some studies report that a chronic activation of PERK
can increase the C/EBP-homologous protein (CHOP)
expression. The increased expression of CHOP retains the
cell cycle and causes cell death by interacting with Bcl-2
pathway (Ron 2002). In addition, UPR signalling pathways
can also activate caspase 12, a marker of directive ER
stress-mediated apoptosis in mouse (Binet et al. 2010),
leading to its translocation from the ER to the cytosol
where it can activate effector caspase-3 (Yoon et al. 2011a,
b).
As above mentioned, phosphorylation of PERK and
eIF2a indicates that cells are undergoing ER stress. Costa
et al. (2013) demonstrated that microglial cells (BV2)
treated with cocaine presented significantly elevated
phosphorylation levels of PERK and eIF2a, maximum of
phosphorylation being observed between 6 and 12 h
compared with the untreated control group. Furthermore,
they assessed the expression of CHOP, the levels of this

Neurotox Res
Fig. 2 Representative
mechanism by which cocaine
induces ER stress and
mitochondrial dysfunction,
leading cell to apoptosis

protein being also significantly elevated following cocaine


exposure, with maximum expression at 24 h. In addition,
they confirmed that cocaine also increases CHOP protein
expression in rats and found that ROS production was
mediated by CHOP signalling, CHOP being the upstream
mediator of ROS. Under these stressful conditions, the
increase of intracellular Ca2? in neuronal cells leads to the
activation of c-Jun-NH2-terminal kinase (JNK) by Ca2?dependent protein kinases, causing neuronal damage (Ko
et al. 1998). Another possible way for cocaine-induced
apoptosis was demonstrated by Ahn et al. (2007), which
observed that acute or repeated cocaine administration
increased caspase-12 expression in rat dorsal striatum. It is
also known that ER stress increases caspase-12 expression
in neurons and glial cells (Shimoke et al. 2004).
Shin et al. (2007) demonstrated that, in addition to PERK,
acute or repeated cocaine administration also increased the

levels of BiP and Ire-1a in rat dorsal striatum. Furthermore,


they found that the activation of these ER stress proteins is
closely related with the activation of DA and Glu receptors.
The increase of BiP levels may have a protective role against
the ER stress induced by cocaine (Morris et al. 1997).
Altogether, these findings suggest that cocaine is closely
related with the increase of Glu release, leading to the
induction of ER stress proteins contributing to neuronal
cell apoptosis.

Cocaine Effects on the Apoptosis Regulator Bcl-2


The B cell lymphoma-2 (Bcl-2) family contains evolutionary proteins with pro-apoptotic (like Bax and Bak) and
anti-apoptotic activities (such as Bcl-2 and Bcl-XL). These
proteins are key regulators of cell death by apoptosis,

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mitochondrial integrity and cytochrome c (Cyt c) release


(Dey et al. 2007). The rate between pro-apoptotic and antiapoptotic activity helps determine, in part, if a cell lives or
dies (Ghribi et al. 2002). Despite Bcl-2 pivotal role in
apoptosis regulation, abnormalities in its function have
been associated with many diseases like cancer, neurodegenerative disorders, ischemia and autoimmune diseases
(Siddiqui et al. 2015). It is believed that Bax induction
leads to the formation of a mitochondrial membrane pore
that then releases the pro-apoptotic Cyt c, leading to initiator caspase-9 activation and subsequent induction of
caspase-3 (Fig. 2) (Brunelle and Letai 2009; Galluzzi et al.
2010). In addition to Bax induction, it was suggested that
caspase-2 is able to engage the mitochondrial apoptotic
pathway by permeabilizing the outer mitochondrial membrane and/or by breaching the association of Cyt c with the
inner mitochondrial membrane (Enoksson et al. 2004).
Many studies showed that programmed cell death plays
an important role in the induction of neuronal loss caused
by cocaine (Cunha-Oliveira et al. 2008, 2013). Moreover,
cocaine-induced PC 12 cell death was associated with a
decrease of the levels of anti-apoptotic Bcl-2 protein, but
no change in the pro-apoptotic Bax, altering, therefore, the
Bax/Bcl-2 ratio, leading to the activation of caspase-3 that
triggers cell apoptosis (Lepsch et al. 2009). In agreement
with these results, Costa et al. (2013) verified a significant
increase of Bax/Bcl-XL ratio in microglial cells, with
activation of caspase-3, indicating the kinetics of cell death
in the presence of cocaine. In addition, cocaine reduced the
levels of mitochondrial Cyt c and activated caspases-2, -3
and -9 in cultured neuronal cortex, stimulating the mitochondrial apoptotic pathway (Cunha-Oliveira et al. 2006).
These results are in agreement with in vitro findings using
foetal locus coeruleus neurons (Dey et al. 2007). Besides
caspase-3, cocaine revealed capacity to activate caspase-9,
but not caspase-8, caspase-9 activity being dependent on
the duration of cocaine treatment. In addition, after cocaine
treatment, a cleavage of key cellular proteins was observed,
namely of a-fodrin and poly (ADP-ribose) polymerase
(PARP) that are essential to membrane skeleton integrity
and DNA repair, respectively, contributing to cell damage
(Dey et al. 2007).
More studies seem to be necessary to establish whether
cocaine increases Bax/Bcl-2 ratio as a consequence of the
raise of ER stress caused by the increase of glutamatergic
transmission, or if cocaine acts directly in the mitochondria
altering the levels of these proteins.
Cocaine Effects on NF-kB Pathway
Cocaine, and the episodic excessive synaptic activity of
catecholamines that it produces, may also induce neurotoxicity via interference with mitochondrial electron

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transport and oxidative phosphorylation (Gluck and Zeevalk 2004; Leon-Velarde et al. 1992), leading to bioenergetic deficits and subsequent activation of a host of
neurodegenerative and apoptotic events. However, oxidative stress is not the only factor associated with the neurotoxic effects of substance use disorder (Numa et al.
2008). Several researchers have reported that cocaine is
also involved in the induction of the immediate expression
of genes that have an important role in cellular death (Maze
and Nestler 2011; Schmidt et al. 2013).
Nuclear factor kappa-B (NF-jB) promotes the expression of proteins that have an important role in inflammatory, cellular defence and apoptotic processes, contributing
to memory formation that could be involved in some drug
toxicity mechanisms (Muriach et al. 2010). It is a heterodimer composed of two subunits: p65 (also called RelA)
and p50 (Baeuerle and Baltimore 1996).
Inhibitory kappa-B (IjB) is a member of a family of
cellular proteins that function to retain NF-jB transcription
factor in the cytoplasm, by masking the nuclear localization signals (NLS) of NF-jB proteins and keeping them in
an inactive state (Hayden and Ghosh 2008). In addition,
IjB blocks the capacity of NF-jB transcription factors to
translocate to the nucleus, which is necessary for NF-jB
proper functioning. When IjB protein is phosphorylated
and subsequently degraded by IjB kinase (IKK) complex,
the activated NF-jB dimer enters in the nucleus and binds
to DNA, to regulate the transcription of genes involved in
the production of anti-apoptotic genes, such as Bcl-2,
inhibitor of apoptosis proteins and brain-derived neurotrophic factor (BDNF). BDNF regulates the differentiation and apoptosis of neurons and glial cells (Thomas and
Davies 2005) and has an important role in the defence
against neuronal damage process caused by cocaine
(Marini et al. 2004).
On the other hand, some reports have associated some
neurodegenerative disorders with the activation of NF-jB
(Gveric et al. 1998) and that a selective inhibition of this
transcription factor may be a therapeutic benefit (Ghosh
et al. 2007). Additionally, in some models of ischemia, NFjB activation promotes the death of neurons, contributing
to brain damage (Schneider et al. 1999). Furthermore,
activation of NF-jB in glial cells (microglia and astrocytes) can lead to the formation of large amounts of proinflammatory cytokines, ROS, and excitotoxins, triggering
neuronal death (John et al. 2003).
In vitro studies showed that cocaine activates the transcription factor NF-jB. It was also demonstrated that GBR
12909 (an inhibitor of DA reuptake), lidocaine (a local
anaesthetic), and DA did not activate NF-jB in the same way
as cocaine. However, the attenuation of NF-jB activity after
the pre-treatment of PC 12 cells with SCH 23390, a D1
receptor antagonist, suggested that the activation of NF-jB

Neurotox Res

by cocaine is, at least partially, due to the activation of


dopamine D1 receptors (Lepsch et al. 2009). D1 receptors
increase the expression of immediate early genes (IEGs), like
c-fos and c-jun that are closely related with the modulation of
the transcription factors, including NF-jB. Moreover, the
activation of NF-jB in PC12 cells revealed to be induced by
the auto-oxidation of DA reported above (Lee et al. 2001). To
confirm NF-jB activation, Lepsch et al. (2009) measured the
levels of IjB-a and verified that cocaine (after 6 h treatment)
increased IjB-a degradation in PC12 cells, inducing the
activation of the p50/p65 subunit of NF-jB complex. This
NF-jB activation by cocaine in PC12 cells could explain the
transitory increase of BDNF mRNA levels in frontal cortex
of rats, observed by Le Foll and colleagues after a single
injection of cocaine (Le Foll et al. 2005). In spite of the
homeostatic protective role of NF-jB in cocaine treatment of
PC12 cells, after 38 h, being associated with the expression
of anti-apoptotic genes, such as BDNF, as described above,
Lepsch et al. (2009) also demonstrated that treatment with
cocaine (1 mM) for 24 h induced DNA fragmentation, cellular membrane rupture and reduction of mitochondrial
activity, being responsible for cell death. This homeostatic
response was not enough to offset the prejudicial neurotoxic
mechanisms of cocaine, leading to PC12 cells death (Lepsch
et al. 2009; Russo et al. 2009). In addition, the authors also
observed an increase of cell death when the cells were subjected to a NF-jB inhibitor, suggesting the important protective role of NF-jB (Lepsch et al. 2009). According with
these results, an in vivo study developed by Ang et al. (2001)
already demonstrated that chronic administration of cocaine
induces NF-jB activation in NAc of mice. The same result
was also obtained with other cell models, namely macrophages and human brain endothelial cells (Dhillon et al.
2007; Lee et al. 2001).
Nevertheless, Muriach, and co-workers verified that NFjB activity in cocaine-treated rats was decreased in frontal
cortex when compared with control group (Muriach et al.
2010). Moreover, McCarthy and colleagues found a transient
decrease in BDNF protein expression in cocaine-exposed
embryonic forebrain early in gestation (McCarthy et al. 2011).
The role of NF-jB in neuronal survival remains somewhat controversial. A potential unifying hypothesis suggested by Mattson and Meffert (2006) is that NF-jB
activation in neurons could promote their survival, whereas
activation of NF-jB in glial cells may induce the production of neurotoxins, leading to cell death. However, more
studies about the role of NF-jB in neuronal cells are
essential to support this hypothesis.
Ethanol
Heavy chronic or acute alcohol exposures can cause, in the
mature brain, severe debilitating diseases of the central and

peripheral nervous systems. Most commonly, the chronic


exposure to ethanol leads to disproportionate loss of cerebral white matter through its action in the myelin formation
(Coutts and Harrison 2015). Moreover, post-mortem studies showed that 75 % of chronic alcoholics have significant
brain damage/degeneration (de la Monte and Kril 2014).
Ethanol also has devastating neurotoxic and teratogenic
effects on the developing brain in association with foetal
alcohol spectrum disorder/foetal alcohol syndrome. Correspondingly, in adolescents and young adults, chronic
heavy and acute intake lead to developing neurocognitive
impairment and neurodegeneration with deficits in learning, memory and executive functions (Tiwari and Chopra
2013).
The mechanism of neurotoxicity associated with ethanol
use disorder has been thoroughly studied in the last decades, addressing issues like the toxic effect of its metabolite (acetaldehyde), neuroinflammation, changes in brain
metabolism, mitochondrial dysfunction, ROS production
and changes in glutamatergic and dopaminergic pathways.
Toxic Effect of Acetaldehyde
Ethanol can exert its harmful effects in the liver, through
the action of alcohol dehydrogenase (ADH). Acetaldehyde
(ACH), the highly toxic metabolite formed, is extremely
reactive and is one mediator of the direct neurotoxic effect.
It is metabolised to acetate by the NAD-dependent enzyme
aldehyde dehydrogenase (ALDH) (Kunitoh et al. 1997).
When the amount of alcohol consumed is higher than the
ability to metabolise acetaldehyde, there is an accumulation of this substance in the body, which can cause facial
flushing, headache, tachycardia, dizziness and nausea
(Borja-Oliveira 2014). The brain does not seem to express
ADH, but there is evidence that acetaldehyde-protein
adducts are also present in this organ (Masaki et al. 2004).
Acetaldehyde probably reaches the brain and other tissues
by the blood flow (Lieber 1998; Masaki et al. 2004).
However, ACH can be formed directly in the brain, to a
lesser extent, by the action of catalase and CYP 2E1 (Zimatkin et al. 2006).
The study of the role of ACH in brain toxicity started in
1987, when it was found that it is able to potentiate the
neurotoxicity provoked by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that causes symptoms of Parkinsons disease permanently, destroying the
dopaminergic neurons of the substantia nigra of the brain
(Corsini et al. 1987). Later, Takeuchi and Saito (2005)
showed that neuronal cell death was dependent on the
concentration of acetaldehyde-derived advanced glycation
end-products (AA-AGE). Moreover, Signorini-Allibe et al.
(2005) demonstrated that, in the presence of ethanol, the
concomitant induction of catalase and inhibition of ALDH

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lead to an accumulation of ACH inside the cells, triggering


a reduction in rat astrocytes viability and a substantial
increase in DNA strand breaks.
Altogether, these results suggest that the neurotoxicity
of ethanol is closely related with the accumulation of
acetaldehyde in the brain.

2002; Pascual et al. 2007). The exact mechanism by which


ethanol activates TLR4/IL-1RI signalling may involve
alterations in lipid raft clustering (Dai et al. 2005) or cell
adhesion complexes and actin cytoskeleton organisation
(Huang et al. 2001).

Neuroinflammation

Changes in Brain Metabolism

Growing evidence indicates the role that inflammation


plays as a potential pathogenetic factor in many CNS diseases, including neurodegenerative diseases (Giovannini
et al. 2003; Hirsch et al. 2003). The hallmark of neuroinflammation is the activation of glial cells and the production of cytokines and inflammatory mediators that trigger
brain damage (Hirsch et al. 2003).
Ethanol, as lipopolysaccharide (LPS) and IL-1, induces
the rapid activation of TLR4 and interleukin-1 receptor
(IL-1R) signalling pathways in astrocytes. Particularly,
ethanol induces the phosphorylation of IL-1R I-associated
kinase (IRAK), ERK1/2, stress-activated protein kinase
(SAPK)/JNK and p38 mitogen-activated protein kinase
(p38 MAPK). The activation of IRAK/MAPK pathway
leads to the stimulation of the transcription factors NF-jB
and AP-1, triggering the induction of inducible nitric oxide
synthase (iNOS), cyclooxygenase-2 (COX-2) and pro-inflammatory cytokines (IL-1b, TNF-a) (Fig. 3) (AlfonsoLoeches et al. 2010; Blanco et al. 2005). The up-regulation
of these inflammatory mediators by ethanol is also associated with an increase of caspase 3 activity in adolescent
rats and a corresponding increase in cell apoptosis in the
neocortex, hippocampus and cerebellum (Olney et al.

The brain has high energy requirements. Glucose is


required as energy substrate of the adult brain. Ethanol can
act altering the normal steps of glucose metabolism and the
oxidant/antioxidant equilibrium. The administration of
ethanol to SpragueDawley rats, at a dose of 4 g/kg body
wt/day for 90 days, decreased the activity of superoxide
dismutase, catalase, GPx and glutathione reductase in the
liver and brain, increasing ROS production and subsequent
oxidative stress (Vidhya et al. 2013). The same group also
showed that ethanol increased the levels of inflammatory
markers (LOX, COX and NOS), fibrosis markers and DNA
fragmentation in brain (Vidhya et al. 2013). A decrease in
the activity of pyruvate dehydrogenase complex (PDHC),
transketolase (TK) and a-ketoglutarate dehydrogenase
(aKGDH) was observed in autopsied cerebellar vermis
samples from alcoholic patients (Butterworth et al. 1993).
This decrease on the enzymatic activity can be explained
by the capacity of ethanol to directly inhibit thiamine
pyrophosphokinase (TPK), reducing the rate of transformation of thiamine to thiamine diphosphate (TDP), an
essential co-factor for the activity of these three enzymes
(Fig. 4) (Rindi et al. 1986). As these enzymes, involved in
brain metabolism, play an important role in essential

Fig. 3 Possible mechanism of


ethanol-induced brain damage
by neuroinflammation. Ethanol
as IL-1b and LPS can activate
the TLR4 and IL-1RI pathways
in glial cells, leading to
inflammatory responses,
triggering the production of
inflammatory mediators that
contribute to brain damage

123

Neurotox Res

pathways of energy transduction, this impairment of cellular energy metabolism can affect the viability of brain
cells (Martin et al. 2003; Sechi and Serra 2007) and can
contribute to brain dysfunction in Alzheimer disease
(Mastrogiacomo et al. 1993). Furthermore, acetyl-CoA is

needed to generate myelin, a substance that forms a sheath


around the axons of many neurons, thereby, a decrease in
acetyl-CoA production cannot ensure a proper neuronal
function and the ability of these neurons to conduct signals
(Fig. 4) (Martin et al. 2003).

Fig. 4 Neurotoxic mechanism


by which ethanol affects
glucose metabolism. TDP
thiamine diphosphate, TPK
thiamine pyrophosphokinase,
TK transketolase, PDHC
pyruvate dehydrogenase
complex, aKGDH aketoglutarate dehydrogenase,
AMP adenosine
monophosphate, ADP adenosine
diphosphate, ATP adenosine
triphosphate

123

Neurotox Res

Mitochondrial Dysfunction and ROS


Under normal physiological conditions, a proper balance
between free radicals and the levels of antioxidants is
required for cell survival. A disturbance in mitochondrial
energy metabolism was described after acute and chronic
ethanol exposure, leading to a decrease in ATP production
and an exacerbated ROS generation, contributing to
increase the susceptibility of cellular apoptosis and/or
death to oxidative stressors (Bailey and Cunningham 1998;
Ivester et al. 1995).
Cyclic adenosine monophosphate (cAMP), a second
messenger derived from ATP by a reaction catalysed by
adenylyl cyclase, is responsible for the activation of protein
kinase A (PKA), an enzyme essential for cAMP response
element-binding protein (CREB) phosphorylation. CREB
phosphorylation is an important molecular event, which plays
a determinant role in synaptic formation and anti-AD potential, leading to peroxisome proliferator-activated receptor-d
co-activator 1a (PGC-1a) expression (Mermelstein 2009;
Tarragon et al. 2014). PGC-1a has important functions in the
maintenance of neuronal integrity and function. It regulates
cellular energy metabolism, mitochondrial biogenesis and
cellular antioxidant mechanism (Friedman 2001; John et al.
2005; ONeill 2000). The down regulation of PGC-1a levels
is associated with a commitment of neural functions and
consequently with neuronal damage.
A recent study showed that ethanol can suppress PGC1a expression by diminishing CREB phosphorylation via
reduction of the intracellular cAMP levels in neuronal
cells. Furthermore, the same work also found that the
expression of PGC-1a target genes (UCP-2 and UCP-3)
that regulate mitochondrial transmembrane proton leakage
and ATP synthesis were down regulated when SH-SY5Y
cells were treated with ethanol (Liu et al. 2014). These
events lead to an increase in the level of intracellular ROS,
mitochondrial dysfunction and subsequently to cell damage
and neurodegeneration that are commonly associated with
alcohol overuse and alcoholism (Chaung et al. 2008; StPierre et al. 2006). In addition, decreased activity of PGC1a has been associated with numerous neurodegenerative
diseases, such as Huntington disease, Alzheimer disease
and Parkinson disease (Cui et al. 2006; Qin et al. 2009;
Shin et al. 2011; St-Pierre et al. 2006). However, more
studies seem to be necessary to establish the mechanism by
which ethanol reduces the levels of cAMP. Liu et al. (2014)
hypothesised that the reduced levels of cAMP may arise
from the capacity of ethanol to mitigate the activity of
adenylyl cyclase, reducing the conversion of ATP to cAMP
(Fig. 5Mechanism 1a). Another hypothesis is that ethanol could stimulate phosphodiesterase (PDE) activity to
catalyse the degradation of cAMP (Fig. 5Mechanism 1b)
(Liu et al. 2014). More experimental studies are necessary

123

Fig. 5 Possible mechanisms by which ethanol regulates PGC-1a


expression,
leading
to
mitochondrial
dysfunction
and
neurodegeneration

to clarify the mechanism by which ethanol reduces cAMP


levels in neuronal cells.
PARIS (ZNF746) is a protein that suppresses the transcription of PGC-1a and the PGC-1a target gene, NRF-1,
by binding to the insulin response sequence in the PGC-1a
promoter (Finck and Kelly 2006; Shin et al. 2011). Liu
et al. (2014) also evaluated if ethanol altered the expression
of PARIS in neuronal cells, contributing to the suppression
of PGC-1a expression. They showed that, indeed, ethanol
increased the expression of PARIS when cells were
exposed to high concentration of ethanol (300 mM)
(Fig. 5Mechanism 2). This result pointed that ethanol
can suppress PGC-1 a expression not only by decreasing
cAMP levels and CREB activity, but also by stimulation of
PARIS expression.
Hereupon, as the overexpression of PGC-1a is associated with beneficial protective effects to the brain in
alcoholics, the modulation of PGC-1a can be a new target
for the treatment of alcohol-induced apoptosis and/or
neurodegeneration.
Changes in Glutamatergic and Dopaminergic Pathways
Glu is an important excitatory brain neurotransmitter that
has a primordial role with respect to neurodegenerative
disorders (Brassai et al. 2015; Ribeiro et al. 2014). The
levels of this amino acid in the cell partly depend on the
activity of a-ketoglutarate dehydrogenase (aKGDH) that is
inhibited in brain mitochondria of alcoholic patients, as
referred above. Studies also suggest that a decrease in the
activity of this enzyme may lead to an increase in Glu
release mediated by NMDAR, resulting in an adverse
effect on cellular integrity (Fig. 4) (Lin et al. 2014; Volkow
et al. 2013). It has been demonstrated that intermittent
ethanol treatment causes a decrease in the expression of the
dopamine receptor type 2 (D2R) and a decrease in phosphorylation of 2B subunit of the NMDA receptor
(NMDAR-2B) in the prefrontal cortex, hippocampus, NAc

Neurotox Res

and only of D2R in the striatum (Pascual et al. 2009). The


excessive release of Glu induces an increase in intracellular
Ca2? levels that triggers a cascade of cellular responses,
leading to neuronal cell death, as mentioned before (Fig. 4)
(Lan et al. 2014).
In addition to these changes in dopaminergic and glutamatergic inputs, ethanol has also shown the capacity to
induce post-translational modifications in chromatin, such
as acetylation, phosphorylation and methylation of histones
on DNA (Grewal and Moazed 2003; Li et al. 2004;
Schroeder et al. 2008). According to these findings, it was
observed that intermittent ethanol treatment caused changes in the acetylation of histones H3 and H4 in the prefrontal cortex, NAc and striatum, suggesting chromatin
remodelling changes, which may mediate long-term alterations, contributing to mitochondrial and cellular damage
(Jung and Metzger 2015). Taken together, these results
seem to evidence that alcohol can sensitise the mesolimbic
and mesocortical dopamine pathways to cause changes in
dopaminergic and glutamatergic signalling, which may
affect the remodelling and functions of the brain (Pascual
et al. 2009). These effects on NMDARs can contribute to
learning and memory dysfunction.
Concurrent Consumption of Ethanol and Cocaine
Most cocaine users also ingest ethanol (McCance-Katz et al.
1993). A recent report about the prevalence of cocaine use
among adolescents in Europe indicates that about 70 % of
them reported that the first use of cocaine was under the effect
of alcohol (Apantaku-Olajide et al. 2013). Cocaethylene (CE)
is an active cocaine metabolite formed by hepatic carboxylesterases during the concurrent consumption of ethanol
and cocaine. Hearn and colleagues demonstrated that CE is
more potent in mediating lethality than cocaine, in female and
male mice (Hearn et al. 1991a). Although this active
metabolite is well known for its toxicity to myocardium, it
appears to enhance the effects of cocaine at the CNS level.
This psychoactive metabolite has the same targets that
cocaine, but is more selective to DAT and has a more prolonged half-life (c.a. 3 to 5-fold higher than cocaine) (Hearn
et al. 1991b; Jatlow et al. 1996), explaining why the combined
use of alcohol and cocaine has been found to produce
increased and prolonged subjective euphoria when compared
to the use of either substance separately (Harris et al. 2003).
According to these results, some researchers demonstrated
that an acute administration of CE augments the in vivo
synaptic levels of DA by approximately 400 % over base-line
levels (Bradberry et al. 1993; Iyer et al. 1995). In addition to
the formation of CE, ethanol also inhibits demethylation of
cocaine to benzoylecgonine, allowing maintaining higher
plasma concentrations of cocaine in the presence of ethanol
(Dean et al. 1997).

The clinical signs of concurrent consumption of these two


drugs are similar to own cocaine administration, however,
with more pronounced effects (Harris et al. 2003). Physical
examination reveals evidence of adrenergic overstimulation
with mydriasis, tachycardia, hypertension, cardiac arrhythmias and hyperthermia (Devlin and Henry 2008). CE was
detected in post-mortem blood, liver and neurological tissues, in concentrations equal to and sometimes exceeding
those of cocaine. Moreover, the pathological effects in
cocaine consumers increase when CE is formed (Andrews
1997; Hearn et al. 1991a). The mechanism of action of CE in
the nervous system is not fully defined, but it appears to act
synergistically with cocaine in blocking the reuptake of
dopamine and promoting the IEG expression in discrete
neurons of the rat caudate putamen and NAc (Hearn et al.
1991b; Horowitz et al. 1997). More studies are necessary to
establish the effects of CE in the Bcl-2 apoptotic pathway and
in the NF-kB pathway and its contribution to neurotoxicity.
Hereupon, it can be inferred that, in addition to the
detrimental effect of isolated ethanol and cocaine consumption, the concurrent consumption of both drugs leads
to more severe neurotoxic effects.
Acknowledgments The authors are grateful for the European Union
(FEDER funds through COMPETE) and National Funds (FCT,
Fundacao para a Ciencia 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.
Conflict of interest

The authors declare no conflict of interest.

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