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Abstract

The effects of alcohol have been widely studied during the past century as alcohol abuse is a major health problem in Western society. In the last years, a growing body of evidence indicates that acetaldehyde, the first oxidation product of ethanol, is one of the mediators of peripheral and central effects of ethanol. Indeed, acetaldehyde has been recently taken into account as the mediator of the rewarding properties of alcohol. The role of acetaldehyde in ethanol-related properties has been proved by enzymatic manipulation studies in which the inactivation of acetaldehyde potentially synthesized in the brain produces the same results as blocking the formation of acetaldehyde by inhibiting brain catalase activity. Moreover, electrophysiological and pharmacological analyses showed that acetaldehyde is able to stimulate dopamine release in the nucleus accumbens through enhancement of firing rate, spikes/burst, and burst firing of ventral tegmental neurons. Thus, the aim of this review is to summarize latest results on the role of acetaldehyde as the mediator of ethanol-central effects.
ACETALDEHYDE EFFECTS IN THE BRAIN
FULVIO PLESCIA1, EMANUELE CANNIZZARO1, ANNA BRANCATO1,2, FRANCESCO MARTINES2, ANGELO DINARO , MARIANNA
MUCIA3, FABIANA PLESCIA4, CARLOTTA VITA1, PIETRO SALVAGO2, ANTONINO MULÈ3, SERENA RIZZO2, FEDERICO SIRECI2,
CARLA CANNIZZARO1
1University of Palermo, Palermo, Department of Sciences for Health Promotion and Mother and Child Care “Giuseppe
D'Alessandro”, Palermo - 2University of Palermo, BioNeC Department, ENT Section, Palermo - 3University of Palermo,
Di.Bi.Me.F, Department, Audiology Section, Palermo - 4University of Palermo, STEBICEF Department, Palermo, Italy
Introduction
Alcohol use disorder is considered a chronic
relapsing and remitting disease defined by the
development of tolerance, abstinence, drug con-
sumption for alleviating abstinence, exaggerated
consumption beyond original intention, failure to
reduce drug consumption, use of a considerable
amount of time to obtaining or recovering from the
substance’s effects, and maintenance of drug con-
sumption, despite facing adverse consequences(1,2).
In particular ethanol (EtOH) produces a wide range
of neurocognitive effects such us impairment in
judgment, learning, memory, perception and psy-
chomotor agitation(3,4,5).
There is a growing body of evidence indicat-
ing that acetaldehyde (ACD), the first oxidation
product of ethanol, is one of the mediators of the
peripheral and central effects of ethanol(6-14). ACD is
usually considered a highly aversive substance: in
the past the indirect use of ACD was taken into
account for discouraging drinking in alcoholic
patients. In fact, several drugs able to inhibit the
activity of aldehyde dehydrogenase (ALDH) such
us disulfiram and calcium carbimide, were widely
used in the treatment of withdrawn alcoholics to
produce an aversion for alcohol(14). Nevertheless, it
was reported that patients under treatment with
ALDH inhibitor declared pleasant relaxing effects,
after taking small doses of ethanol, highlighting
Acta Medica Mediterranea, 2015, 31: 813
Received November 30, 2014; Accepted May 02, 2015
ABSTRACT
The effects of alcohol have been widely studied during the past century as alcohol abuse is a major health problem in Western
society. In the last years, a growing body of evidence indicates that acetaldehyde, the first oxidation product of ethanol, is one of the
mediators of peripheral and central effects of ethanol. Indeed, acetaldehyde has been recently taken into account as the mediator of
the rewarding properties of alcohol. The role of acetaldehyde in ethanol-related properties has been proved by enzymatic manipula-
tion studies in which the inactivation of acetaldehyde potentially synthesized in the brain produces the same results as blocking the
formation of acetaldehyde by inhibiting brain catalase activity. Moreover, electrophysiological and pharmacological analyses
showed that acetaldehyde is able to stimulate dopamine release in the nucleus accumbens through enhancement of firing rate,
spikes/burst, and burst firing of ventral tegmental neurons. Thus, the aim of this review is to summarize latest results on the role of
acetaldehyde as the mediator of ethanol-central effects.
Key words: Acetaldehyde, Alcoholism, Ethanol-related effects, Dopaminergic pathway.
that ACD might exert positive emotional as well as
motivational effects. More recently, many reports
pointed out the role of centrally formed ACD(16,17),
which can facilitate locomotor activity, may pro-
duce anxiolytic effect in rats(7) and can contribute
to the overall psychotropic action of alcohol con-
sumption(18).
Thus, many researches support the theory that
the motivational properties of ethanol might
depend upon the action of its metabolites in the
central nervous system (CNS), and by ACD in par-
ticular(8, 19-22). Given these premises the issue
addressed in this review is an overview of the lat-
est data on the role of ACD as the mediator of the
central effects of ethanol, focusing on its capacity
to affect the neurocircuitries and neuropeptides
involved in addictive behaviour(23).
Materials and methods
The author’s search targeted evidence-based
guidelines, evidence-based summaries, systematic
reviews and recent experimental research on
acetaldehyde formation in the brain and its role as
the mediator of ethanol-central effects. The key-
words used were “ACD’’ or ‘ACD” in the brain’’ or
‘‘do pa mi nerg ic pathw ay ’’ or ‘‘Et OH -c entr al effec ts ’’
or ‘‘ACD and VTA’ or ‘‘ACD and EtOH-related
addictive behaviour’’. Through this simple strategy
we identified more than 10000 using two primary
sources for identify relevant information: PubMed
and SCOPUS (last accessed via PubMed and SCO-
PUS on February 16, 2015).
ACD Formation In The Brain
ACD formation by the oxidative metabolism
of ethanol takes place in different organs and
involves multiple enzymes, including alcohol
dehydrogenase (ADH), catalase and cytochrome
P4502E1 (CYP2E1)(24). In detail, ACD is obtained
from peripheral metabolism of EtOH by the activi-
ty of ADH-1, the most important enzyme that
metabolizes ethanol in the liver(25,26). In the brain,
ADH is idle(27), and ACD formation from EtOH
occurs by the catalase system, whose presence in
the central nervous system has been demonstrated
through the study of ethanol metabolism in neu-
ronal cultures and brain homogenates(27), and by the
CYP2E1(28). Finally, in the liver ACD is converted
rapidly into acetic acid by ALDH.
The concentration of ACD in the brain is
important for mediating the pharmacological
effects of EtOH. ACD formed in the liver pene-
trates into the brain from the periphery with diffi-
culty because of the presence of ALDH in the
microvasculature of the brain(30). Therefore, the
blood–brain barrier limits ACD diffusion into the
brain, such that little ACD produced by peripheral
ethanol metabolism penetrates into the brain under
normal conditions(31). Further research indicates
that the saturation of peripheral ALDH, given by a
high concentration of ACD, allows it to reach the
brain(20). Studies showing central effects of periph-
erally administered ACD seem to validate this pos-
sibility(22,32). Several groups have shown that brain
ACD is produced during in situ ethanol oxida-
tion(29). Brain catalase activity modulates ACD for-
mation in the brain from ethanol metabolism and
has been involved in the regulation of ethanol-
induced behaviours(33-37). Different studies have
shown that inactivating ACD potentially synthe-
sized in the brain with the sequestering agent D-
penicillamine (DP) produces the same results as
blocking the formation of ACD by inhibiting brain
catalase activity(8,38).
In addition to catalase system, CYP2E1, the
major ethanol inducible CYP, expressed in the neu-
ronal cells in rat and human brain (39,40), might
play a role in the production of brain ACD by
EtOH metabolism. This enzyme has been shown to
be expressed in mammalian brain, although the
levels of CYP2E1 reported in the brain vary con-
siderably among laboratories. Most studies have
indicated that CYP2E1 is expressed at extremely
low levels in the brain(41), whereas other reports
have shown much higher expression of CYP2E1 in
control rat brain(39).
Recently, in vitro studies conducted by
Zimatkin et al., in 2006(29) have emphasized that
CYP2E1 contributes to brain ethanol metabolism
into ACD for about 20%, whith respect to 80% of
the catalase.
ACD And VTA Regulation
All substances of abuse are able to influence
behaviour through their ability to stimulate
dopamine (DA) release in the mesocorticolimbic
system, composed of ventral striatum, extended
amygdala, hippocampus, anterior cingulate, pre-
frontal cortex and insula, which are innervated by
dopaminergic projections from the ventral tegmen-
814 Fulvio Plescia, Emanuele Cannizzaro et Al
tal area (VTA)(42-44). EtOH, as well as other sub-
stances of abuse, has numerous specific actions on
DA VTA neurons: electrophysiological studies
have showed that acute EtOH increases VTA neu-
ronal activity(45,46) and augments DA release in
nucleus accumbens (Nacc) shell(47). Increasing evi-
dence focuses on ACD as one of the mediators of
the rewarding and motivational properties of
ethanol: indeed, ACD itself, and as a consequence
of the metabolism of EtOH, has been reported to
possess its own reinforcing effects. In particular,
Foddai et al., 2004(48) have shown that acute intra-
venous ACD administration increases the firing
rate, spikes/burst, and burst firing of VTA neurons.
Moreover, micro-dialysis and electrophysiology
studies have demonstrated that oral ACD adminis-
tration increases dopamine levels in the NAcc shell
and promotes VTA DA neuronal spontaneous
activity(12).
Beautifully performed electrophysiological
and pharmacological experiments have showed
that ACD exerts a modulatory activity on two dif-
ferent ion channels, A-type K+ and hyperpolariza-
tion-activated cation channels. In particular, it
seems that inhibition of A-type K+ channels and
activation of hyperpolarization-activated cation
channels contribute to the enhancing effect of ACD
on DA firing(49).
Other studies have investigated the role and
the effects of ACD in the activation of the reward
pathway, through the pharmacological modulation
of peripheral metabolism and activity of ACD. In
particular, the reduction in ACD in the presence of
its tapping agent, penicillin-derived sulfhydryl
amino acid DP, was able to interfere with EtOH
action, strongly supporting the hypothesis that
some of the behavioural and rewarding(21) effects of
ethanol are mediated by ACD. Rats pretreated with
an ADH inhibitor, 4-methyl-pyrazole (4-MP),
showed no increase in striatal dopamine levels fol-
lowing ethanol intragastric administration(12,48).
In the last years many researchers have
focused their attention on the role played by addic-
tive drugs in the activation of extracellular signal
regulated kinases (ERK), a biochemical index
taken into account to better understand the ability
of a drug to activate DA-neuronal activation(50,51),
and therefore proposed as a selective marker for
addictive compounds(52). In this regard, Ibba et al.,
2009(53) have reported that ethanol, similarly to
other addictive drugs, activates ERK in Nacc and
in the extended amygdala via a DA D1 receptor-
mediated mechanism, suggesting that this pathway
plays a crucial role in the primary mechanism of
ethanol rewarding and motivational effect.
Recently Vinci et al., 2010(54), in order to assess the
role of ACD in the modulation of ERK, have
demonstrated that the inhibition of EtOH metabo-
lism by 4-MP, and the sequestration of newly
formed ACD by DP prevent ERK activation by
EtOH, just blocking ERK phosphorylation by
ACD. Furthermore, many studies have focused
their attention on the role of DA in the activation of
ERK via D1-receptors in the Nacc and extended
amygdala. In particular, it has been reported that
treatment with SCH 39166, a D1 receptor antago-
nist, prevents ACD-elicited ERK activation(54) and
ACD-induced conditioning place preference(50). The
clear influence of D1 receptor activity on ACD-
induced ERK activation provides further evidence
of ACD incentive properties, whose contribution
must be taken into account in studying and treating
ethanol-related behaviours.
Conclusions
The functional data obtained by different
research groups in the last years emphasize the role
played by ACD as the mediator of consumption,
tolerance, and reinforcement induced by EtOH
intake. Nevertheless, despite recent progress in
ACD- and EtOH-related addictive behaviour
research, several outstanding questions remain.
Indeed if the elucidation of ACD mechanisms of
action in the induction and maintenance of the
operant drinking behaviour have emphasized the
direct and indirect (through the endocannabinoi-
dergic system) involvement of DA transmis-
sion(11,14), a central need is the comprehension of the
relationship and degree of overlap between ACD’s
addictive, emotional and cognitive properties.
In addition, more observations are necessary
in order to fully understand the intrinsic mecha-
nisms by which the formation of ACD from EtOH
can be able to induce a readaptation of the neuro-
transmitter and peptidergic circuitries that con-
tribute to the onset and the maintenance of alcohol
addiction.
In conclusion, in order to quantify the contri-
bution of ACD to the central effect of EtOH, the
study of ethanol metabolism, with a focus on brain
catalase and CYP2E1, may help clarifying the ele-
ments of individual vulnerability to alcohol addic-
tion, in order to arrange a more effective and tai-
Acetaldehyde effects in the brain 815
lored strategy aimed to the prevention and the
treatment of alcohol abuse.
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________
Correspoding author
DR. FULVIO PLESCIA
Department of Sciences for Health Promotion and Mother and
Child Care “G. D’Alessandro”, University of Palermo
Via del Vespro 129
90127 Palermo
(Italy)
Acetaldehyde effects in the brain 817
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... Indeed, anxiogenic drugs increase the avoidance of the open arms, while anxiolytic drugs reduce it. 26 Therefore, the high values in the percentage of entries and time spent on the open arms of the elevated plus maze, observed in perinatally 5-MT-exposed rats, suggest a lower emotional response to the stressful environment than perinatally vehicleexposed rats. This evidence appears to be consistent with what observed in the open field test confirming a reduced emotional response during non-aversive stress-related behavioural tasks. ...
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... [21][22][23] Whatever its source, either as original substance or as EtOH bioderivate, ACD possesses stimulating effects on some areas of the reward pathway in the brain, i.e., ventral tegmental area (VTA) and nucleus accumbens (NAc), leading to DA release, positive reinforcement and induction of dependence. [24][25][26][27] In the intracranial self-administration paradigm, whereby rats receive response-contingent infusions of a compound directly into a discrete brain region, rats readily self-administer ACD into the VTA. 28,29 Specifically within the VTA, ACD is able to activate DA neurons by significantly increasing their firing rate, similarly to EtOH. ...
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