ArticlePDF Available


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.
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
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
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-
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
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.
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
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.
1) Problems; 1992. 10th edn. Geneva: World Health
2) American Psychiatric Association, Diagnostic and
Statistical Manual of Mental Disorders; 1994. 4th edn.
Washington, DC: American Psychiatric Press..
3) Prat G, Adan A, Pérez-Pàmies M, Sànchez-Turet M.
Neurocognitive effects of alcohol hangover. Addict
Behav 2008; 33: 15-23.
4) Dom G, De Wilde B, Hulstijn W, Van den Brink W,
Sabbe B. Decision-making deficits in alcohol-depen-
dent patients with and without comorbid personality
disorder. Alcohol Clin Exp Res 2006; 30: 1670-1677.
5) Cannizzaro E, Cannizzaro C, Plescia F, Martines F,
Soleo L, Pira E, Lo Coco D. Exposure to ototoxic
agents and hearing loss: a review of current knowl-
edge. Hearing Balance and Communication 2014; 12;
6) Brancato A, Plescia F, Marino RA, Maniaci G, Navarra
M, Cannizzaro C. Involvement of dopamine D2 recep-
tors in addictive-like behaviour for acetaldehyde. PLoS
One 2014; 13; 9(6): e99454.
7) Cacace S, Plescia F, Barberi I, Cannizzaro C.
Acetaldehyde oral self administration: evidence from
the operant-conflict paradigm. Alcohol Clin Exp Res
2012; 36: 1278-1287.
8) Correa M, Manrique HM, Font L, Escrig MA, Aragon
CM. Reduction in the anxiolytic effects of ethanol by
centrally formed acetaldehyde: the role of catalase
inhibitors and acetaldehyde-sequestring agents.
Psychopharmacology 2008; 200: 455-464.
9) Correa M, Salamone JD, Segovia KN, Pardo M,
Longoni R, Spina L, et al. Piecing together the puzzle
of acetaldehyde as a neuroactive agent. Neurosci
Biobehav Rev 2012; 36: 404-430.
10) Cannizzaro C, La Barbera M, Plescia F, Cacace S,
Tringali G. Ethanol modulates corticotropin releasing
hormone release from the rat hypothalamus: does
acetaldehyde play a role? Alcohol Clin Exp Res 2010;
34: 588-593.
11) Cannizzaro C, Plescia F, Cacace S. Role of acetalde-
hyde in alcohol addiction: current evidence and future
perspectives. Malta Med J 2011; 23: 27.
12) Diana M, Peana AT, Sirca D, Lintas A, Melis M, Enrico
P. Crucial Role of Acetaldehyde in Alcohol Activation
of the Mesolimbic Dopamine System. Ann NY Acad Sci
2008; 1139: 307-317.
13) Plescia F, Cannizzaro C. Alcohol addiction: a role for
acetaldehyde. Acta Medica Mediterranea, 2009; 25: 97.
14) Plescia F, Brancato A, Marino RA, Cannizzaro C.
Acetaldehyde as a drug of abuse: insight into AM281
administration on operant-conflict paradigm in rats.
Front Behav Neurosci 2013; 11; 7: 64.
15) Quertemont E. Genetic polymorphism in ethanol metab-
olism: acetaldehyde contribution to alcohol abuse and
alcoholism. Mol. Psychiatry 2004; 9: 570-581.
16) Correa M, Pascual M, Sanchis-Segura C, Guerri C,
Aragon CM. Lead-induced catalase activity differen-
tially modulates behaviors induced by short-chain
alcohols. Pharmacol Biochem Behav 2005; 82: 443-
17) Peana AT, Enrico P, Assaretti AR, Pulighe E,
Muggironi G, Nieddu M, et al. Key role of ethanol-
derived acetaldehyde in the motivational properties
induced by intragastric ethanol: a conditioned place
preference study in the rat. Alcohol Clin Exp Res.
2008; 32: 249-258.
18) Tambour S, Didone V, Tirelli E, Quertemont E.
Dissociation between the locomotor and anxiolytic
effects of acetaldehyde in the elevated plus-maze:
Evidence that acetaldehyde is not involved in the anxi-
olytic effects of ethanol in mice. Eur
Neuropsychopharmacol 2005; 15: 655-662.
19) Deitrich RA. Acetaldehyde: déjà vu du jour. J Stud
Alcohol 2004; 65:557–572.
20) Quertemont E, Tambour S, Tirelli E. The role of
acetaldehyde in the neurobehavioral effects of ethanol:
a comprehensive review of animal studies. Prog
Neurobiol 2005; 75: 247-274.
21) Font L, Aragon CM, Miquel M. Voluntary ethanol con-
sumption decreases after the inac-tivation of central
acetaldehyde by d-penicillamine. Behav Brain Res
2006; 171: 78-86.
22) Peana AT, Assaretti AR, Muggironi G, Enrico P, Diana
M. Reduction of ethanol-derived acetal¬dehyde
induced motivational properties by L-cysteine. Alcohol
Clin Exp Res 2009; 33: 43-48.
23) Plescia F, Brancato A, Marino RA, Vita C, Navarra M,
Cannizzaro C. Effect of Acetaldehyde Intoxication and
Withdrawal on NPY Expression: Focus on
Endocannabinoidergic System Involvement. Front
Psychiatry 2014; 1; 5: 138.
24) Lieber CS. Carbohydrate deficient transferrin in alco-
holic liver disease: mechanisms and clinical implica-
tions. Alcohol 1999; 19(3): 249-254.
25) Smith BR, Aragon CM, Ami Z. Catalase and the pro-
duction of brain acetaldehyde: a possible mediator for
the psychopharmacological effects of ethanol.
Addiction Biol 1997; 2: 227-289.
26) Quertemont E, De Witte P. Conditioned stimulus pref-
erence after acetaldehyde but not ethanol injections.
Pharmacol Biochem Behav 2001; 68: 449-454.
27) Zimatkin SM, Liopo AV, Deitrich RA. Distribution and
kinetics of ethanol metabolism in rat brain. Alcohol
Clin Exp Res 1998; 22: 1623-1627.
28) Hamby-Mason R, Chen JJ, Schenker S, Perez A,
Henderson GI. Catalase mediates acetaldehyde forma-
tion from ethanol in fetal and neonatal rat brain.
Alcohol Clin Exp Res 1997; 21(6): 1063-1072.
29) Zimatkin SM, Pronko SP, Vasiliou V, Gonzalez FJ,
Deitrich RA. Enzymatic mechanisms of ethanol oxida-
tion in the brain. Alcohol Clin Exp Res 2006; 30: 1500-
30) Hunt WA. Role of acetaldehyde in the actions of
ethanol on the brain–a review. Alcohol 1996; 13: 147–
31) Quertemont E, Tambour S. Is ethanol a pro-drug? The
role of acetaldehyde in the central effects of ethanol.
Trends Pharmacol Sci 2004; 25: 130-134.
32) Peana AT, Muggironi G, Diana M. Acetaldehyde rein-
forcing effects: a study on oral self-administration
behavior. Front Psychiatry 2010; 1:23. doi:
33) Aragon CM, Amit Z. Differences in ethanol-induced
behaviors in normal and acatalasemic mice: systematic
examination using a biobehavioral approach.
Pharmacol Biochem Behav 1993; 44: 547-554.
816 Fulvio Plescia, Emanuele Cannizzaro et Al
34) Correa M, Miquel M, Sanchis-Segura C, Aragon CM.
Effects of chronic lead administration on ethanol-
induced locomotor and brain catalase activity. Alcohol
1999; 19: 43-49.
35) Correa M, Miquel M, Aragon CM. Lead acetate poten-
tiates brain catalase activity and enhances ethanol-
induced locomotion in mice. Pharmacol Biochem
Behav 2000; 66: 137-142.
36) Correa M, Sanchis-Segura C, Aragon CM. Influence of
brain catalase on ethanol-induced loss of righting
reflex in mice. Drug Alcohol Depend 2001; 65: 9-15.
37) Correa M, Sanchis-Segura C, Pastor R, Aragon CM.
Ethanol intake and motor sensitization: the role of
brain catalase activity in mice with different genotypes.
Physiol Behav 2004; 82: 231-240.
38) Serrano E, Pozo OJ, Beltrán J, Hernández F, Font L,
Miquel M, Aragon CM. Liquid chromatography/tan-
dem mass spectrometry determination of (4S,2RS)-
2,5,5- trimethylthiazolidine-4-carboxylic acid, a stable
adduct formed between D-(-)-penicillamine and
acetaldehyde (main biological metabolite of ethanol),
in plasma, liver and brain rat tissues. Rapid Commun
Mass Spectrom 2007; 21: 1221-1229.
39) Upadhya SC, Tirumalai PS, Boyd MR, Mori T,
Ravindranath V. Cytochrome P4502E (CYP2E) in
brain: constitutive expression, in-duction by ethanol
and localization by fluorescence in situ hybridization.
Arch Biochem Biophys 2000; 373: 23-34.
40) Yadav S, Dhawan A, Singh RL, Seth PK, Parmar D.
Expression of constitutive and inducible cytochrome
P450 2E1 in rat brain. Mol Cell Biochem 2006; 286:
41) Parmar D, Dayal M, Seth, PK. Expression of
cytochrome P450s (P450s) in brain: Physiological,
pharmacological and toxicological consequences.
Proceedings of Indian National Academy of Sciences
(PINSA–B) 2003; 6: 905-928.
42) Hyman S, Chisholm D, Kessler R, Patel V, Whiteford
H. Mental Disorders. Jamison DT, Breman JG,
Measham AR, Alleyne G, Claeson M, Evans DB, Jha P,
Mills A, Musgrove P, editors. Disease Control
Priorities in Developing Countries. 2nd edition.
Washington (DC): World Bank; 2006. Chapter 31.
43) Nestler EJ. The neurobiology of cocaine addiction. Sci
Pract Perspect 2005; 3: 4-10.
44) Wanat MJ, Willuhn I, Clark JJ, Phillips PE. Phasic
dopamine release in appetitive behaviors and drug
addiction. Curr Drug Abuse Rev 2009; 2: 195-213.
45) Koyama S, Brodie MS, Appel SB. Ethanol inhibition of
m-current and ethanol-induced direct excitation of ven-
tral tegmental area dopamine neurons. J Neurophysiol
2007; 97: 1977-1985.
46) McDaid J, McElvain MA, Brodie MS. Ethanol e
on dopaminergic ventral tegmental area neurons dur-
ing block of Ih: involvement of barium-sensitive potas-
sium currents. J Neurophysiol 2008; 100: 1202-1210.
47) Imperato A, Di Chiara G. Preferential stimulation of
dopamine release in the nucleus accumbens of freely
moving rats by ethanol. J Pharmacol Exp Ther 1986;
239: 219-228.
48) Foddai M, Dosia G, Spiga S, Diana M. Acetaldehyde
increases dopaminergic neuronal activity in the VTA.
Neuropsychopharmacology 2004; 29: 530-536.
49) Melis M, Enrico P, Peana AT, Diana M. Acetaldehyde
mediates alcohol Activation of the mesolimbic
dopamine system. Eur J Neurosci 2007; 26: 2824-2833.
50) Acquas E, Pisanu A, Spiga S, Plumitallo A, Zernig G,
Di Chiara G. Differential effects of intravenous R,S-(±)-
3,4methylenedioxymethamphetamine (MDMA, ecstasy)
and its S(+)- and R(-)-enantiomers on dopamine trans-
mission and extracellular signal regulated kinase phos-
phorylation (pERK) in the rat nucleus accumbens shell
and core. J Neurochem 2007; 102: 121-132.
51) Girault JA, Valjent E, Caboche J, Hervè D. ERK2: a
logical AND gate critical for drug-induced plasticity?
Curr Opin Pharmacol 2007; 7: 77-85.
52) Valjent E, Pascoli V, Svenningsson P, Paul S, Enslen H,
Corvol JC, Stipanovich A, Caboche J, Lombroso PJ,
Nairn AC, Greengard P, Hervé D, Girault JA.
Regulation of a protein phosphatase cascade allows
convergent dopamine and glutamate signals to activate
ERK in the 6striatum. Proc Natl Acad Sci U S A 2005;
102: 491-496.
53) Ibba F,Vinci S, Spiga S, Peana AT, Assaretti AR, Spina
L, et al. Ethanol-induced extracellular signal regulated
kinase: role of dopamine D1 receptors. Alcohol. Clin
Exp Res 2009; 33: 858-867.
54) Vinci S, Ibba F, Longoni R, Spina L, Spiga S, Acquas
E. Acetaldehyde elicits ERK phosphorylation in the rat
nucleus accumbens and extended amygdala. Synapse
2010; 64: 916-927.
Correspoding author
Department of Sciences for Health Promotion and Mother and
Child Care “G. D’Alessandro”, University of Palermo
Via del Vespro 129
90127 Palermo
Acetaldehyde effects in the brain 817
... Work-related stress is considered a major risk factor for the onset of physical and mental health disorders such as cardiovascular diseases, metabolic syndrome, depression, cognitive impairment and cancer [5][6][7]. Work pressure may be associated with factors like the use of drugs, respiratory tract infections, etc., that may contribute to increase the stress response during the course of human life [8][9][10][11][12][13][14]. Workers define the stress they perceive at work as a "sense of fatigue" [15,16]. ...
Full-text available
Work-related stress can induce a break in homeostasis by placing demands on the body that are met by the activation of two different systems, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Night-shift work alters the body's exposure to the natural light-dark schedule and disrupts circadian (daily) rhythms. The greatest effect of night-shift work is the disruption of circadian rhythms. The impact that these disruptions may have on the pathogenesis of many diseases, including cancer, is unknown. This study aims to discover the relationship among three different job activities of security guards and their stress-related responses by evaluating salivary cortisol levels and blood pressure. Methods: Ninety security guards, including night-time workers and night-time and daily-shift workers, were recruited for this study. Each security guard provided two saliva samples before and after three scheduled time points: (i) at 22:00, (ii) at 06:30, and (iii) at 14:00. Results: The results of the study showed a significant alteration in cortisol levels. Night-time shift cortisol levels significantly increased before and after the work shifts. A physiological prevalence of the vagal tone on the cardiocirculatory activity was found during night-shift work. Conclusions: This study indicates that cortisol levels and blood pressure are sensitive markers of biological responses to severe work stress. Shift-change consequences may occur at the end of the night shift when there is a significant increase in the cortisol level and a significant variation in cardiovascular parameters.
... Nevertheless, this pilot study shows that FT may be effective for treating GD. Considering the similarities between GD and drug addiction (37,38,39,40) a next step would be a larger randomized controlled trial to compare FT to a controlled condition and verify if the improvements are maintained during a follow-up period. In conclusion, this was the first study reporting a positive outcome in PGs treated with a structured FT program that highlights a strong improvement in gambling behavior, in reducing impulsivity, depression, anxiety and perceived stress, thus obtaining good compliance and only a few abandonments from the therapy. ...
Full-text available
Background: Despite the great progress achieved by treatment approaches for Gambling Disorder (GD) the relevance of studying efficacious therapies still remains high. This pilot study aims at the evaluation of the efficacy of a standardized protocol based on Functional theory for GD. Functional Therapy (FT) is an integrated body-mind therapy. Methods: Twenty-eight pathological gamblers completed the FT protocol consisted in 16 sessions, two times a week for a total duration of two months, in an individual setting. No one of the patients was taking any psychopharmacological therapy. Psychological assessment both at baseline (T0) and at the end of the treament (T1) includes the South Oaks Gambling Screen, the PG-Yale-Brown Obsessive-Compulsive Scale (PG-YBOCS), State-Trait Anxiety Inventory (STAI), the Beck Depression Inventory - II version (BDI-II), the Barrat Impulsiveness Scale 11th version (BIS-11) and the Measurement of Psychological Stress (MSP). Results: a significant reduction of GD (gambling frequency, duration, money inserted, and expenditure) in pathological gamblers was revealed together with a significant reduction of depression, anxiety, impulsivity and perceived stress. Conclusions: the structured FT program for GD highlights a strong improvement in gambling behavior, in reducing impulsivity, depression, anxiety and perceived stress, thus obtaining a good compliance and a few dropout.
... Overall, binge-like alcohol drinking seems to be responsible for a depressive-oriented phenotype, when animals are tested on abstinence days, which includes anhedonia-and despair-, whereas HAD rather induces an anxiety-oriented behavior. The repeated cycles of alcohol exposure and withdrawal typical of binge-like drinking may lead to enduring aberrant plasticity in strategic brain circuitries that drive a transition from positive to negative reinforcement-based alcohol seeking, and abstinenceinduced affective disturbances [57,[63][64][65][66][67][68][69][70][71][72][73][74]. Supplementary and in depth evidence on the subject are available on seminal reviews [75]. ...
Full-text available
Although binge drinking is on the rise in women of reproductive age and during pregnancy, the consequences in the offspring, in particular the inheritance of alcohol-related mood disturbances and alcohol abuse vulnerability, are still poorly investigated. In this study, we modeled both Habitual- and Binge Alcohol Drinking (HAD and BAD) in female rats by employing a two-bottle choice paradigm, with 20% alcohol and water. The exposure started 12 weeks before pregnancy and continued during gestation and lactation. The consequences induced by the two alcohol drinking patterns in female rats were assessed before conception in terms of behavioral reactivity, anxiety- and depressive-like behavior. Afterwards, from adolescence to young-adulthood, male offspring was assessed for behavioral phenotype and alcohol abuse vulnerability. At pre-conceptional time BAD female rats showed higher mean alcohol intake and preference than HAD group; differences in drinking trajectories were attenuated during pregnancy and lactation. Pre-conceptional BAD induced a prevalent depressive/anhedonic-like behavior in female rats, rather than an increase in anxiety-like behavior, as observed in HAD rats. In the adolescent offspring, peri-gestational BAD did not affect behavioral reactivity in the open field and anxiety-like behavior in the elevated plus maze. Rather, BAD dams offspring displayed higher despair-behavior and lower social interaction with respect to control- and HAD dams progeny. Notably, only binge drinking exposure increased offspring vulnerability to alcohol abuse and relapse following forced abstinence. This is the first report showing that binge-like alcohol consumption from pre-conceptional until weaning induces relevant consequences in the affective phenotype of both the mothers and the offspring, and that such effects include heightened alcohol abuse vulnerability in the offspring. These findings highlight the need for more incisive public education campaigns about detrimental consequences of peri-gestational alcohol exposure.
... 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. ...
Full-text available
Manipulations of the serotonin transmission during early development induce long-lasting changes in the serotonergic circuitry throughout the brain. However, little is known on the developmental consequences in the female progeny. Therefore, this study aimed at exploring the behavioural effects of pre- and postnatal stimulation of the serotonergic system by 5-methoxytryptamine in adolescent female rats on behavioural reactivity and anxiety- like phenotype. Our results show that perinatal 5- methoxythyptamine decreased total distance travelled and rearing frequency in the novel enviroment, and increased the preference for the centre of the arena in the open field test. Moreover, perinatal 5-methoxytryptamine increased the percentages of entries and time spent on the open arms of the elevated plus maze, with respect to perinatally vehicle-exposed rats. Thus, perinatal stimulation of serotonin receptors does not impair the functional response to the emotional challenges in female rats, favouring the occurrence of a stress-resilient phenotype.
... [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. ...
Full-text available
In the last years, numerous studies have supported the idea that, at least in part, motivational and neuropharmacological effects of ethanol are mediated by its first brain-derived metabolite, acetaldehyde, and its bioderivate salsolinol. This review aims at gathering and shaping as a whole the evidence on their role in the mechanism of action of ethanol. Acetaldehyde and salsolinol interact with the reward brain system and are involved as primum movens of motivational and addictive behaviour that can be especially relevant to ethanol use disorders. Understanding the neurobiology of acetaldehyde and salsolinol holds promising potential for the development of novel pharmacological approaches for reducing ethanol abuse.
Full-text available
During adolescence, internal and external factors contribute to engaging with alcohol binge drinking (ABD), putting at risk the neurodevelopment of brain regions crucial for emotional control and stress coping. This research assessed the prevalence of ABD in late adolescent students of Southern Italy and characterized their psychological profile and drinking motives. Translational effects of alcohol binge drinking in the animal model were also studied. Seven hundred and fifty-nine high school students of both sexes (aged 18–20) were recruited. Alcohol Use Disorder Identification Test-Consumption (AUDIT-C), Drinking Motives Questionnaire-Revised Short Form, Millon Clinical Multiaxial Inventory-Third Ed., State-Trait Anxiety Inventory, Connor-Davidson Resilience Scale, and Basic Self-Esteem Scale identified alcohol habits, drinking motives, and psychopathological profile. Eighty-five percentage of the students drank alcohol and 28% of them engaged in ABD; AUDIT-C correlated with enhancement, coping, and conformity motives. ABD was related to a greater likelihood of presenting clinical syndromes and personality disorders, as well as low resilience and self-esteem. Thereafter, in the pre-clinical model, adolescent male rats were exposed to alcohol (3.5 g/kg) in an intermittent binge-like paradigm and tested during prolonged abstinence. Rats were evaluated for anxiety-like behavior, motivated behaviors, resilience, and stress response following a psychosocial challenge. Binge-like alcohol-exposed adolescent rats displayed high integrated z-score for social- and novelty-induced anxiety, altered motivation-driven output, decreased resilience, and a blunted HPA axis response to psychosocial stress, with respect to respective controls. Our data confirm that ABD is the chosen pattern of drinking in a significant percentage of high school students in Southern Italy, and highlights AUDIT-C score as a relevant parameter able to predict the occurrence of affective disturbances. The evidence from the preclinical model shows that ABD produces detrimental consequences in the adolescent rat brain, resulting in negative affect, emotional dysregulation, and aberrant stress response, pointing to decreasing excessive alcohol drinking as a primary goal for the global act for brain health.
Background Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), i.e. the neural hub for processing reward and aversive responses. Methods As socially stressful events pose particular challenges at developmental stages, this research applied the resident–intruder paradigm as a model of social stress, to highlight behavioural neuroendocrine and molecular maladaptive plasticity in rats at withdrawal from binge-like alcohol exposure in adolescence. In search of a rescue agent, cannabidiol (CBD) was selected due to its favourable effects on alcohol- and stress-related harms. Results Binge-like alcohol exposed intruder rats displayed a compromised defensive behaviour against the resident and a blunted response of the stress system, in addition to indexes of abnormal dopamine (DA)/glutamate plasticity and dysfunctional spine dynamics in the NAc. CBD administration (60 mg/kg) was able to: (1) increase social exploration in the binge-like alcohol exposed intruder rats, at the expenses of freezing time, and in control rats, which received less aggressive attacks from the resident; (2) reduce corticosterone levels independently on alcohol previous exposure; (3) restore DA transmission and (4) facilitate excitatory postsynaptic strength and remodelling. Conclusions Overall, the maladaptive behavioural and synaptic plasticity promoted by the intersection between binge-like alcohol withdrawal and exposure to adverse social stress can be rescued by a CBD détente effect that results in a successful defensive strategy, supported by a functional endocrine and synaptic plasticity. The current data highlight CBD's relevant therapeutic potential in alcohol- and stress-related harms, and prompt further investigation on its molecular targets.
Full-text available
The sleep-wake cycle plays a fundamental role in maintaining the physiological balance of our body. Its alteration favours the genesis of several organic alterations and diseases including sleep disorders and the consumption of several substances of abuse. It has been reported that the work activity, especially that carried out during the night, is able to influence the sleep-wake cycle, promoting the development of insomnia, which, in turn, would subject the worker to a stressful condition such as to encourage adverse behaviour such as the use/abuse of psychotropic substances. Based on the above premises, the aim of our research was to evaluate, in night workers: (i) the pattern of consumption of alcoholic beverages; (ii) the presence of insomnia; and (iii) the possible correlation between alcohol consumption and insomnia disorder. We used the AUDIT-C test (the abbreviated version of the Alcohol Use Disorders Identification Test) and the Insomnia Severity Index to assess alcohol consumption and insomnia disorder, respectively. All questionnaires were completed by workers of both sexes belonging to different types of work activities, exclusively day or night. The results of our research show a higher propensity of night workers to consume alcoholic beverages than those who work during daytime hours, often in binge-drinking mode. In addition, an increase in the amount of alcohol consumed was found to be related to insomnia disorder, especially in night workers. This study provides further awareness of the importance of the negative impact of alcohol consumption on sleep quality in night worker.
Full-text available
Sensorineural hearing loss (SNHL) is an inner ear disease which affect from 1 to 3 per 1000 newborns; the World Health Organization estimated a lower prevalence of congenital hearing loss in industrialized countries (2 to 4 per 1000 live births) with respect to developing countries. Particularly, among children admitted to neonatal intensive care unit (NICU) and those with other audiologic risk factors (e.g., very low birthweight, craniofacial abnormalities, intrauterine infections, family history of hearing loss, ototoxic drugs, mechanical ventilation, etc.), hearing loss may have a prevalence 10-20 fold higher. A severe to profound bilateral hearing loss, if not treated, can compromise the normal development of the child, interfering with the process of speech development. Thus, identification and knowledge of non-genetic etiologies of neonatal SNHL may help in developing an early and effective rehabilitation plan.
Full-text available
Although drug-abusing women try to moderate their drug and alcohol use during pregnancy, they often relapse at a time when childcare needs are high and maternal bonding is critical to an infant’s development. In the clinical setting, the search for the neural basis of drug-induced caregiving deficits is complex due to several intervening variables. Rather, the preclinical studies that control for drug dose and regimen, as well as for gestational and postpartum environment, allow a precise determination of the effects of drugs on maternal behaviour. Given the relevance of the issue, this review will gather reports on the phenotypic correlates of maternal behaviour in preclinical studies, and focus on the detrimental consequences on the mother-infant interaction exerted by the perinatal use of alcohol, nicotine, cannabis, cocaine and stimulants and opiates. The drug-induced disruptions of this maternal repertoire are associated with adverse maternal and infant outcomes. A comprehensive overview will help promote the refinement of the treatment approaches toward maternal drug use disorders and maternal misbehaviour, in favour of augmented parenting resiliency.
Full-text available
Acetaldehyde (ACD), the first alcohol metabolite, plays a pivotal role in the rewarding, motivational, and addictive properties of the parental compound. Many studies have investigated the role of ACD in mediating neurochemical and behavioral effects induced by alcohol administration, but very little is known about the modulation of neuropeptide systems following ACD intoxication and withdrawal. Indeed, the neuropeptide Y (NPY) system is altered during alcohol withdrawal in key regions for cerebrocortical excitability and neuroplasticity. The primary goal of this research was to investigate the effects of ACD intoxication and withdrawal by recording rat behavior and by measuring NPY immunoreactivity in hippocampus and NAcc, two brain regions mainly involved in processes which encompass neuroplasticity in alcohol dependence. Furthermore, on the basis of the involvement of endocannabinoidergic system in alcohol and ACD reinforcing effects, the role of the selective CB1 receptor antagonist AM281 in modulating NPY expression during withdrawal was assessed. Our results indicate that (i) ACD intoxication induced a reduction in NPY expression in hippocampus and NAcc; (ii) symptoms of physical dependence, similar to alcohol's, were scored at 12 h from the last administration of ACD; and (iii) NPY levels increased in early and prolonged acute withdrawal in both brain regions examined. The administration of AM281 was able to blunt signs of ACD-induced physical dependence, to modulate NPY levels, and to further increase NPY expression during ACD withdrawal both in hippocampus and NAcc. In conclusion, the present study shows that complex plastic changes take place in NPY system during ACD intoxication and subsequent withdrawal in rat hippocampal formation and NAcc. The pharmacological inhibition of CB1 signaling could counteract the neurochemical imbalance associated with ACD, and alcohol withdrawal, likely boosting the setting up of homeostatic functional recovery.
Full-text available
Acetaldehyde, the first metabolite of ethanol, is active in the central nervous system, where it exerts motivational properties. Acetaldehyde is able to induce drinking behaviour in operant-conflict paradigms that resemble the core features of the addictive phenotype: drug-intake acquisition and maintenance, drug-seeking, relapse and drug use despite negative consequences. Since acetaldehyde directly stimulates dopamine neuronal firing in the mesolimbic system, the aim of this study was the investigation of dopamine D2-receptors' role in the onset of the operant drinking behaviour for acetaldehyde in different functional stages, by the administration of two different D2-receptor agonists, quinpirole and ropinirole. Our results show that acetaldehyde was able to induce and maintain a drug-taking behaviour, displaying an escalation during training, and a reinstatement behaviour after 1-week forced abstinence. Acetaldehyde operant drinking behaviour involved D2-receptor signalling: in particular, quinpirole administration at 0.03 mg/kg, induced a significant decrease in the number of lever presses both in extinction and in relapse. Ropinirole, administered at 0.03 mg/kg during extinction, did not produce any modification but, when administered during abstinence, induced a strong decrease in acetaldehyde intake in the following relapse session. Taken together, our data suggest that acetaldehyde exerts its own motivational properties, involving the dopaminergic transmission: indeed, activation of pre-synaptic D2-receptors by quinpirole, during extinction and relapse, negatively affects operant behaviour for acetaldehyde, likely decreasing acetaldehyde-induced dopamine release. The activation of post-synaptic D2-receptors by ropinirole, during abstinence, decreases the motivation to the consecutive reinstatement of acetaldehyde drinking behaviour, likely counteracting the reduction in the dopaminergic tone typical of withdrawal. These data further strengthen the evidence that acetaldehyde may play a crucial role as mediator of ethanol's central effects.
Full-text available
Increasing evidence focuses on acetaldehyde (ACD) as the mediator of the rewarding and motivational properties of ethanol. Indeed, ACD stimulates dopamine release in the nucleus accumbens and it is self-administered under different conditions. Besides the dopaminergic transmission, the endocannabinoid system has been reported to play an important role in ethanol central effects, modulating primary alcohol rewarding effect, drug-seeking, and relapse behavior. Drug motivational properties are highlighted in operant paradigms which include response-contingent punishment, a behavioral equivalent of compulsive drug use despite adverse consequences. The aim of this study was thus to characterize ACD motivational and rewarding properties employing an operant-conflict paradigm in which rats, trained to lever press in order to get ACD solution (0.9%), undergo extinction, reinstatement and conflict sessions, according to a modified Geller-Seifter procedure. Furthermore, the role played by CB1 receptor system in modulating ACD-induced effects were investigated through the administration of CB1 receptor antagonist, AM281 (1 mg/kg, i.p.) during the extinction-, relapse-, and conflict-experiments. Our results indicate that ACD is able to induce and maintain an operant behavior, a high number of responses during extinction, an increase in the lever presses during the reinstatement phase, and a higher emission of punished responses during the conflict experiments, when compared to controls. The administration of AM281 is able to decrease ACD-seeking behavior during extinction, the number of lever presses during reinstatement and to strongly decrease the punished responses for ACD. Our data strengthen the idea that ACD may be responsible for the central effects of ethanol, and pinpoint at the CB1 system as one of the neural substrates underlying its addictive properties.
Full-text available
The effects of alcohol have been widely studied during the past century, corroborating the idea that this tiny chemical compound acts throughout most of our neurotransmitter systems since it is capable of inducing addictive behaviour. Two of the most serious problems of alcohol addiction are craving and relapse; several studies have demonstrated that relapse is related to the anxious state which occurs during withdrawal, and it has been proved that this behavioural modifications results from an alteration of the dopaminergic and serotonergic systems. An important role in the neurobiology of alcohol addiction is played by acetaldehyde (ACD), ethanol first metabolite.
Alcoholism is a chronically relapsing disorder characterized by cycles of repeated high alcohol intake and negative emotional consequences of withdrawal thought to contribute to excessive drinking and susceptibility to relapse. In the past years, the pharmacological and behavioural effects of alcohol, such us sedation, memory and learning impairment, were assigned to the main component of alcoholic drinks, ethanol. Recently acetaldehyde, the first metabolite of ethanol, seems to exert biological activity, besides its adverse effects. The aim of the present review is to elucidate the putative role of acetaldehyde in mediating the neuronal and behavioural features induced by ethanol intake.
It was found that the accumulation of acetaldehyde produced from 50 mM ethanol in rat brain homogenates takes place in all major brain regions. The velocity varied between 3.5 to 7.1 nmol/mg of protein/hr. The rate increased in the following order: brain hemispheres, striatum, brainstem, hypothalamus, and cerebellum. Significant regional differences in this process were found: in the initial period of incubation (5 min), acetaldehyde accumulation was maximal in the brain hemispheres; but, in the 30- to 60-min period, it became significantly higher in the cerebellum. Inhibition of this process by the catalase inhibitor, 3-amino-1,2,4-triazole (8 mM), was minimal in the brainstem (27%) end maximal (57%) in the cerebellum, despite nearly complete inhibition of catalase. This would indicate that processes other than catalase activity must contribute to acetaldehyde accumulation.
Several experimental and clinical studies have shown that a variety of ototoxic agents (such as drugs, industrial chemicals and noise) can cause sensorineural hearing loss. The most common ototoxic drugs used in clinical practice include: aminoglycoside and macrolide antibiotics, quinoline anti-malarials, platinum analog antineoplastics, loop diuretics, and acetylsalicylic acid. Among chemical agents with potential ototoxic properties are: organic solvents, heavy metals, organotins, nitriles, asphyxiants, and pesticides/herbicides. Acoustic exposure to high intensity and/or prolonged noise can also cause permanent threshold shifts in auditory perception. Ototoxic agents can influence auditory function by different mechanisms: ROS overload, inhibition of mitochondrial protein synthesis, DNA/RNA damage, activation of the apoptotic pathways, excessive calcium influx, increase of proinflammatory cytokines, interference with fluid and electrolyte balance of the endolymph, atrophy of the stria vascularis, changes in blood-labyrinth barrier and overstimulation of the stereocilia of the ear cells. Since noise exposure and many drugs or chemical compounds frequently share the same ototoxic mechanisms, this may explain why hearing loss can be potentiated by combined exposure to these agents. However, a great variability in the individual’s response to a given xenobiotic exists and depends on a complex interplay between endogenous and exogenous factors.
Several reports have demonstrated that acute lead acetate administration enhances brain catalase activity in animals. Other reports have shown a role of brain catalase in ethanol-induced behaviors. In the present study we investigated the effect of acute lead acetate on brain catalase activity and on ethanol-induced locomotion, as well as whether mice treated with different doses of lead acetate, and therefore, with enhanced brain catalase activity, exhibit an increased ethanol-induced locomotor activity. Lead acetate or saline was injected IP in Swiss mice at doses of 50, 100, 150, or 200 mg/kg. At 7 days following this treatment, ethanol (0.0, 1.5, 2.0, 2.5, or 3.0 g/kg) was injected IP, and the animals were placed in the open-field chambers. Results indicated that the locomotor activity induced by ethanol was significantly increased in the groups treated with lead acetate. Maximum ethanol-induced locomotor activity increase was found in animals treated with 100 mg/kg of lead acetate and 2.5 g/kg of ethanol. Total brain catalase activity in lead-pretreated animals also showed a significant induction, which was maximum at 100 mg/kg of lead acetate treatment. No differences in blood ethanol levels were observed among treatment groups. The fact that brain catalase and ethanol-induced locomotor activity followed a similar pattern could suggest a relationship between both lead acetate effects and also a role for brain catalase in ethanol-induced behaviors.