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Acetaldehyde is the first active breakdown product (i.e., metabolite) generated during alcohol metabolism. It has toxic properties but also exerts other actions on the body (i.e., has pharmacological properties). Recent studies have shown that the direct administration of acetaldehyde, especially into the brain, induces several effects that mimic those of alcohol. High doses of acetaldehyde induce sedative as well as movement- and memory-impairing effects, whereas lower doses produce behavioral effects (e.g., stimulation and reinforcement) that are characteristic of addictive drugs. When acetaldehyde accumulates outside the brain (i.e., in the periphery), adverse effects predominate and prevent further alcohol drinking. To investigate the role of acetaldehyde in mediating alcohol's effects, investigators have pharmacologically manipulated alcohol metabolism and the production of acetaldehyde within the body (i.e., endogenous acetaldehyde production). Studies manipulating the activity of the enzyme catalase, which promotes acetaldehyde production in the brain, suggest that acetaldehyde contributes to many behavioral effects of alcohol, especially its stimulant properties. However, it remains controversial whether acetaldehyde concentrations obtained under normal physiological conditions are sufficient to induce significant pharmacological effects. Current evidence suggests that the contribution of acetaldehyde to alcohol's effects is best explained by a process in which acetaldehyde modulates, rather than mediates, some of alcohol's effects.
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Role of Acetaldehyde in
Mediating the Pharmacological
and Behavioral Effects of Alcohol
Etienne Quertemont, Ph.D., and Vincent Didone
an associate professor and V
IDONE is a research assistant in the
Centre de Neurosciences Cognitives et
Comportementales, Université de Liège,
Liège, Belgium.
Acetaldehyde is the first active breakdown product (i.e., metabolite) generated during alcohol
metabolism. It has toxic properties but also exerts other actions on the body (i.e., has pharmacological
properties). Recent studies have shown that the direct administration of acetaldehyde, especially into
the brain, induces several effects that mimic those of alcohol. High doses of acetaldehyde induce
sedative as well as movement- and memory-impairing effects, whereas lower doses produce behavioral
effects (e.g., stimulation and reinforcement) that are characteristic of addictive drugs. When
acetaldehyde accumulates outside the brain (i.e., in the periphery), adverse effects predominate and
prevent further alcohol drinking. To investigate the role of acetaldehyde in mediating alcohol’s effects,
investigators have pharmacologically manipulated alcohol metabolism and the production of
acetaldehyde within the body (i.e., endogenous acetaldehyde production). Studies manipulating the
activity of the enzyme catalase, which promotes acetaldehyde production in the brain, suggest that
acetaldehyde contributes to many behavioral effects of alcohol, especially its stimulant properties.
However, it remains controversial whether acetaldehyde concentrations obtained under normal
physiological conditions are sufficient to induce significant pharmacological effects. Current evidence
suggests that the contribution of acetaldehyde to alcohol’s effects is best explained by a process in
which acetaldehyde modulates, rather than mediates, some of alcohol’s effects. K
EY WORDS: Ethanol
metabolism; ethanol-to-acetaldehyde metabolism; acetaldehyde; aldehyde dehydrogenases (ALDHs); alcohol
dehydrogenase (ADH); alcohol metabolite; catalase; brain; central nervous system; protective factors; alcohol
flush reaction; pharmacology and toxicology
any chemical compounds,
including many medications
and drugs, are eliminated
from the body through their metabolism,
which leads to the production of break-
down products (i.e., metabolites) that
are readily excreted. In general, these
metabolites are biologically inactive;
accordingly, metabolism of the original
compound terminates its biological
activity. Some metabolites, however,
may exert potent effects on the body
(i.e., have pharmacological properties)
or have toxic properties; these are referred
to as active metabolites. Finally, some
medications or drugs actually are pharma-
cologically inactive compounds; these
so-called prodrugs must be converted
to biologically active metabolites in order
to exert their pharmacological effects.
Acetaldehyde is the first product
generated during the metabolism of
alcohol (chemically known as ethanol).
It is generated primarily in the liver by
the enzyme alcohol dehydrogenase
(ADH). The acetaldehyde then is con-
verted rapidly to acetate by the enzyme
aldehyde dehydrogenase (ALDH). (For
more information on the pathways of
ethanol metabolism, see the article by
Zakhari in this issue.)
Acetaldehyde is an active metabolite
that induces a range of toxic, pharma-
cological, and behavioral effects. However,
the role of acetaldehyde in mediating
alcohol’s effects, especially its effects on
the brain (i.e., its central effects), has
been controversial for more than two
decades (Deitrich 2004; Quertemont
and Tambour 2004). Some investiga-
tors argue that acetaldehyde is a key
mediator of ethanol’s pharmacological
and behavioral effects. According to the
most radical version of this theory, ethanol
would be a mere prodrug whose effects
are fully mediated by its first metabolite,
acetaldehyde. It even has been suggested
that instead of “alcoholism,” the term
acetaldehydism” would be more
appropriate to describe alcohol abuse
and addiction (Raskin 1975). Conversely,
other scientists deny any significant
role for acetaldehyde in ethanols phar-
macological effects. These investigators
generally contend that following nor-
Alcohol Research & Health 258
Role of Acetaldehyde in Mediating Alcohol’s Effects
mal alcohol consumption, acetaldehyde
concentrations in the blood and brain
are far too low to induce any significant
pharmacological or behavioral effects
(see discussion in Deitrich 2004).
An intermediate, and probably more
sustainable, position states that the
pharmacological properties of acetalde-
hyde modulate (rather than mediate)
some, but not all, of ethanol’s effects. This
modulatory action of acetaldehyde
probably greatly depends on specific
conditions. For example, acetaldehyde
may contribute only to those alcohol
effects that occur at high alcohol con-
centrations, which also result in high
acetaldehyde levels. Moreover, the con-
tribution of acetaldehyde to alcohol’s
effects likely varies across individuals,
in part due to individual differences
in alcohol-metabolizing enzymes
(Quertemont 2004).
This article provides an overview
of acetaldehydes pharmacological and
behavioral effects in the body and reviews
some of the mechanisms that may
underlie these effects. It then explores
the issue of acetaldehyde concentra-
tions in the brain and periphery before
summarizing the results of studies in
which ethanol metabolism was manip-
ulated in order to more specifically
delineate acetaldehydes contribution to
ethanols effects.
Pharmacological and
Behavioral Effects
The hypothesis that acetaldehyde
mediates or contributes to the effects of
ethanol implies that acetaldehyde itself
can exert effects similar to those observed
after alcohol administration. Therefore,
the first step to support such a theory is
to demonstrate acetaldehydes direct
pharmacological and behavioral effects.
Because acetaldehyde is highly toxic,
however, most studies using direct
administration of acetaldehyde have
been carried out in laboratory animals,
particularly rodents. In humans, most
of the knowledge about acetaldehyde’s
properties has been gathered indirectly
by studying people carrying a deficient
variant (i.e., allele) of the gene encoding
the ALDH enzyme known as ALDH2*2.
This allele results in the production of
an inactive ALDH enzyme. If people
carrying the deficient ALDH2*2 gene
consume alcohol, their bodies cannot
metabolize acetaldehyde, which there-
fore accumulates to high concentra-
tions. Additional information comes
from observations of alcoholics who
were treated with ALDH inhibitors
(e.g., the medication disulfiram) to
deter further alcohol consumption but
who nevertheless drank alcohol and
therefore also accumulated acetaldehyde.
The major problem associated with
these observations in humans is the
lack of control over acetaldehyde con-
centrations. Because the bulk of any
ingested ethanol is metabolized to
acetaldehyde in the liver, genetically or
pharmacologically induced deficiencies
in ALDH activity lead to high peripheral
concentrations of acetaldehyde, allow-
ing no precise determination of the
dose-response pattern of acetaldehyde
effects. Furthermore, the peripheral
effects of these high acetaldehyde levels
may mask the compound’s more spe-
cific actions in the nervous system (i.e.,
neuropharmacological properties).
Therefore, such studies in humans are
not well suited for studying the effects
of acetaldehyde in the central nervous
system (CNS), particularly the brain.
Physiological Effects in the Periphery
Acetaldehyde accumulation in the
periphery produces a pattern of effects
commonly defined by the term “alco-
hol sensitivity” because these symptoms
most often are observed when people
with deficient ALDH activity drink
alcohol (Eriksson 2001). These typical
physiological effects include peripheral
widening of the blood vessels (i.e.,
vasodilation), resulting in increased
skin temperature and facial flushing;
increased heart and respiration rates;
pounding or racing of the heart (i.e.,
palpitations); lowered blood pressure;
narrowing of the airways (i.e., bron-
choconstriction); nausea; and headache.
The mechanisms by which acetaldehyde
induces these symptoms are complex
and involve multiple molecular targets,
including the following (for a review,
see Eriksson 2001):
Acetaldehyde stimulates the release
of signaling molecules called
epinephrine and norepinephrine
from certain nerve cells (i.e., sympa-
thetic nerve cells) and from a gland
located atop the kidneys (i.e., the
adrenal gland). These signaling
molecules lead to the cardiovascular
symptoms of the alcohol sensitivity
Acetaldehyde also induces the
enhanced release of signaling
molecules called histamine and
bradykinin, which cause vasodila-
tion and facial flushing.
Although intermediate acetaldehyde
concentrations induce rapid heart
beat (i.e., tachycardia) and elevated
blood pressure (i.e., hypertension),
further increases in acetaldehyde levels
lead to abnormally low heart rate
and blood pressure, probably because
of acetaldehydes direct effects on
the muscles making up the inner
organs (i.e., smooth muscles).
In people with deficient ALDH
activity, these peripheral effects together
generally lead to an adverse reaction
to alcohol and prevent further drink-
ing, thereby reducing these people’s
susceptibility to develop alcohol abuse
or dependence.
The causal role of acetaldehyde in
the alcohol sensitivity reaction has been
supported further by studies of people
who carry the deficient ALDH2*2
allele or in whom ALDH activity had
been pharmacologically inhibited.
Investigators treated these people with
the compound 4-methylpyrazole—an
inhibitor of the ADH enzyme that pre-
vents acetaldehyde production in the
periphery. This treatment prevented or
reduced the alcohol sensitivity reaction,
confirming that acetaldehyde forma-
tion is associated with this reaction
(Eriksson 2001).
Vol. 29, No. 4, 2006 259
Behavioral Effects
At the behavioral level, many studies
have demonstrated that acetaldehyde is
a psychoactive compound whose pattern
of effects is similar to that of alcohol
(for a review, see Quertemont et al. 2005).
At high doses, acetaldehyde induces
sedative effects with a loss of conscious-
ness and impaired ability to coordinate
movements (i.e., ataxia) with a charac-
teristic straggling gait. It also leads to a
significant aversion to any flavor associ-
ated with acetaldehyde administration.
Moreover, recent studies have indicated
that high to intermediate doses of
acetaldehyde produce strong memory-
impairing (i.e., amnesic) effects in labo-
ratory rodents (Quertemont et al. 2004).
The specific effects appear to depend
also on the site of administration. Studies
in rats found that acetaldehyde stimulates
locomotor activity if it is administered
directly into the brain (Arizzi-LaFrance
et al. 2006) but induces predominantly
sedative effects if it is injected in the
At lower doses, acetaldehyde induces
behavioral effects that are characteristic
of addictive drugs, such as stimulation
and reinforcement. Several studies have
focused on the reinforcing properties of
acetaldehyde. In humans, there only is
anecdotic evidence of these effects. For
example, some people who were treated
with the ALDH inhibitor disulfiram
(which results in acetaldehyde accumu-
lation) reported that they experienced
the ethanol–disulfiram interaction and
resultant acetaldehyde accumulation as
pleasurable (Quertemont 2004). The
reinforcing effects of acetaldehyde are
better documented in laboratory rats.
For example, rats readily self-administer
acetaldehyde into the fluid-filled cavities
(i.e., ventricles) in the brain, and the
voluntary self-administration is much
easier to establish for acetaldehyde than
for ethanol (Brown et al. 1979). More
recently, Rodd-Henricks and colleagues
(2002) demonstrated that acetaldehyde
is a 1,000-fold more potent reinforcer
than ethanol when rats are trained to
self-administer these agents into a brain
region called the ventral tegmental area,
which is strongly involved in ethanols
reinforcing effects. Finally, Belluzzi and
colleagues (2005) found that concur-
rent administration of acetaldehyde
enhanced the acquisition of nicotine
self-administration in rats.
Taken together, these findings indicate
that with increasing doses, acetaldehyde
induces the same biphasic pattern of
effects as ethanol on both locomotor
activity (stimulation at low doses fol-
lowed by sedation at high doses) and
motivation (reinforcing effects followed
by aversion). It also is noteworthy,
however, that acetaldehyde does not
share all of ethanol’s behavioral properties.
For example, in contrast to ethanol,
acetaldehyde seems to lack anxiety-
reducing (i.e., anxiolytic) properties
(Tambour et al. 2005).
How Does Acetaldehyde Exert Its
Behavioral Effects?
The chemical processes in the nervous
system (i.e., neurochemical mechanisms)
that underlie acetaldehydes behavioral
effects remain largely unknown. Although
several hypotheses have been proposed,
to date none of them has been supported
by strong experimental evidence. For
example, researchers have suggested that
acetaldehyde alters various brain signaling
mechanisms, including the following
(Quertemont et al. 2005):
Signaling mechanisms involving brain
chemicals (i.e., neurotransmitters)
known as catecholamines, which
include dopamine, epinephrine, and
norepinephrine; these neurotrans-
mitters act on peripheral muscles
and the heart as well as on the CNS.
Signaling mechanisms involving
brain chemicals called endogenous
opioids, which modulate the actions
of other neurotransmitters, can
induce pain relief and euphoria and
contribute to alcohol reinforcement.
Signaling mechanisms involving the
activity of neuronal calcium channels,
which are pores in the membrane
surrounding nerve cells (i.e., neurons)
that can be opened and closed to
regulate the levels of calcium ions in
the neurons, thereby modifying the
excitability of those neurons.
Several studies suggest that acetalde-
hyde stimulates the activity of a key
component of the brains reward system,
the mesolimbic dopamine system (e.g.,
Foddai et al. 2004). Most drugs of
abuse, including alcohol, stimulate the
activity of the mesolimbic dopamine
system, and this action is believed to
mediate, at least in part, the rewarding
effects of these drugs. Therefore, the
reinforcing effects of acetaldehyde also
may be mediated by activation of this
brain system, although further studies
are needed to confirm this explanation.
Overall, however, evidence supporting
any of the mechanisms listed above is
rather scarce.
As a highly reactive compound,
acetaldehyde can react with many
molecules naturally found in the body,
including neurotransmitters and pro-
teins (e.g., enzymes), to form new
compounds known as adducts that
may mediate some of the effects
observed after alcohol consumption.
Many studies have focused on stable
adducts that are formed when acetalde-
hyde interacts with various proteins.
Such acetaldehyde–protein adducts are
believed to contribute to the toxic effects
associated with chronic alcohol con-
sumption (Freeman et al. 2005).
Moreover, certain adducts formed by
the reaction of acetaldehyde with cate-
cholamines and other structurally related
molecules (e.g., compounds known as
) have pharmacological
effects on the nervous system, includ-
ing reinforcing properties (see Table).
The adducts formed by the interaction
of acetaldehyde with catecholamines
are called tetrahydroisoquinoline (TIQ)
alkaloids, and the adducts formed by
the interaction of acetaldehyde with
indoleamines are called tetrahydro-β-
carboline (THBC) alkaloids.
One of the TIQs that has been
extensively studied is salsolinol, which
is formed by the reaction of acetaldehyde
with dopamine. In addition, acetalde-
hyde contributes to the accumulation
of another TIQ, tetrahydropapavero-
line, which is produced by the reaction
Both catecholamines and indoleamines belong to the
group of biogenic amines, which are organic compounds
formed during biochemical processes in plants and ani-
mals that carry a nitrogen atom as a central molecule.
Alcohol Research & Health 260
Role of Acetaldehyde in Mediating Alcohol’s Effects
of dopamine with dopaldehyde, an
intermediate in dopamine metabolism.
Acetaldehyde inhibits the normal
breakdown of dopaldehyde, leading to
its accumulation and increased formation
of tetrahydropapaveroline. Both salsoli-
nol and tetrahydropapaveroline exhibit
reinforcing properties and induce a long-
lasting increase in voluntary alcohol
consumption in rodents and monkeys
(Quertemont et al. 2004). Both com-
pounds therefore are believed to con-
tribute to the development of alcoholism;
however, their neurochemical mecha-
nisms of action remain unknown.
Similarly, it is unclear whether the con-
centrations of these TIQ and THBC
alkaloids that are achieved in the brain
after alcohol consumption are pharma-
cologically relevant. The answers to these
questions are critical for determining
whether these acetaldehyde adducts do
indeed play a role in the neuropharma-
cological effects of alcohol.
In summary, acetaldehyde is a phar-
macologically active compound that
acts either directly or through the for-
mation of adducts to induce effects in
both the periphery and the brain. Of
particular interest, some of the behavioral
effects of acetaldehyde are similar to
those of ethanol, leading to the sugges-
tion that acetaldehyde may be involved
in mediating these effects of alcohol.
For example, a growing body of evidence
indicates that acetaldehyde shows rein-
forcing properties. Therefore, it has been
speculated that acetaldehyde contributes
to the motivation to drink alcohol and,
consequently, to the development of
alcoholism (Brown et al. 1979; Rodd-
Henricks et al. 2002). However, it is far
too early to claim that acetaldehyde shares
all of ethanol’s properties, and further
studies are required to better characterize
the effects of direct acetaldehyde admin-
istration and to identify the molecular
targets that mediate these effects.
Physiological Acetaldehyde
Controversial Issue
Although acetaldehyde unquestionably
is an active compound with both phar-
macological and toxic properties,
Table Chemical Structures of the Main Condensation Products of Acetaldehyde
With Endogenous Biogenic Amines
Biogenic Amines Condensing Name of
With Acetaldehyde Condensation Product Chemical Structure
Dopamine 6,7-dihydroxy-1-methyl-
Serotonin 6-hydroxy-1-methyl-1,2,3,4-
Tryptamine 1-methyl-1,2,3,4-tetrahydro-
Tryptophan 3-carboxy-1-methyl-1,2,3,4-
researchers have not been able to con-
clusively establish that acetaldehyde can
induce these effects in the living organ-
ism (i.e., in vivo) at the physiological
concentrations obtained after alcohol
consumption. Although this question
has long been debated, controversy still
exists. After alcohol ingestion, acetalde-
hyde mainly is produced during ethanol
breakdown in the liver, which primarily
involves the enzyme ADH but also
cytochrome P4502E1 and the enzyme
catalase. Because of the high efficiency
of the liver ALDH, however, acetalde-
hyde is rapidly converted to acetate and
little acetaldehyde reaches the blood
circulation. Therefore, under normal
physiological conditions, acetaldehyde
concentrations in the blood following
alcohol administration usually are very
low or even undetectable. Higher con-
centrations of circulating acetaldehyde
have been reported only in chronic
alcohol consumers and in people carry-
ing the deficient ALDH2*2 allele.
Because acetaldehyde must act on
the brain to induce behavioral effects,
the physiological acetaldehyde concen-
trations in the brain and other organs
also have been investigated. ADH, the
main ethanol-metabolizing enzyme, is
not physiologically active in the brain,
and researchers long have assumed that
the CNS cannot metabolize alcohol
and produce acetaldehyde. However,
recent findings suggest that the brain
can produce acetaldehyde from local
ethanol metabolism involving mainly
catalase and cytochrome P4502E1
(Zimatkin et al. 2006). Moreover, studies
conducted with cultured cells (i.e., in
vitro studies) have indicated that phar-
macologically significant acetaldehyde
concentrations should be obtainable in
the brain following ethanol administra-
tion (Zimatkin and Deitrich 1997). To
date, however, it has not been unambigu-
ously shown that brain acetaldehyde
concentrations are high enough in vivo
to contribute significantly to ethanol’s
effects on the brain. This failure also may
be due to the fact that acetaldehyde
concentrations after ethanol adminis-
tration differ among brain regions
because the acetaldehyde-producing
enzymes are not evenly distributed
across various brain cells (Zimatkin and
Lindros 1996). It is therefore possible
that past attempts to measure brain
acetaldehyde concentrations underesti-
Vol. 29, No. 4, 2006 261
mated its potential neurochemical
actions. Moreover, it is possible that
although low acetaldehyde concentrations
themselves have no measurable effects,
they may suffice to synergistically
enhance the effects of ethanol.
In summary, it remains unclear
whether the acetaldehyde concentrations
achieved in different organs, especially
in the brain, after alcohol consumption
under normal physiological conditions
are biologically relevant. Finding the
answer to this question will be critical
for definitively determining whether
acetaldehyde contributes to the effects
of ethanol in vivo. Another strategy to
determining whether acetaldehyde
mediates or modulates the effects of
ethanol is to modify physiological
acetaldehyde concentrations by interfer-
ing with normal ethanol metabolism.
This approach is described in the next
Effects of Altering
Ethanol Metabolism
Although direct administration of
acetaldehyde to an organism can show
researchers what effects acetaldehyde
can have at the sometimes very high
concentrations achieved, such experi-
ments do not reflect acetaldehydes actual
effects during alcohol intoxication
(Deitrich 2004). To test the hypothesis
that acetaldehyde mediates or modulates
ethanols effects, researchers instead
have sought to modify the acetaldehyde
concentrations that result from endoge-
nous ethanol metabolism after alcohol
administration and then to assess the
consequences of this manipulation on
ethanol’s effects. To this end, several
animal studies have used pharmacolog-
ical agents that alter normal ethanol
As mentioned earlier, the bulk of
any ingested ethanol is metabolized to
acetaldehyde by liver ADH; neverthe-
less, manipulation of ADH activity usu-
ally is not a useful experimental strategy
for studying the role of acetaldehyde in
alcohol’s effects for several reasons:
In the CNS, ADH is not physiolog-
ically active and brain acetaldehyde
concentrations therefore do not
depend on ADH activity.
In the periphery, the high efficiency
of liver ALDH prevents acetaldehyde
produced in the liver from escaping
into the blood circulation; as a result,
changes in ADH activity do not sig-
nificantly alter blood acetaldehyde
concentrations if ALDH is not
inhibited at the same time.
To circumvent these problems,
changes in peripheral or CNS acetalde-
hyde concentrations are typically
achieved by modulating the activity of
ALDH and of the acetaldehyde-pro-
ducing enzyme catalase (see Figure 1).
Several ALDH inhibitors have been used
to cause massive acetaldehyde accumu-
lation after alcohol consumption, most
commonly disulfiram and cyanamide.
Because catalase is believed to account
for most of the acetaldehyde production
in the brain, various modulators of its
activity have been tested to specifically
assess the contribution of acetaldehyde
to ethanol’s effects on the brain.
Effects of ALDH Inhibition
Ethanol administration to animals or
humans following treatment with
ALDH inhibitors leads to the typical
alcohol sensitivity reaction, which then
deters further alcohol consumption.
Accordingly, most animal studies using
ALDH inhibitors have focused on
measuring subsequent alcohol con-
sumption in order to establish a model
for predicting the efficacy of ALDH
inhibitors as alcohol-deterrent medica-
tions in alcoholism treatment. These
studies generally concluded that ALDH
inhibition and acetaldehyde accumulation
strongly reduce voluntary alcohol con-
sumption and potentiate the aversion
for moderate to high ethanol doses
(Quertemont et al. 2005).
Another approach to interfering with
ALDH activity was used by Isse and
colleagues (2005), who generated mice
that no longer produced active ALDH2
(i.e., ALDH2 knockout mice) because
the function of the gene that controls
ALDH2 production was altered in
these animals. As a result of the manip-
ulation, these mice lack active ALDH
in the liver and therefore eliminate
acetaldehyde at a very low rate. Like
humans carrying the deficient
ALDH2*2 allele, these mice showed
higher blood acetaldehyde concentra-
tions after alcohol administration.
They also displayed the typical symp-
toms of the alcohol sensitivity reaction,
such as redness of the skin (i.e., the
typical flushing reaction found in
humans). Additionally, the ALDH2
knockout mice avoided voluntary alco-
hol consumption, confirming that high
blood acetaldehyde levels induce adverse
effects that prevent alcohol consump-
tion. Together with the studies using
ALDH inhibitors, these findings suggest
that acetaldehyde may contribute to the
aversive effects of high ethanol doses.
An important disadvantage of these
studies, however, is the lack of control
over acetaldehyde concentrations. Indeed,
ethanol administration to animals or
humans pretreated with ALDH inhibitors
leads to peripheral acetaldehyde con-
centrations that are substantially higher
than the normal range of physiological
concentrations. This limitation makes
interpretations in terms of acetaldehyde
contribution to the effects of ethanol
Effects of Manipulation of Catalase
A second strategy that has been widely
used to unravel the contribution of
acetaldehyde to the central effects of
ethanol is based on pharmacological
manipulations of catalase activity.
Catalase plays an important role in
acetaldehyde production in the brain,
and manipulations of catalase levels
were shown to alter acetaldehyde con-
centrations when brain tissue studied
in vitro was treated with ethanol
(Smith et al. 1997). Similarly, catalase
inhibition is expected to decrease brain
acetaldehyde concentrations, and cata-
lase activation is expected to increase
brain acetaldehyde levels after ethanol
administration in vivo. However, cata-
lase only marginally contributes to
ethanol metabolism in the liver, and
experimental manipulation of catalase
activity therefore should have no signif-
Alcohol Research & Health 262
Role of Acetaldehyde in Mediating Alcohol’s Effects
icant effects on peripheral acetaldehyde
Several studies conducted in mice
have investigated the role that acetalde-
hyde and its production by catalase
play in ethanol’s locomotor stimulant
effects. The results of these studies gen-
erally are consistent with the idea that
acetaldehyde contributes to the stimulant
effects of ethanol (Quertemont et al.
2005). For example, various treatments
resulting in inhibition of catalase activity
reduced the locomotor stimulant effects
of ethanol (e.g., Escarabajal et al. 2000).
Conversely, the potentiation of catalase
activity enhanced ethanol-induced
locomotion (e.g., Correa et al. 2005).
Consistent with these findings, researchers
observed that mice which exhibit a 60-
percent reduction in brain catalase
activity compared with normal mice
showed a reduced sensitivity to the
locomotor stimulant effects of ethanol
(Aragon et al. 1992).
Pharmacological inhibition of cata-
lase activity also led to a reduction in a
range of behavioral effects of ethanol
(e.g., ethanol-induced sedation, aversion,
and memory impairment) and increased
the dose at which ethanol was lethal to
the animals (Smith et al. 1997). Finally,
several studies have investigated the
role of acetaldehyde in the motivational
and reinforcing effects of ethanol by
evaluating the effects of catalase inhibitors
and activators on various indicators
of voluntary alcohol consumption in
rodents (Aragon and Amit 1992; He et
al. 1997). However, these studies have
yielded conflicting results that are diffi-
cult to reconcile, as have studies inves-
tigating the relationship between brain
catalase activity and the natural propen-
sity to drink alcohol in rodents. There-
fore, it is difficult to conclude from the
catalase studies conducted to date if and
how brain acetaldehyde levels impact
ethanols motivational and reinforcing
Thus, although studies on brain cata-
lase activity suggest that acetaldehyde
might be involved in or even mediate
some of ethanols behavioral effects,
particularly its stimulant effects, the
role of acetaldehyde in the motivational
and reinforcing properties of alcohol
remains inconclusive. Furthermore, all
of the catalase-modulating studies suf-
fer from several important weaknesses.
First, because brain acetaldehyde levels
are difficult to measure in vivo, these
studies did not attempt to measure the
effects of their experimental treatments
on acetaldehyde concentrations but
instead only resorted to making
assumptions on the effectiveness of
their manipulations (Deitrich 2004).
In particular, the effects of catalase acti-
vation on brain acetaldehyde concen-
Figure 1 Schematic representation of the metabolism of ethanol (ETOH) and the
effects of aldehyde dehydrogenase (ALDH) inhibitors and catalase modula-
tors. Under normal physiological conditions, ethanol is metabolized to
acetaldehyde (ACA) through several enzymatic pathways involving alcohol
dehydrogenase (ADH), cytochrome P4502E1 (CYP2E1), or catalase.
When ALDH is pharmacologically inhibited, acetaldehyde accumulates to
high concentrations both in the brain and in the periphery. Catalase metab-
olizes about 60 percent of ethanol in the brain. Therefore, inhibition of cata-
lase is believed to reduce brain acetaldehyde levels, whereas enhance-
ment of catalase activity is believed to increase brain acetaldehyde levels.
Vol. 29, No. 4, 2006 263
trations as depicted in Figure 1 remain
speculative and have not been experi-
mentally demonstrated. Second, most
of the pharmacological agents that are
commonly used to alter catalase activity
have a poor specificity—that is, they
also interfere with other physiological
reactions (Quertemont et al. 2005).
As a result, alternative explanations for
the observed effects that do not involve
acetaldehyde often are possible. There-
fore, the role of acetaldehyde in the
observed effects remains hypothetical,
and caution should be used when
interpreting the results of catalase stud-
ies as evidence of the contribution of
acetaldehyde to ethanol’s effects.
Figure 2 Schematic representation of three alternative models that account for
the role of acetaldehyde in ethanol’s (ETOH’s) effects. According to the
ethanol model, acetaldehyde (ACA) does not contribute at all to ethanol’s
overall pharmacological effects, and all effects are mediated directly by
the molecular action of ethanol. The full prodrug model states that all
pharmacological effects of ethanol are mediated by acetaldehyde. According
to this model, ethanol would be a mere prodrug without pharmacological
effect of its own. Finally, the intermediate modulation model stipulates that
acetaldehyde synergistically interacts with ethanol to modulate ethanol’s
pharmacological effects.
Acetaldehyde is an active metabolite
with a range of toxic and pharmacolog-
ical effects, and many of the effects
induced by direct acetaldehyde applica-
tion mimic those of ethanol. In particular,
administration of low doses of acetalde-
hyde to the brain produces behavioral
effects that are typical of addictive
drugs, such as psychostimulation and
reinforcement. In contrast, accumula-
tion of high acetaldehyde levels in the
periphery leads to a strong alcohol aversion
and prevents further alcohol drinking.
The contribution of such acetalde-
hyde-induced effects to the overall
effects of alcohol consumption under
normal physiological conditions still is
controversial. The main issue in these
discussions is the acetaldehyde concen-
tration that typically is achieved after
alcohol consumption in vivo, under
normal physiological conditions. Never-
theless, studies involving alteration of
catalase activity provide, despite their
obvious weaknesses, converging evi-
dence that acetaldehyde contributes to
various behavioral effects of ethanol,
especially its stimulant properties.
Three alternative models regarding
the contribution of acetaldehyde to
ethanols effects have been put forward
(see Figure 2):
The ethanol model posits that
acetaldehyde does not contribute at
all to the pharmacological effects of
ethanol. This model is mainly based
on the contention that the in vivo
concentrations of acetaldehyde in
target organs are insufficient to induce
significant pharmacological actions.
The full prodrug model contends
that acetaldehyde mediates all of the
pharmacological effects of ethanol.
The modulation model states that
the pharmacological actions of
acetaldehyde modulate some of
ethanol’s effects.
Whereas the full prodrug model
seems to be least likely, it currently is
difficult to decide between the other
two models. The modulation model
Alcohol Research & Health 264
Role of Acetaldehyde in Mediating Alcohol’s Effects
appears to best account for the results
of the studies using acetaldehyde
administration or modulation of catalase
activity. However, it is possible and
even likely that the three models coexist
for different effects of ethanol. For
example, whereas acetaldehyde might
not be involved at all in ethanol’s anxi-
olytic effects (Tambour et al. 2005), it
could mediate ethanol’s stimulant
properties. Further studies, especially
in vivo assessments of acetaldehyde
concentrations, clearly are needed to
clarify the role of acetaldehyde in the
effects of alcohol consumption. Only
when the actual acetaldehyde concen-
trations found in vivo in various organs
following alcohol consumption are
known can reliable conclusions on the
involvement of acetaldehyde in ethanols
effects be drawn.
Financial Disclosure
The authors declare that they have no
competing financial interests.
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... The polymorphism induced by rs671 produces an inactive subunit of ALDH2, which leads to accumulation of acetaldehyde after alcohol intake (Takeshita et al.,, 1993). Acetaldehyde elevation lowers blood pressure through vasodilation, which is linked to the characteristic physiological effects such as high temperature, increased heart and respiration rates, palpitations seen among ALDH2 *2*2 homozygotes, the frequency of which varies across different ancestry groups (Quertemont & Didone, 2006). ...
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Cardiovascular diseases (CVDs) are complex in their aetiology, arising due to a combination of genetics, lifestyle and environmental factors. By nature of this complexity, different CVDs vary in their molecular mechanisms, clinical presentation and progression. Although extensive efforts are being made to develop novel therapeutics for CVDs, genetic heterogeneity is often overlooked in the development process. By considering molecular mechanisms at an individual and ancestral level, a richer understanding of the influence of environmental and lifestyle factors can be gained and more refined therapeutic interventions can be developed. It is therefore expedient to understand the molecular and clinical heterogeneity in CVDs that exists across different populations. In this review, we highlight how the mechanisms underlying CVDs vary across diverse population ancestry groups due to genetic heterogeneity. We then discuss how such genetic heterogeneity is being leveraged to inform therapeutic interventions and personalised medicine, highlighting examples across the CVD spectrum. Finally, we present an overview of how polygenic risk scores and Mendelian randomisation can foster more robust insight into disease mechanisms and therapeutic intervention in diverse populations. Fulfilment of the vision of precision medicine requires more exhaustive leveraging of the genetic variability across diverse ancestry populations to improve our understanding of disease onset, progression and response to therapeutic intervention.
... Alcohol is oxidized in hepatocytes by ethanol dehydrogenase to acetaldehyde, and then metabolized to acetic acid by acetaldehyde dehydrogenase. Alcohol and its metabolites have toxic, neurodegenerative, or cancerogenic properties (Correa et al., 2003;Quertemont and Didone, 2006;Nieminen and Salaspuro, 2018). ROS elevation is closely associated with the pathology of ALD, and high levels of ROS damage cell structure and lead to cell death by oxidizing nucleic acids, proteins, and lipids (Mittler, 2002). ...
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Alcoholic liver disease (ALD) is a worldwide healthcare problem featured by inflammation, reactive oxygen species (ROS), and lipid dysregulation. Roxadustat is used for chronic kidney disease anemia treatment. As a specific inhibitor of prolyl hydroxylase, it can maintain high levels of hypoxia-inducible factor 1α (HIF-1α), through which it can further influence many important pathways, including the three featured in ALD. However, its effects on ALD remain to be elucidated. In this study, we used chronic and acute ALD mouse models to investigate the protective effects of roxadustat in vivo. Our results showed that long- and short-term alcohol exposure caused rising activities of serum transaminases, liver lipid accumulation, and morphology changes, which were reversed by roxadustat. Roxadustat-reduced fatty liver was mainly contributed by the reducing sterol-responsive element-binding protein 1c (SREBP1c) pathway, and enhancing β-oxidation through inducing peroxisome proliferator-activated receptor α (PPARα) and carnitine palmitoyltransferase 1A (CPT1A) expression. Long-term alcohol treatment induced the infiltration of monocytes/macrophages to hepatocytes, as well as inflammatory cytokine expression, which were also blocked by roxadustat. Moreover, roxadustat attenuated alcohol caused ROS generation in the liver of those two mouse models mainly by reducing cytochrome P450 2E1 (CYP2E1) and enhancing superoxidase dismutase 1 (SOD1) expression. In vitro, we found roxadustat reduced inflammation and lipid accumulation mainly via HIF-1α regulation. Taken together, our study demonstrates that activation of HIF-1α can ameliorate ALD, which is contributed by reduced hepatic lipid synthesis, inflammation, and oxidative stress. This study suggested that roxadustat could be a potential drug for ALD treatment.
... In this study, the histopathology examination of rat brain, ovaries, muscle and liver tissues exposed to herbal liquors showed intact and normal cellular architecture in the control group as well as in all the groups administered with herbal liquors. The concentrations of acetaldehyde in the brain are not high enough to produce negative effects, because the brain has a unique barrier that protects it from toxic products circulating in the bloodstream (17). ...
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The increase in consumption of herbal liquors in Nigeria is a cause for alarm. These are consumed with the mis-conception that they are without toxic effects. The aim of this study is to investigate the genotoxic and histopathological alterations in rats exposed to herbal liquors. Female rats were exposed to herbal liquors for 6 weeks. The histopathological and genotoxic evaluation were done to assess extent of damage. Pathological examination revealed incidences of aggregates chronic inflammatory cell infiltrates in the heart of Jedi treated group while the heart of the other groups had no abnormalities. The histologic sections of the kidney tissue revealed congested vessels while the lung showed reduction in air filled alveolar spaces with infiltration of alveoli and interstitium by aggregates of inflammatory cells indnadicating moderate to severe pulmonary inflammation. Histologic sections of lung tissue in rats treated with herbal liquors reveals congestion of pulmonary vessels and interstitial hemorrhages. Genotoxic evaluation of rat lymphocytes exposed to herbal liquors via comet assay shows that rats administered with the different herbal liquors developed significant (p < 0.05) as revealed in the % DNA in tail, % DNA in head, olive moment, tail length and tail moment which indicates the presence of DNA strand breaks and a marker for oxidative DNA damage. This result reveals that herbal liquors contain substances that produce reactive oxygen species that have pathological effect on certain organs as well as inducing DNA strand breaks that could compromise the integrity of the DNA which can lead to mutation.
... In a second step, acetaldehyde is quickly converted via aldehyde dehydrogenase to more harmless acetic acid (AA) which in a third step is finally oxidized to carbon dioxide and water [18]. EtOH and its metabolites all appear to have effects of their own ranging from well-known delirious to addictive actions, toxic, neurodegenerative, or cancerogenic properties [11,20,23,33,40]. In the brain, acetate is primarily produced by metabolizing sugar, acetylcholine, and ethanol [51]. ...
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Acetaldehyde and acetic acid/acetate, the active metabolites of alcohol (ethanol, EtOH), generate actions of their own ranging from behavioral, physiological, to pathological/cancerogenic effects. EtOH and acetaldehyde have been studied to some depth, whereas the effects of acetic acid have been less well explored. In this study, we investigated the effect of acetic acid on big conductance calcium-activated potassium (BK) channels present in GH3 rat pituitary tumor cells in more detail. In whole cell voltage clamp recordings, extracellular application of acetic acid increased total outward currents in a dose-dependent manner. This effect was prevented after the application of the specific BK channel blocker paxilline. Acetic acid action was pH-dependent—in whole cell current and single BK channel recordings, open probability (Po) was significantly increased by extracellular pH reduction and decreased by neutral or base pH. Acetic acid hyperpolarized the membrane potential, whereas acidic physiological solution had a depolarizing effect. Moreover, acetic acid reduced calcium (Ca²⁺) oscillations and exocytosis of growth hormone contained secretory granules from GH3 cells. These effects were partially prevented by BK inhibitors—tetraethylammonium or paxillin. In conclusion, our experiments indicate that acetic acid activates BK channels in GH3 cells which eventually contribute to acetic acid-induced membrane hyperpolarization, cessation of Ca²⁺ oscillations, and decrease of growth hormone release.
Alcohol use disorder is a condition in which the individual keeps drinking alcohol despite repeated attempts to stop or control such behavior, which in turn generates negative social, occupational, and health consequences. Animal models have been developed to reproduce the deleterious effects of excessive ethanol intake, including ethanol-induced conditioned inflammation. There are several mechanisms underlying ethanol-induced toxicity. The excitotoxicity and downstream effects resultant of an imbalance in excitatory/inhibitory currents and the products of ethanol metabolism, in conjunction with the oxidative microenvironment product of oxidative/nitrosative stress rank among the most accepted mechanisms contributing to ethanol-induced neuronal dysfunction. Yet the emergence of mitochondrial dysfunction that decreases ATP along with increases in intracellular Ca2 + concentrations, plus the disruption of the NADH/NAD⁺ ratio is also relevant. Ferrous Fe overload and the inflammatory damage due to excessive alcohol intake or withdrawal are also key players underlying ethanol-induced neurotoxicity. Furthermore, a relationship between neuroinflammation and oxidative stress is recognized as a result of dopamine metabolism, inadequate functionality of the cystine-glutamate antiporter, mitochondrial dysfunction, and peripheral inflammation, that altogether lead to cell death. On this basis, a few therapeutic approaches have been approved to treat alcohol use disorder, albeit many others are still under scrutiny. The knowledge of the cellular and molecular mechanisms underlying alcohol use disorder is needed to provide new insights that fuel the development of new pharmacologically-relevant treatments.
Excessive alcohol consumption contributes to a broad clinical spectrum of liver diseases, from simple steatosis to end-stage hepatocellular carcinoma. The liver is the primary organ that metabolizes ingested alcohol and is exquisitely sensitive to alcohol intake. Alcohol metabolism is classified into two pathways: oxidative and non-oxidative alcohol metabolism. Both oxidative and non-oxidative alcohol metabolisms and their metabolites have toxic consequences for multiple organs, including the liver, adipose tissue, intestine, and pancreas. Although many studies have focused on the effects of oxidative alcohol metabolites on liver damage, the importance of non-oxidative alcohol metabolites in cellular damage has also been discovered. Furthermore, extrahepatic alcohol effects are crucial for providing additional information necessary for the progression of alcoholic liver disease. Therefore, studying the effects of alcohol-producing metabolites and interorgan crosstalk between the liver and peripheral organs that express ethanol-metabolizing enzymes will facilitate a comprehensive understanding of the pathogenesis of alcoholic liver disease. This review focuses on alcohol-metabolite-associated hepatotoxicity due to oxidative and non-oxidative alcohol metabolites and the role of interorgan crosstalk in alcoholic liver disease pathogenesis.
Alcoholic liver disease has become one of the main causes of liver injury, and its prevention and cure are important medical tasks. Silibinin, a natural flavonoid glycoside, is a conventional hepatic protectant. This study elucidates the modulation of ferroptosis in silibinin's protective effects on ethanol- or acetaldehyde-induced liver cell damage by using human carcinomatous liver HepG2 cells and immortalized liver HL7702 cells. Our results show that ferroptosis is induced in the cells treated with ethanol or acetaldehyde, as evidenced by the increased ROS stress and iron level. Silibinin resolves the oxidative stress and reduces iron level. Ferroptosis induced by ethanol- or acetaldehyde involving nuclear receptor co-activator 4 (NCOA4)-dependent autophagic degradation of ferritin, a protein for storing iron is rescued by silibinin. PINK1 and Parkin-mediated mitophagy is arrested in ethanol- or acetaldehyde-treated cells but reversed by silibinin. Ferritin degradation and ROS level are further increased when PINK1 or Parkin is silenced in the cells treated with ethanol or acetaldehyde. Collectively, our study reveals that silibinin inhibits ethanol- or acetaldehyde-induced ferroptosis in two liver cell lines, HepG2 and HL7702 cells, providing new therapeutic strategies for alcoholic liver injury.
Background : Moringa oleifera (M. oleifera) is cultivated throughout the world and it is known by numerous regional names and is consumed as medication for various diseases such as hypertension, diabetes, HIV and is potential source of nutrients and natural antioxidants making it among the most useful trees. Methods : We evaluated the therapeutic potential of M. oleifera on ethanol-induced fatty liver. The mice were treated with 30% ethanol (EtOH) alone or in combination with different concentration of M. oleifera extracts (100, 200 and 400 mg/kg). We performed biochemical estimation for the serum of important liver damage markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT) and triglyceride (TG). We performed histopathological analysis from the liver tissues of different mice groups. We also performed ELISA assay, western blotting analysis and SPECT imaging to obtain our results. Results : The results for serum (AST, p<0.0001), (ALT, p<0.0006) and triglyceride (TG, p<0.0003) were found to be significantly reduced in all doses of M. oleifera extract treatment groups in comparison with the ethanol group. H&E staining analysis and scoring revealed a significant reduction in lipid droplet accumulation and a significant reduction of liver steatosis (p<0.0001), lobular inflammation (p<0.0013), ballooning (p<0.0004) and immunohistochemistry for TNF-α. M. oleifera also ameliorated ethanol-induced oxidative stress evaluated through MDA (p<0.0001), H2DCFDA, JC-1 staining and a significant down-regulation of CYP2E1 enzyme (p<0.0001) in the 200 and 400 mg/kg groups in comparison with EtOH groups. M. oleifera extract also boosted the antioxidant response evaluated through total GSH assay (p<0.0001) and nuclear translocation of Nrf2. Furthermore, we performed SPECT imaging and evaluated the liver uptake value (LUV) to assess the extent of liver damage. LUV was observed to be lower in the ethanol group, whereas LUV was higher in control and M. olifera treated groups. Conclusion : In summary, from this experiment we conclude that M. oleifera extract has the potential to ameliorate ethanol-induced liver damage.
Alcoholic beverages are socially accepted around the world and consumed mostly to socialize, celebrate, and relax. The pleasant effects of alcohol are attributed to (i) an increase in GABAergic (inhibitory signals), OPergic, and 5HTergic (euphoric effects) neuronal activities and (ii) a decrease in DAergic (“want” signal or craving), Gluergic (excitatory signals), and NEergic (stress signals) neuronal and the HPA axis (stress hormones) activities. If alcohol drinking continues, the receptors are sensitized, resulting in the development of tolerance when alcohol drinking must be increased to achieve the desired effects. In genetically/environmentally predisposed subjects, chronic alcohol drinking results in the development of addiction, characterized by a condition when alcohol caseation results in a rapid onset of withdrawal symptoms including, but not limited to, alcohol craving and moderate to severe discomfort. Because pharmacotherapy alone or in combination with behavioral approaches are only modestly effective in treating alcoholism symptoms, there is an urgent need for the development of effective and safe therapies. At present, a lack of clear understanding of the mechanisms underlying addiction hinders possible development of new treatment strategies. Therefore, this chapter aims to discuss the mechanisms underlying (i) the euphoric, relaxing, and adverse effects of alcohol drinking and (ii) addiction and the withdrawal symptoms.
Acetaldehyde is suspected of being involved in the central mechanism of central nervous system depression and addiction to ethanol, but in contrast to ethanol, it can not penetrate easily from blood into the brain because of metabolic barriers. Therefore, the possibility of ethanol metabolism and acetaldehyde formation inside the brain has been one of the crucial questions in biomedical research of alcoholism. This article reviews the recent progress in this area and summarizes the evidence on the first stage of ethanol oxidation in the brain and the specific enzyme systems involved. The brain alcohol dehydrogenase and microsomal ethanol oxidizing systems, including cytochrome P450 II E1 and catalase are considered. Their physicochemical properties, the isoform composition, substrate specificity, the regional and subcellular distribution in CNS structures, their contribution to brain ethanol metabolism, induction under ethanol administration and the role in the neurochemical mechanisms of psychopharmacological and neurotoxic effects of ethanol are discussed. In addition, the nonoxidative pathway of ethanol metabolism with the formation of fatty acid ethyl esters and phosphatidylethanol in the brain is described.
This review represents an attempt to assess the available data on the role of catalase in the mediation of the behavioral actions of ethanol and the regulation of voluntary ethanol consumption. It is argued that acetaldehyde may be formed in brain through the peroxidatic activity of catalase. Furthermore, acetaldehyde formed centrally through the activity of this enzyme, may be responsible, at least in part, for some of the motivational, behavioral and neurotoxic effects of ethanol.
The possibility that acetaldehyde is responsible for some of the central nervous system effects of ethanol has been a popular hypothesis for many years. This review examines the evidence of a role for acetaldehyde in the actions of ethanol in the brain. The literature review was confined primarily to effects of acetaldehyde in the central nervous system in the realization that a great deal of information is also available on the actions of acetaldehyde in the periphery. The emphasis is on more recent findings, with only occasional references to older work. There are studies implicating acetaldehyde in nearly every central nervous system effect of ethanol that has been studied. With a few exceptions, the evidence for most of these effects is conflicting. For many years the dogma was that the brain did not metabolize ethanol. Any effects of acetaldehyde were therefore held to be due to acetaldehyde diffusing in from the blood. Recently, however, it has been established that ethanol is metabolized to acetaldehyde (primarily by catalase) and then to acetate (by aldehyde dehydrogenase) in the brain. These findings remove the problem that acetaldehyde does not penetrate the brain very well but leave questions as to what it does there. Almost invariably, the concentrations of acetaldehyde in the brain, under normal conditions of ethanol intoxication, are in the low micromolar range. Inhibition of aldehyde dehydrogenase will lead to increases of both peripheral and central acetaldehyde and usually to increases in the effects of ethanol or to behaviorally aversive effects. Stimulation of catalase should lead to increased levels of acetaldehyde in the brain, but this has not been directly demonstrated. Inhibition of catalase should lead to decreased acetaldehyde concentrations in vivo, but, again, this has not been directly demonstrated. Various effects of the direct application of acetaldehyde to the brain have been noted, but in most studies the concentration of acetaldehyde resulting from such manipulations has not been determined, and it is probably higher than that occurring during ethanol intoxication. These experiments tell us what acetaldehyde is capable of doing, not what it does after administration of ethanol. Still, this is a first step. Acetaldehyde is a product of ethanol metabolism in the brain. It clearly has central nervous system effects in its own right. The jury is still out as to whether it has effects under normal conditions of ethanol intoxication. This will remain the case until direct measurement of acetaldehyde concentrations in the brain is routinely accomplished under conditions in which behavioral effects of ethanol are also measured.
For 11 consecutive days, naive rats were maintained in operant chambers where they were given the opportunity to self-administer acetaldehyde (1,2, or 5% v/v), ethanol (2 or 10% v/v), or pH control solutions directly into the cerebral ventricles. Only the animals that had access to the 2 and 5% acetaldehyde solutions showed rates of lever pressing significantly higher than controls. It is suggested that acetaldehyde rather than ethanol itself may mediate the positive reinforcing effects of ethanol in the brain.
Prolonged, excessive use of ethyl alcohol (ethanol) is associated with alterations in structure and function of a number of organs. These disorders have given rise to controversy over the relative importance of a direct toxic action of alcohol and the effects of the nutritional deficiencies that are often associated with chronic alcoholism. Recent evidence suggests that disorders of the liver, heart, and bone marrow, although aggravated and accelerated by nutritional deficiencies, are probably caused by cytotoxic actions of alcohol. The biochemical basis of this cytotoxicity is uncertain. Korsten and his colleagues suggest that acetaldehyde, a metabolite of ethanol and a known potent cytotoxin, may contribute to the pathogenesis of these alcoholic disorders.
The effects of the catalase inhibitor, 3-amino-1,2,4-triazole (AT), on maintenance of voluntary consumption of ethanol was tested in male Long-Evans rats. AT produced a dose-dependent reduction in ethanol intake but did not affect total fluid consumption. AT also produced a dose-dependent inhibition of brain catalase lasting throughout the drinking period. These results suggest a role for brain catalase in determining the level of ethanol intake in rats.
The role of brain catalase in modulating the psychopharmacological effects of ethanol was investigated by examining ethanol induced motor activity in normal, C3H-N, and a corresponding group of acatalasemic C3H-A, mice. Following administration of one of three doses of ethanol (0.8, 1.6, and 3.2 g/kg) or saline, mice were placed in open field chambers and locomotor and rearing activity was measured during a 10-min testing period. A significant increase in locomotor activity was recorded in both groups of mice at lower doses of ethanol, while the higher dose produced a marked depression. Normal mice demonstrated more locomotor activity than acatalasemic mice at all ethanol doses. No differences between both groups of mice were observed in rearing activity. Also, no differences in blood ethanol levels were observed between the two substrains. Brain and liver residual catalase activity in the acatalasemic mice was found to be 40% and 50%, respectively, of normal mice. Furthermore, evidence for possible involvement of the peroxidatic activity in ethanol-induced motor activity is presented. These results suggest a role for centrally formed acetaldehyde as a factor mediating some of ethanol's psychopharmacological effects.
Ethanol is metabolized at a slow but measurable rate in rodent brain. Recent studies indicate that this process is mediated mainly by catalase. The spatial distribution of this enzyme in different brain structures is poorly known. To explore possible local imbalances between the production and elimination of ethanol-derived acetaldehyde, we investigated the regional and cellular distribution of catalase, histo- and immunohistochemically, using serial cryostat sections from male Wistar rats. Compared to the strong peroxisomal staining seen in liver, brain catalase staining was weak and was not immunologically detected with an anti-sheep bovine catalase antibody. Activity was observed only in microperoxisomes, mainly in perikaryons of aminergic neurons, in the known groups of adrenergic, nonadrenergic and serotonergic neurons of the brain stem. Little peroxisomal staining was seen in other types of brain structures. This result contrasted to that of aldehyde dehydrogenase, which we previously observed to be widely distributed in brain structures, but with low activity in perikaryons of aminergic (especially catecholaminergic) neurons, as compared to cholinergic neurons. Our data indicate that catalase-mediated oxidation of ethanol to acetaldehyde takes place mainly in aminergic neurons, which seem to have a limited capacity for the subsequent removal via aldehyde dehydrogenase. This suggests that locally produced acetaldehyde could mediate CNS effects of ethanol in these structures.
Genetic factors are known to influence the preference for drinking alcohol-in humans as well as certain inbred strains of laboratory animals. Here we examined the possible role of the aromatic hydrocarbon receptor (AHR) in alcohol-preferring C57BL/6J (B6, high-affinity AHR) and alcohol-avoiding DBA/2J (D2, low-affinity AHR) inbred mouse strains, and in the two congenic lines B6.D2-Ahrd (> 99% B6 genome with the D2 low-affinity AHR) and D2.B6-Ahrb-1 (> 99% D2 genome with the B6 high-affinity AHR). This laboratory had previously shown an association between resistance to intraperitoneal ethanol-induced toxicity and the high-affinity AHR. Offering the choice between drinking water and 10% ethanol, we found that alcohol preference is three- to four-fold greater in B6 than D2 mice, as well as three- to four-fold greater in B6.D2-Ahrd than D2.B6-Ahrb-1 mice-indicating that alcohol preference is AHR-independent. The prototype AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) did not affect the rates of chronic alcohol consumption in B6 or D2 mice, suggesting that dioxin-inducible metabolism does not play a major role in alcohol drinking preference. In B6 mice, we found that oral treatment with the aldehyde dehydrogenase (ALDH) inhibitor disulfiram decreased alcohol preference by 50%, whereas oral treatment of the catalase inhibitor 3-amino-1,2,4-triazole increased alcohol drinking preference by 15-20%. Although liver and brain ALDH activities were both significantly higher in D2 than B6, these activities were not related to alcohol consumption. Hepatic and brain catalase activities, on the other hand, were two- to three-fold higher in D2 and D2.B6-Ahrb-1 mice, compared with that in B6 and B6.D2-Ahrd. Furthermore, brain acetaldehyde levels were inversely related to the quantity of alcohol voluntarily consumed. We conclude that the alcohol drinking preference between the B6 and D2 inbred mouse strains is independent of the Ah receptor-but is genetically determined, in part, by the level of brain catalase activity which, in turn, regulates brain acetaldehyde concentrations.
The present experiments analyze the effects of the brain catalase inhibitor 3-amino-1,2,4-triazole (AT) on the locomotor activity induced by ethanol. In the first experiment, mice received injections of either AT (0.5 g/kg) or saline (S) 5 hours prior to an ethanol injection (0, 0.8, 1.6, 2.4, 3.2 or 4 g/kg). In the second experiment, five different groups of mice received injections of AT (0, 0.010, 0.030, 0.060, 0.125, 0.250 or 0.500 g/kg) 5 hours prior to being injected with 1.6 g/kg of ethanol. In the third experiment, six groups of mice were treated with AT (0.5 g/kg), simultaneously, 2.5, 5, 10 or 20 hours before the administration of 1.6 g/kg of ethanol. Immediately after ethanol injection, mice were placed individually in the open-field apparatus for 20 minutes. In another set of experiments, the effects of AT on brain catalase activity were studied. Animals were injected with AT at 0, 0.010, 0.030, 0.060, 0.125, 0.250 or 0.500 g/kg, and 5, 10 or 20 hours following AT treatment mice were perfused and the brain was removed. Pretreating mice with AT reduces ethanol-induced locomotor activity (1.6, 2.4 and 3.2 g/kg) without altering spontaneous locomotion. Pretreatment with AT (from 0.125 g/kg to 0.5 g/kg) produced a clear dose-dependent decrease of ethanol locomotion and brain catalase activity. The effect of AT was observed 5 and 10 hours after the injection of this drug, and it disappeared 20 hours following AT treatment. Current data showed a parallel property of AT in producing a remarkable dose- and time-dependent decrease in catalase activity and ethanol locomotion.