Role of acetaldehyde in mediating the pharmacological and behavioral effects of alcohol

Abstract

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.

Full text

Role of Acetaldehyde in
Mediating the Pharmacological
and Behavioral Effects of Alcohol
Etienne Quertemont, Ph.D., and Vincent Didone
E
TIENNE QUERTEMONT, PH.D., is
an associate professor and V
INCENT
D
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
M
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 ethanol’s 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 acetaldehyde’s 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 acetaldehyde’s contribution to
ethanol’s effects.
Acetaldehyde’s
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 acetaldehyde’s 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
reaction.
• 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 acetaldehyde’s 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
periphery.
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 ethanol’s
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 acetaldehyde’s 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 brain’s 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
indoleamines
1
) 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
1
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
Concentrations—A
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-
1,2,3,4-tetrahydroisoquinoline
(Salsolinol)
Serotonin 6-hydroxy-1-methyl-1,2,3,4-
tetrahydro-β-carboline
(6-OH-MTBC)
Tryptamine 1-methyl-1,2,3,4-tetrahydro-
β-carboline
(MTBC)
Tryptophan 3-carboxy-1-methyl-1,2,3,4-
tetrahydro-β-carboline
(3-MTBC)
NH
CH
3
OH
OH
N
H
NH
CH
3
OH
N
H
NH
CH
3
N
H
NH
CH
3
-COOH
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
section.
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 acetaldehyde’s actual
effects during alcohol intoxication
(Deitrich 2004). To test the hypothesis
that acetaldehyde mediates or modulates
ethanol’s 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
metabolism.
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
difficult.
Effects of Manipulation of Catalase
Activity
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
levels.
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
ethanol’s motivational and reinforcing
effects.
Thus, although studies on brain cata-
lase activity suggest that acetaldehyde
might be involved in or even mediate
some of ethanol’s 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.
Conclusions
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
ethanol’s 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 ethanol’s
effects be drawn.
■
Financial Disclosure
The authors declare that they have no
competing financial interests.
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