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Role of Acetaldehyde in Mediating the Pharmacological and Behavioral Effects of

Etienne Quertemont, Ph.D., and Vincent Didone

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 , 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. KEY WORDS: metabolism; ethanol-to-acetaldehyde metabolism; acetaldehyde; (ALDHs); alcohol (ADH); alcohol metabolite; catalase; brain; central nervous system; protective factors; ; pharmacology and toxicology

any chemical compounds, Acetaldehyde is the first product mediator of ethanol’s pharmacological including many medications generated during the metabolism of and behavioral effects. According to the Mand drugs, are eliminated alcohol (chemically known as ethanol). most radical version of this theory, ethanol from the body through their metabolism, It is generated primarily in the by would be a mere prodrug whose effects which leads to the production of break­ the enzyme are fully mediated by its first metabolite, down products (i.e., metabolites) that (ADH). The acetaldehyde then is con- acetaldehyde. It even has been suggested are readily excreted. In general, these verted rapidly to acetate by the enzyme that instead of “,” the term aldehyde dehydrogenase (ALDH). (For “acetaldehydism” would be more metabolites are biologically inactive; more information on the pathways of appropriate to describe accordingly, metabolism of the original ethanol metabolism, see the article by and (Raskin 1975). Conversely, compound terminates its biological Zakhari in this issue.) other scientists deny any significant activity. Some metabolites, however, Acetaldehyde is an active metabolite role for acetaldehyde in ethanol’s phar­ may exert potent effects on the body that induces a range of toxic, pharma- macological effects. These investigators (i.e., have pharmacological properties) cological, and behavioral effects. However, generally contend that following nor- or have toxic properties; these are referred the role of acetaldehyde in mediating to as active metabolites. Finally, some alcohol’s effects, especially its effects on ETIENNE QUERTEMONT, PH.D., is medications or drugs actually are pharma- the brain (i.e., its central effects), has an associate professor and VINCENT cologically inactive compounds; these been controversial for more than two DIDONE is a research assistant in the so-called prodrugs must be converted decades (Deitrich 2004; Quertemont Centre de Neurosciences Cognitives et to biologically active metabolites in order and Tambour 2004). Some investiga- Comportementales, Université de Liège, to exert their pharmacological effects. tors argue that acetaldehyde is a key Liège, Belgium.

258 Alcohol Research & Health Role of Acetaldehyde in Mediating Alcohol’s Effects mal alcohol consumption, acetaldehyde the ALDH enzyme known as ALDH2*2. including the following (for a review, concentrations in the blood and brain This allele results in the production of see Eriksson 2001): are far too low to induce any significant an inactive ALDH enzyme. If people pharmacological or behavioral effects carrying the deficient ALDH2*2 gene • Acetaldehyde stimulates the release (see discussion in Deitrich 2004). consume alcohol, their bodies cannot of signaling called An intermediate, and probably more metabolize acetaldehyde, which there­ epinephrine and sustainable, position states that the fore accumulates to high concentra­ from certain nerve cells (i.e., sympa­ pharmacological properties of acetalde­ tions. Additional information comes thetic nerve cells) and from a gland hyde modulate (rather than mediate) from observations of alcoholics who located atop the kidneys (i.e., the some, but not all, of ethanol’s effects. This were treated with ALDH inhibitors adrenal gland). These signaling modulatory action of acetaldehyde (e.g., the medication ) to molecules lead to the cardiovascular probably greatly depends on specific deter further alcohol consumption but symptoms of the alcohol sensitivity conditions. For example, acetaldehyde who nevertheless drank alcohol and may contribute only to those alcohol therefore also accumulated acetaldehyde. reaction. effects that occur at high alcohol con­ The major problem associated with centrations, which also result in high these observations in humans is the • Acetaldehyde also induces the acetaldehyde levels. Moreover, the con­ lack of control over acetaldehyde con­ enhanced release of signaling tribution of acetaldehyde to alcohol’s centrations. Because the bulk of any molecules called and effects likely varies across individuals, ingested ethanol is metabolized to bradykinin, which cause vasodila­ in part due to individual differences acetaldehyde in the liver, genetically or tion and facial flushing. in alcohol-metabolizing pharmacologically induced deficiencies (Quertemont 2004). in ALDH activity lead to high peripheral • Although intermediate acetaldehyde This article provides an overview concentrations of acetaldehyde, allow­ concentrations induce rapid heart of acetaldehyde’s pharmacological and ing no precise determination of the beat (i.e., tachycardia) and elevated behavioral effects in the body and reviews dose-response pattern of acetaldehyde blood pressure (i.e., hypertension), some of the mechanisms that may effects. Furthermore, the peripheral further increases in acetaldehyde levels underlie these effects. It then explores effects of these high acetaldehyde levels the issue of acetaldehyde concentra­ lead to abnormally low heart rate may mask the compound’s more spe­ tions in the brain and periphery before and blood pressure, probably because cific actions in the nervous system (i.e., summarizing the results of studies in of acetaldehyde’s direct effects on which ethanol metabolism was manip­ neuropharmacological properties). the muscles making up the inner ulated in order to more specifically Therefore, such studies in humans are organs (i.e., smooth muscles). delineate acetaldehyde’s contribution to not well suited for studying the effects ethanol’s effects. of acetaldehyde in the central nervous In people with deficient ALDH system (CNS), particularly the brain. activity, these peripheral effects together generally lead to an adverse reaction Acetaldehyde’s Physiological Effects in the Periphery Pharmacological and to alcohol and prevent further drink­ Behavioral Effects Acetaldehyde accumulation in the ing, thereby reducing these people’s periphery produces a pattern of effects susceptibility to develop alcohol abuse The hypothesis that acetaldehyde commonly defined by the term “alco­ or dependence. mediates or contributes to the effects of hol sensitivity” because these symptoms The causal role of acetaldehyde in ethanol implies that acetaldehyde itself most often are observed when people the alcohol sensitivity reaction has been can exert effects similar to those observed with deficient ALDH activity drink supported further by studies of people after alcohol administration. Therefore, alcohol (Eriksson 2001). These typical who carry the deficient ALDH2*2 the first step to support such a theory is physiological effects include peripheral allele or in whom ALDH activity had widening of the blood vessels (i.e., to demonstrate acetaldehyde’s direct been pharmacologically inhibited. vasodilation), resulting in increased pharmacological and behavioral effects. Investigators treated these people with Because acetaldehyde is highly toxic, skin temperature and facial flushing; the compound 4-methylpyrazole—an however, most studies using direct increased heart and respiration rates; administration of acetaldehyde have pounding or racing of the heart (i.e., inhibitor of the ADH enzyme that pre­ been carried out in laboratory animals, palpitations); lowered blood pressure; vents acetaldehyde production in the particularly rodents. In humans, most narrowing of the airways (i.e., bron­ periphery. This treatment prevented or of the knowledge about acetaldehyde’s choconstriction); nausea; and . reduced the alcohol sensitivity reaction, properties has been gathered indirectly The mechanisms by which acetaldehyde confirming that acetaldehyde forma­ by studying people carrying a deficient induces these symptoms are complex tion is associated with this reaction variant (i.e., allele) of the gene encoding and involve multiple molecular targets, (Eriksson 2001).

Vol. 29, No. 4, 2006 259 Behavioral Effects colleagues (2005) found that concur­ Several studies suggest that acetalde­ At the behavioral level, many studies rent administration of acetaldehyde hyde stimulates the activity of a key have demonstrated that acetaldehyde is enhanced the acquisition of component of the brain’s reward system, a psychoactive compound whose pattern self-administration in rats. the mesolimbic system (e.g., of effects is similar to that of alcohol Taken together, these findings indicate Foddai et al. 2004). Most drugs of (for a review, see Quertemont et al. 2005). that with increasing doses, acetaldehyde abuse, including alcohol, stimulate the activity of the mesolimbic dopamine At high doses, acetaldehyde induces induces the same biphasic pattern of system, and this action is believed to sedative effects with a loss of conscious­ effects as ethanol on both locomotor mediate, at least in part, the rewarding ness and impaired ability to coordinate activity (stimulation at low doses fol­ effects of these drugs. Therefore, the movements (i.e., ataxia) with a charac­ lowed by sedation at high doses) and reinforcing effects of acetaldehyde also teristic straggling gait. It also leads to a motivation (reinforcing effects followed may be mediated by activation of this significant aversion to any flavor associ­ by aversion). It also is noteworthy, brain system, although further studies ated with acetaldehyde administration. however, that acetaldehyde does not share all of ethanol’s behavioral properties. are needed to confirm this explanation. Moreover, recent studies have indicated Overall, however, evidence supporting that high to intermediate doses of For example, in contrast to ethanol, acetaldehyde seems to lack anxiety- any of the mechanisms listed above is acetaldehyde produce strong memory- rather scarce. impairing (i.e., amnesic) effects in labo­ reducing (i.e., anxiolytic) properties (Tambour et al. 2005). As a highly reactive compound, ratory rodents (Quertemont et al. 2004). acetaldehyde can react with many The specific effects appear to depend molecules naturally found in the body, also on the site of administration. Studies How Does Acetaldehyde Exert Its Behavioral Effects? including and pro­ in rats found that acetaldehyde stimulates teins (e.g., enzymes), to form new locomotor activity if it is administered The chemical processes in the nervous compounds known as adducts that directly into the brain (Arizzi-LaFrance system (i.e., neurochemical mechanisms) may mediate some of the effects et al. 2006) but induces predominantly that underlie acetaldehyde’s behavioral observed after alcohol consumption. sedative effects if it is injected in the effects remain largely unknown. Although Many studies have focused on stable periphery. several hypotheses have been proposed, adducts that are formed when acetalde­ At lower doses, acetaldehyde induces to date none of them has been supported hyde interacts with various proteins. behavioral effects that are characteristic by strong experimental evidence. For Such acetaldehyde–protein adducts are of addictive drugs, such as stimulation example, researchers have suggested that believed to contribute to the toxic effects and reinforcement. Several studies have acetaldehyde alters various brain signaling associated with chronic alcohol con­ focused on the reinforcing properties of mechanisms, including the following sumption (Freeman et al. 2005). acetaldehyde. In humans, there only is (Quertemont et al. 2005): Moreover, certain adducts formed by anecdotic evidence of these effects. For the reaction of acetaldehyde with cate­ example, some people who were treated • Signaling mechanisms involving brain cholamines and other structurally related with the ALDH inhibitor disulfiram chemicals (i.e., neurotransmitters) molecules (e.g., compounds known as (which results in acetaldehyde accumu­ known as , which indoleamines1) have pharmacological lation) reported that they experienced include dopamine, epinephrine, and effects on the nervous system, includ­ the ethanol–disulfiram interaction and norepinephrine; these neurotrans­ ing reinforcing properties (see Table). resultant acetaldehyde accumulation as mitters act on peripheral muscles The adducts formed by the interaction pleasurable (Quertemont 2004). The and the heart as well as on the CNS. of acetaldehyde with catecholamines reinforcing effects of acetaldehyde are are called tetrahydroisoquinoline (TIQ) better documented in laboratory rats. • Signaling mechanisms involving , and the adducts formed by For example, rats readily self-administer brain chemicals called endogenous the interaction of acetaldehyde with acetaldehyde into the fluid-filled cavities opioids, which modulate the actions indoleamines are called tetrahydro-β­ (i.e., ventricles) in the brain, and the of other neurotransmitters, can carboline (THBC) alkaloids. voluntary self-administration is much induce pain relief and euphoria and One of the TIQs that has been easier to establish for acetaldehyde than contribute to alcohol reinforcement. extensively studied is salsolinol, which for ethanol (Brown et al. 1979). More is formed by the reaction of acetaldehyde recently, Rodd-Henricks and colleagues • Signaling mechanisms involving the with dopamine. In addition, acetalde­ (2002) demonstrated that acetaldehyde activity of neuronal calcium channels, hyde contributes to the accumulation is a 1,000-fold more potent reinforcer which are pores in the membrane of another TIQ, tetrahydropapavero­ than ethanol when rats are trained to surrounding nerve cells (i.e., neurons) line, which is produced by the reaction self-administer these agents into a brain that can be opened and closed to region called the ventral tegmental area, regulate the levels of calcium ions in 1Both catecholamines and indoleamines belong to the group of biogenic , which are organic compounds which is strongly involved in ethanol’s the neurons, thereby modifying the formed during biochemical processes in plants and ani­ reinforcing effects. Finally, Belluzzi and excitability of those neurons. mals that carry a atom as a central .

260 Alcohol Research & Health Role of Acetaldehyde in Mediating Alcohol’s Effects of dopamine with dopaldehyde, an intermediate in dopamine metabolism. Table Chemical Structures of the Main Condensation Products of Acetaldehyde Acetaldehyde inhibits the normal With Endogenous Biogenic Amines breakdown of dopaldehyde, leading to its accumulation and increased formation Biogenic Amines Condensing Name of of tetrahydropapaveroline. Both salsoli­ With Acetaldehyde Condensation Product Chemical Structure nol and tetrahydropapaveroline exhibit OH reinforcing properties and induce a long- Dopamine 6,7-dihydroxy-1-methyl­ lasting increase in voluntary alcohol 1,2,3,4-tetrahydroisoquinoline NH OH (Salsolinol) consumption in rodents and monkeys CH (Quertemont et al. 2004). Both com­ 3 pounds therefore are believed to con­ tribute to the development of alcoholism; 6-hydroxy-1-methyl-1,2,3,4­ OH NH however, their neurochemical mecha­ tetrahydro-β-carboline N CH (6-OH-MTBC) 3 nisms of action remain unknown. H Similarly, it is unclear whether the con­ centrations of these TIQ and THBC NH alkaloids that are achieved in the brain 1-methyl-1,2,3,4-tetrahydro­ after alcohol consumption are pharma­ β-carboline CH N 3 cologically relevant. The answers to these (MTBC) H questions are critical for determining whether these acetaldehyde adducts do -COOH indeed play a role in the neuropharma­ Tryptophan 3-carboxy-1-methyl-1,2,3,4­ NH cological effects of alcohol. tetrahydro-β-carboline CH In summary, acetaldehyde is a phar­ (3-MTBC) N 3 macologically active compound that H acts either directly or through the for­ mation of adducts to induce effects in researchers have not been able to con­ main ethanol-metabolizing enzyme, is both the periphery and the brain. Of clusively establish that acetaldehyde can not physiologically active in the brain, particular interest, some of the behavioral induce these effects in the living organ­ and researchers long have assumed that effects of acetaldehyde are similar to ism (i.e., in vivo) at the physiological the CNS cannot metabolize alcohol those of ethanol, leading to the sugges­ concentrations obtained after alcohol and produce acetaldehyde. However, tion that acetaldehyde may be involved consumption. Although this question recent findings suggest that the brain in mediating these effects of alcohol. has long been debated, controversy still can produce acetaldehyde from local For example, a growing body of evidence exists. After alcohol ingestion, acetalde­ ethanol metabolism involving mainly indicates that acetaldehyde shows rein­ hyde mainly is produced during ethanol catalase and cytochrome P4502E1 forcing properties. Therefore, it has been breakdown in the liver, which primarily (Zimatkin et al. 2006). Moreover, studies speculated that acetaldehyde contributes involves the enzyme ADH but also conducted with cultured cells (i.e., in to the motivation to drink alcohol and, cytochrome P4502E1 and the enzyme vitro studies) have indicated that phar­ consequently, to the development of catalase. Because of the high efficiency macologically significant acetaldehyde alcoholism (Brown et al. 1979; Rodd- of the liver ALDH, however, acetalde­ concentrations should be obtainable in Henricks et al. 2002). However, it is far hyde is rapidly converted to acetate and the brain following ethanol administra­ too early to claim that acetaldehyde shares little acetaldehyde reaches the blood tion (Zimatkin and Deitrich 1997). To all of ethanol’s properties, and further circulation. Therefore, under normal date, however, it has not been unambigu­ studies are required to better characterize physiological conditions, acetaldehyde ously shown that brain acetaldehyde the effects of direct acetaldehyde admin­ concentrations in the blood following concentrations are high enough in vivo istration and to identify the molecular alcohol administration usually are very to contribute significantly to ethanol’s targets that mediate these effects. low or even undetectable. Higher con­ effects on the brain. This failure also may centrations of circulating acetaldehyde be due to the fact that acetaldehyde have been reported only in chronic concentrations after ethanol adminis­ Physiological Acetaldehyde alcohol consumers and in people carry­ tration differ among brain regions Concentrations—A ing the deficient ALDH2*2 allele. because the acetaldehyde-producing Controversial Issue Because acetaldehyde must act on enzymes are not evenly distributed the brain to induce behavioral effects, across various brain cells (Zimatkin and Although acetaldehyde unquestionably the physiological acetaldehyde concen­ Lindros 1996). It is therefore possible is an active compound with both phar­ trations in the brain and other organs that past attempts to measure brain macological and toxic properties, also have been investigated. ADH, the acetaldehyde concentrations underesti-

Vol. 29, No. 4, 2006 261 mated its potential neurochemical concentrations therefore do not ulation, these mice lack active ALDH actions. Moreover, it is possible that depend on ADH activity. in the liver and therefore eliminate although low acetaldehyde concentrations acetaldehyde at a very low rate. Like themselves have no measurable effects, • In the periphery, the high efficiency humans carrying the deficient they may suffice to synergistically of liver ALDH prevents acetaldehyde ALDH2*2 allele, these mice showed enhance the effects of ethanol. produced in the liver from escaping higher blood acetaldehyde concentra­ In summary, it remains unclear into the blood circulation; as a result, tions after alcohol administration. whether the acetaldehyde concentrations changes in ADH activity do not sig­ They also displayed the typical symp­ achieved in different organs, especially nificantly alter blood acetaldehyde toms of the alcohol sensitivity reaction, in the brain, after alcohol consumption concentrations if ALDH is not such as redness of the skin (i.e., the under normal physiological conditions inhibited at the same time. typical flushing reaction found in are biologically relevant. Finding the humans). Additionally, the ALDH2 answer to this question will be critical To circumvent these problems, knockout mice avoided voluntary alco­ for definitively determining whether changes in peripheral or CNS acetalde­ hol consumption, confirming that high acetaldehyde contributes to the effects hyde concentrations are typically blood acetaldehyde levels induce adverse of ethanol in vivo. Another strategy to achieved by modulating the activity of effects that prevent alcohol consump­ determining whether acetaldehyde ALDH and of the acetaldehyde-pro­ tion. Together with the studies using mediates or modulates the effects of ducing enzyme catalase (see Figure 1). ALDH inhibitors, these findings suggest ethanol is to modify physiological Several ALDH inhibitors have been used that acetaldehyde may contribute to the acetaldehyde concentrations by interfer­ to cause massive acetaldehyde accumu­ aversive effects of high ethanol doses. ing with normal ethanol metabolism. lation after alcohol consumption, most An important disadvantage of these This approach is described in the next commonly disulfiram and . studies, however, is the lack of control section. Because catalase is believed to account over acetaldehyde concentrations. Indeed, for most of the acetaldehyde production ethanol administration to animals or Effects of Altering in the brain, various modulators of its humans pretreated with ALDH inhibitors Ethanol Metabolism activity have been tested to specifically leads to peripheral acetaldehyde con­ assess the contribution of acetaldehyde centrations that are substantially higher Although direct administration of to ethanol’s effects on the brain. than the normal range of physiological acetaldehyde to an organism can show concentrations. This limitation makes researchers what effects acetaldehyde Effects of ALDH Inhibition interpretations in terms of acetaldehyde can have at the sometimes very high contribution to the effects of ethanol Ethanol administration to animals or difficult. concentrations achieved, such experi­ humans following treatment with ments do not reflect acetaldehyde’s actual ALDH inhibitors leads to the typical effects during Effects of Manipulation of Catalase alcohol sensitivity reaction, which then Activity (Deitrich 2004). To test the hypothesis deters further alcohol consumption. that acetaldehyde mediates or modulates Accordingly, most animal studies using A second strategy that has been widely ethanol’s effects, researchers instead ALDH inhibitors have focused on used to unravel the contribution of have sought to modify the acetaldehyde measuring subsequent alcohol con­ acetaldehyde to the central effects of concentrations that result from endoge­ sumption in order to establish a model ethanol is based on pharmacological nous ethanol metabolism after alcohol for predicting the efficacy of ALDH manipulations of catalase activity. administration and then to assess the inhibitors as alcohol-deterrent medica­ Catalase plays an important role in consequences of this manipulation on tions in alcoholism treatment. These acetaldehyde production in the brain, ethanol’s effects. To this end, several studies generally concluded that ALDH and manipulations of catalase levels animal studies have used pharmacolog­ inhibition and acetaldehyde accumulation were shown to alter acetaldehyde con­ ical agents that alter normal ethanol strongly reduce voluntary alcohol con­ centrations when brain tissue studied metabolism. sumption and potentiate the aversion in vitro was treated with ethanol As mentioned earlier, the bulk of for moderate to high ethanol doses (Smith et al. 1997). Similarly, catalase any ingested ethanol is metabolized to (Quertemont et al. 2005). inhibition is expected to decrease brain acetaldehyde by liver ADH; neverthe­ Another approach to interfering with acetaldehyde concentrations, and cata­ less, manipulation of ADH activity usu­ ALDH activity was used by Isse and lase activation is expected to increase ally is not a useful experimental strategy colleagues (2005), who generated mice brain acetaldehyde levels after ethanol for studying the role of acetaldehyde in that no longer produced active ALDH2 administration in vivo. However, cata­ alcohol’s effects for several reasons: (i.e., ALDH2 knockout mice) because lase only marginally contributes to the function of the gene that controls ethanol metabolism in the liver, and • In the CNS, ADH is not physiolog­ ALDH2 production was altered in experimental manipulation of catalase ically active and brain acetaldehyde these animals. As a result of the manip­ activity therefore should have no signif-

262 Alcohol Research & Health Role of Acetaldehyde in Mediating Alcohol’s Effects icant effects on peripheral acetaldehyde of the catalase-modulating studies suf- on acetaldehyde concentrations but levels. fer from several important weaknesses. instead only resorted to making Several studies conducted in mice First, because brain acetaldehyde levels assumptions on the effectiveness of have investigated the role that acetalde­ are difficult to measure in vivo, these their manipulations (Deitrich 2004). hyde and its production by catalase studies did not attempt to measure the In particular, the effects of catalase acti­ play in ethanol’s locomotor stimulant effects of their experimental treatments vation on brain acetaldehyde concen- 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 Figure 1 Schematic representation of the metabolism of ethanol (ETOH) and the effects of aldehyde dehydrogenase (ALDH) inhibitors and catalase modula­ effects. tors. Under normal physiological conditions, ethanol is metabolized to Thus, although studies on brain cata­ acetaldehyde (ACA) through several enzymatic pathways involving alcohol lase activity suggest that acetaldehyde dehydrogenase (ADH), cytochrome P4502E1 (CYP2E1), or catalase. might be involved in or even mediate When ALDH is pharmacologically inhibited, acetaldehyde accumulates to some of ethanol’s behavioral effects, high concentrations both in the brain and in the periphery. Catalase metab­ particularly its stimulant effects, the olizes about 60 percent of ethanol in the brain. Therefore, inhibition of cata­ role of acetaldehyde in the motivational lase is believed to reduce brain acetaldehyde levels, whereas enhance­ and reinforcing properties of alcohol ment of catalase activity is believed to increase brain acetaldehyde levels. remains inconclusive. Furthermore, all

Vol. 29, No. 4, 2006 263 trations as depicted in Figure 1 remain ethanol. This model is mainly based • The modulation model states that speculative and have not been experi­ on the contention that the in vivo the pharmacological actions of mentally demonstrated. Second, most concentrations of acetaldehyde in acetaldehyde modulate some of of the pharmacological agents that are target organs are insufficient to induce ethanol’s effects. commonly used to alter catalase activity significant pharmacological actions. have a poor specificity—that is, they Whereas the full prodrug model also interfere with other physiological • The full prodrug model contends seems to be least likely, it currently is reactions (Quertemont et al. 2005). that acetaldehyde mediates all of the difficult to decide between the other As a result, alternative explanations for pharmacological effects of ethanol. two models. The modulation model 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.

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, Figure 2 Schematic representation of three alternative models that account for especially its stimulant properties. the role of acetaldehyde in ethanol’s (ETOH’s) effects. According to the Three alternative models regarding ethanol model, acetaldehyde (ACA) does not contribute at all to ethanol’s the contribution of acetaldehyde to overall pharmacological effects, and all effects are mediated directly by ethanol’s effects have been put forward the molecular action of ethanol. The full prodrug model states that all pharmacological effects of ethanol are mediated by acetaldehyde. According (see Figure 2): to this model, ethanol would be a mere prodrug without pharmacological effect of its own. Finally, the intermediate modulation model stipulates that • The ethanol model posits that acetaldehyde synergistically interacts with ethanol to modulate ethanol’s acetaldehyde does not contribute at pharmacological effects. all to the pharmacological effects of

264 Alcohol Research & Health Role of Acetaldehyde in Mediating Alcohol’s Effects

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