Piecing together the puzzle of acetaldehyde as a neuroactive agent

Neuroscience and Biobehavioral Reviews 36 (2012) 404–430

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Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

Review

Piecing together the puzzle of acetaldehyde as a neuroactive agent Mercè Correa a,b,∗ , John D. Salamone b , Kristen N. Segovia b , Marta Pardo a , Rosanna Longoni c,d , Liliana Spina c,d , Alessandra T. Peana e , Stefania Vinci c , Elio Acquas c,d,f,∗∗ a

Department of Psychobiology, University Jaume I, 12071 Castelló, Spain Department of Behavioral Neuroscience, University of Connecticut, 06269-1020, Storrs, USA Department of Toxicology, University of Cagliari, Italy d INN – National Institute of Neuroscience, University of Cagliari, Italy e Department of Drug Sciences, University of Sassari, Italy f Centre of Excellence on Neurobiology of Addiction, University of Cagliari, I-09124 Cagliari, Italy b c

a r t i c l e

i n f o

Article history: Received 17 February 2011 Received in revised form 14 July 2011 Accepted 21 July 2011 Keywords: Acetaldehyde Alcohol dehydrogenase Aldehyde dehydrogenase Catalase CYP2E1 Dopamine Ethanol Salsolinol

a b s t r a c t Mainly known for its more famous parent compound, ethanol, acetaldehyde was first studied in the 1940s, but then research interest in this compound waned. However, in the last two decades, research on acetaldehyde has seen a revitalized and uninterrupted interest. Acetaldehyde, per se, and as a product of ethanol metabolism, is responsible for many pharmacological effects which are not clearly distinguishable from those of its parent compound, ethanol. Consequently, the most recent advances in acetaldehyde’s psychopharmacology have been inspired by the experimental approach to test the hypothesis that some of the effects of ethanol are mediated by acetaldehyde and, in this regard, the characterization of metabolic pathways for ethanol and the localization within discrete brain regions of these effects have revitalized the interest on the role of acetaldehyde in ethanol’s central effects. Here we present and discuss a wealth of experimental evidence that converges to suggest that acetaldehyde is an intrinsically active compound, is metabolically generated in the brain and, finally, mediates many of the psychopharmacological properties of ethanol. © 2011 Elsevier Ltd. All rights reserved.

Contents 1. 2.

Acetaldehyde in every day life: foods and foodstuff, cigarette smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Behavioral pharmacology of acetaldehyde: central or peripheral? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Is central formation of acetaldehyde possible? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The issue of the quantitative determination of acetaldehyde in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Acetaldehyde and the blood brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

405 406 406 407 407

Abbreviations: 4MP, 4-methylpyrazole; AA, Alko alcohol; Acb, nucleus accumbens; AcbSh, nucleus accumbens shell; AcbC, nucleus accumbens core; aCSF, artificial cerebrospinal fluid; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; ANA, alko non-alcohol; ANT, alcohol sensitive rats; ARH, arcuate nucleus of the hypothalamus; ASOs, antisense phosphorothioate oligonucleotides; AT, alcohol-resistant; ATZ, aminotriazole; BAAC, blood acetaldehyde concentration; BBB, blood brain barrier; BEC, blood ethanol concentration; BSTL, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; CPA, conditioned place avoidance; CPP, conditioned place preference; CTA, conditioned taste aversion; CTP, conditioned taste preference; CYP, cytochrome P450 ; DA, dopamine; DMS, dorsomedial striatum; DDTC, diethyl dithiocarbamate; DOPAL, dihydroxyphenylacetaldehyde; DOPAC, dihydroxyphenylacetic acid; DRL, differential-reinforcement-of-low-rates-of-responding; ER, exploration ratio; ERK, extracellular signal regulated kinase; HAP, high alcohol-preference rats; FR, fixed ratio; HPV, paraventricular nucleus of the hypothalamus; IA , A-type potassium current; Ih , hyperpolarization-activated inward potassium current; i.c., intracisternal administration; i.c.v., intracerebroventricular administration; i.g., intragastric administration; i.p., intraperitoneal administration; IRT, inter-response time; i.v., intravenous administration; KO, knock out; LAP, low alcohol-preference rats; MAPK, mitogen activated protein kinases; MEK, mitogen-activating ERK kinase; NTS, nucleus of the solitary tract; P, Alcohol preferring rats; PBN, parabrachial nucleus; SC, superior colliculus; SNc, substantia nigra, pars compacta; SNr, substantia nigra, pars reticulata; THP, tetrahydropapaveroline; ThPV/PF, paraventricular/parafascicular nuclei of thalamus; TR, taste reactivity; UChA, University of Chile high alcohol drinkers; UChB, University of Chile low alcohol drinkers; VLS, ventrolateral striatum; VP, ventral pallidum; VTA, ventral tegmental area; WT, wild type. ∗ Corresponding author at: Department of Psychobiology, University Jaume I, 12071 Castelló, Spain. ∗∗ Corresponding author at: Department of Toxicology, University of Cagliari, Italy. E-mail addresses: [email protected] (M. Correa), [email protected] (E. Acquas). 0149-7634/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2011.07.009

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Behavioral effects of endogenously formed acetaldehyde after ethanol administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1. Ethanol consumption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2. Anxiolytic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.3. Implicit learning: perception memory, conditioned taste and place avoidance and approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.4. Psychomotor studies: locomotion, locomotor sensitization and loss of righting reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Behavioral effects after direct administration of acetaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.1. Self-administration studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.2. Anxiety and disinhibition studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.3. Drug-discrimination studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.4. Studies of conditioned effects: active and passive place or taste avoidance and approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.5. Psychomotor studies: locomotion, loss of righting reflex and operant performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain nuclei involved in acetaldehyde modulation of behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Modulation of neurotransmitter release by acetaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acetaldehyde and the opioid system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intracellular actions of acetaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Beyond acetaldehyde: acetaldehyde’s adducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Beyond acetaldehyde: the role of ALDH in addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2.4.

3. 4. 5. 6. 7. 8. 9.

1. Acetaldehyde in every day life: foods and foodstuff, cigarette smoke Acetaldehyde is abundantly present in every day life. In fact, since its production occurs both biologically and artificially, this can be easily understood if one considers that sources of potentially significant pharmacological and toxicological amounts of this simple molecule are available in foods, beverages, cigarette smoke and, even, automobile exhausts. Acetaldehyde is a colorless and highly volatile liquid with an unpleasant, pungent and irritating odor, at room temperature and pressure. It is an extremely reactive, electrophilic compound with a very short (minutes) plasmatic elimination half-life (Freundt, 1968; Hobara et al., 1985; Myers et al., 1982a). In nature, acetaldehyde is formed through pyruvic fermentation by the direct action of pyruvic acid decarboxylase, but also as an intermediate of lactic and alcoholic fermentations, and as a consequence of the fermentation of soy beans and cereal grains (Feng et al., 2007). The reaction by which different strains of Lactobacilli and Streptococchi produce acetaldehyde depends upon the activity of l-threonine acetaldehyde lyases (aldolases), which convert the four carbon amino acid threonine into the simplest two carbon molecules acetaldehyde and glycine (Wilkins et al., 1986; Liu et al., 1997). Hence the presence of significant and detectable amounts of acetaldehyde has been reported in a number of dietary products, including bread, instant tea and coffee, roasted coffee beans and dairy products such as milk, yogurt (Miyake and Shibamoto, 1993) and cottage cheese (Drake et al., 2009), and in many alcoholic and non-alcoholic beverages (Clemente˜ Jimenez et al., 2005; Miyake and Shibamoto, 1993; Munoz et al., 2005). The content of acetaldehyde in yogurt, for instance, may depend upon many factors such as the temperature reached during home-made and/or industrial manufacture (the higher the temperature the greater acetaldehyde’s concentration in the final product), the fat content of milk, and the addition of milk protein fortifying agents (Soukoulkis et al., 2007). Operationally, in yogurt as well as in cottage cheese, acetaldehyde is the chemical marker most closely related to sensory attributes such as flavor intensity or aromas reminiscent of green apples (Soukoulkis et al., 2007; Drake et al., 2009). Interestingly, low concentrations of acetaldehyde in dairy products are considered necessary to impart a balanced flavor, while higher concentrations would result in flavor defects. A similar criterion regulates the acceptability of acetaldehyde’s presence in wines and in the wine making industry. In fact, acetaldehyde represents one of the most appreciated

sensory carbonyl compounds that provide, when in appropriate concentrations, fruity (peach) aromas to both white and red wines ˜ et al., (Clemente-Jimenez et al., 2005; Osborne et al., 2000; Munoz 2005); furthermore, acetaldehyde concentrations in wines are also ˜ used as an index to assess their biological aging (Munoz et al., 2005). Sources of acetaldehyde in the environment include wood and cigarette smoke, and also automobile exhausts. Acetaldehyde is largely formed in the combustion process in the initial oxidative pyrolysis of the fuel, and its content in tail-pipe emissions, where it can reach concentrations between 0.39 and 0.81 mg/km run, would highly depend on different fuel blends (Schuetzle et al., 1994; Karavalakis et al., 2009). More interestingly, in particular from the pharmacological and toxicological points of view, acetaldehyde is present in cigarette smoke; in this source it represents the product of mono- and disaccharides pyrolysis, and its content varies largely depending upon the percentages of saccharides added to tobacco (Hoffmann et al., 1997; Seeman et al., 2002). However, the combustion of naturally occurring polysaccharides (i.e. cellulose) in tobacco, rather than that of the added mono-, di- or polysaccharides, represents the main source of acetaldehyde that is found in the vapor phase of tobacco smoke. Thus, acetaldehyde can be present in tobacco smoke in concentrations as high as half of the nicotine content itself (i.e. 400–1400 ␮g/cigarette for acetaldehyde and 100–3000 ␮g/cigarette for nicotine; Hoffmann, 2001). Interestingly, although nicotine is commonly indicated as the main psychoactive ingredient among the many chemicals (≥5000) found in tobacco smoke, the presence of acetaldehyde in such relevant concentration has, indeed, inspired some authors to prompt the concept of “tobacco dependence” rather than simply of “nicotine dependence” (Talhout et al., 2007). In addition, nicotine, compared for instance to cocaine, behaves as a weak reinforcer in animal models of dependence and, interestingly, the abuse of pure nicotine has never been demonstrated (Dar and Frenk, 2004). On the basis of these premises, indeed, the role of acetaldehyde in nicotine self-administration (Belluzzi et al., 2005) and in other central and peripheral nicotine’s effects (Cao et al., 2007) has been investigated. In particular, Belluzzi et al. (2005) demonstrated that intravenous (i.v.) acetaldehyde (16.0 ␮g/injection) increases the acquisition of nicotine self-administration and that this synergism is reciprocal, i.e. that nicotine (30 ␮g/injection) can, similarly, enhance the acquisition of acetaldehyde self-administration. These reciprocal effects on the acquisition of self-administration between nicotine and acetaldehyde appear restricted, however, to juvenile rats. These

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observations led Belluzzi et al. (2005) to speculate that, since juvenile rats (beginning at postnatal days 22–32) are more sensitive than adult rats (postnatal days 86–87+), they may better mimic the condition of human adolescence in which exposure to nicotine is critical for the development of further dependence (Acosta et al., 2008). Furthermore, the role of acetaldehyde in the pharmacological effects of tobacco smoke on neuronal activation (c-fos expression) and behavioral measures (locomotion) has also been investigated in a model of non-contingent administration of these compounds. These experiments revealed the existence of quite complex interactions between acetaldehyde and nicotine. In fact, acetaldehyde could increase nicotine-elicited locomotion in juvenile rats, and also increase nicotine-reduced locomotion in adult rats (Cao et al., 2007); in addition, the combined administration of nicotine (30 ␮g/kg i.v.) and acetaldehyde (16 ␮g/kg i.v.) differentially affected c-fos expression in the superior colliculus and central nucleus of the amygdala (CeA) (potentiation of nicotine effect) but not in the shell of the nucleus accumbens (AcbSh) nor in the bed nucleus of the stria terminalis (BSTL) (no difference between the effect of nicotine alone and nicotine + acetaldehyde). Overall, these results, while revealing a complex interplay between nicotine and acetaldehyde in their reciprocal pharmacological effects, await further investigations to clarify the mechanisms that mediate such interactions. 2. Behavioral pharmacology of acetaldehyde: central or peripheral? The oxidative metabolism of ethanol into its first metabolite, acetaldehyde, can involve several organs and multiple enzymes, including alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1) and catalase-H2 O2 (Lieber, 2004). Acetaldehyde is then metabolized into acetic acid (acetate), primarily by NAD-linked aldehyde dehydrogenase (ALDH) (Deng and Deitrich, 2008), an enzyme that is widely distributed across multiple brain structures (Zimatkin, 1991). Since ADH 1, the main enzyme that metabolizes ethanol in the liver, is not present in the brain (Galter et al., 2003), the local formation of acetaldehyde in this organ after ethanol intake has been a topic of some controversy (Hunt, 1996; Hipólito et al., 2007; Deng and Deitrich, 2008), more so when considering that two other enzymatic systems (CYP2E1 and catalase) have a minor role in removing ethanol from blood circulation under physiological conditions (Lieber, 2004). For example, after acute administration, CYP2E1 seems to contribute only about 3% to the removal of ethanol from the body (see Hipólito et al., 2007), and catalase inhibition produced in various ways has been demonstrated to determine no alteration in peripheral levels of ethanol (Aragon et al., 1989; Correa et al., 1999a,b, 2000; Sanchis-Segura et al., 1999a). Moreover, the rates of blood ethanol elimination following intraperitoneal (i.p.) administration were found to be similar regardless of dose or genetic stock in a recent study using acatalasemic, CYP2E1 knock-out (KO) mice and double KO animals (Vasiliou et al., 2006). Nevertheless, despite the fact that ethanol and peripherally produced acetate reach the brain in significant amounts, acetaldehyde derived from the peripheral metabolism of ethanol penetrates from blood to brain with difficulty because of the metabolic barrier presented by ALDH across the blood brain barrier (BBB) (Deitrich, 1987; Eriksson and Sippel, 1977; Hunt, 1996; Zimatkin, 1991) (see Section 2.3). Moreover, in the liver ADLH rapidly converts acetaldehyde into acetate, and therefore very low levels of acetaldehyde are detected in blood after the administration of moderate doses of ethanol (Quertemont and Tambour, 2004). In addition, the isoform of ALDH present in the erythrocytes is the same one that predominates in the liver (ALDH 2 of low Km) (Deng and Deitrich, 2008), possibly contributing to the peripheral metabolism of high levels of acetaldehyde that

escape liver metabolism. Furthermore, there is also rapid removal of administered acetaldehyde throughout reduction to ethanol by alcohol dehydrogenase 1 (ADH 1) in the liver (Deng and Deitrich, 2008). In spite of all these factors, alternative evidence indicates that acetaldehyde can be formed locally in the brain and that significant quantities of blood acetaldehyde can saturate the enzymatic barrier between blood and brain, and therefore cross into the brain. In the next three sections (2.1, 2.2, and 2.3) these data will be reviewed. 2.1. Is central formation of acetaldehyde possible? A plausible source of acetaldehyde in the brain is the in situ synthesis from some of the ethanol that escapes peripheral metabolism. Consistent with this idea, increases in acetaldehydemetabolizing enzymes in the brain have been reported after repeated ethanol exposure in rats, suggesting that acetaldehyde is present in the brain after consumption of ethanol (Amit et al., 1977). More than 30 years ago it was suggested that acetaldehyde can be formed directly in the brain in part via the enzyme catalase (Cohen et al., 1980). Thus, it was argued that in the neonatal rat brain ethanol metabolism is done via catalase, since there is a general lack of ADH 1 (Cohen et al., 1980), and because catalase levels are very high in several brain structures, which would allow for substantial central metabolism of ethanol into acetaldehyde (Del Maestro and McDonald, 1987). Since then, it has been shown that ethanol is metabolized to acetaldehyde in rodent brain homogenates (Aragon and Amit, 1993; Aragon et al., 1992; Gill et al., 1992; Zimatkin and Lindros, 1996; Zimatkin et al., 1998), as well as in neural tissue cultures (Reddy et al., 1995; Eysseric et al., 1997; Hamby-Mason et al., 1997) via the peroxidative activity of catalase. In addition to these in vitro data, it has been reported that in vivo ethanol administration effectively protects brain catalase from several inhibitors (Aragon et al., 1991a). Protection of catalase by ethanol constitutes indirect evidence for the in vivo oxidation of ethanol by the peroxidatic activity of catalase in the brain (Aragon et al., 1991a). Immunohistochemistry studies have shown that catalase is localized in catecholaminergic neurons, and is specially concentrated in several nuclei of the adult rat brain (Moreno et al., 1995; Zimatkin and Lindros, 1996), which suggests that acetaldehyde could be generated locally in pharmacologically significant amounts. Thus, more recently, catalase inhibition by several pharmacological tools has been demonstrated to reduce the amount of acetaldehyde accumulation measured by microdialysis in the striatum of freely moving rats (Jamal et al., 2007). However, since part of ethanol oxidation is not affected after catalase inhibition (Aragon et al., 1992; Gill et al., 1992; Hamby-Mason et al., 1997; Zimatkin et al., 1998), the involvement of some other enzymes in this process should also be considered. As is the case for catalase, CYP2E1 is induced by ethanol in liver, brain and other organs (for a recent review see Hipólito et al., 2007). It has been demonstrated that CYP2E1 is widely present in the human brain (Miksys and Tyndale, 2004) and in different areas and types of brain cells in rodents (Montoliu et al., 1995; Tindberg and Ingelman-Sundberg, 1996; Vaglini et al., 2004; Sanchez-Catalan et al., 2008). In fact, in some of these cells it can be induced by a relatively low concentration of ethanol (Tindberg and Ingelman-Sundberg, 1996; Sanchez-Catalan et al., 2008). On the contrary, there is a reduction in acetaldehyde levels in brain and liver microsomes after incubation with ethanol in transgenic KO CYP2E1 mice relative to their wild type (WT) counterparts (Vasiliou et al., 2006). Pharmacological manipulations that specifically inhibit CYP2E1, also reduced acetaldehyde accumulation in rat brain homogenates incubated with ethanol (Zimatkin et al., 2006). Thus, there is clear evidence of brain ethanol metabolism and it has been proposed that approximately 60% of brain ethanol

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metabolism is accounted by catalase, while only 20% is mediated by CYP2E1 (Zimatkin et al., 2006). Different other sources must mediate the rest of this local formation of acetaldehyde (Zimatkin et al., 1998, 2006). 2.2. The issue of the quantitative determination of acetaldehyde in the brain As discussed above, there is now robust evidence that acetaldehyde can be produced into the brain by metabolic transformation of ethanol. However this is not, by any means, proof of the fact that there is indeed endogenous acetaldehyde in the brain, or that acetaldehyde’s concentration in the brain, consistently and reproducibly, increases above a threshold level (i.e. above the detection limit of the available analytical approaches) after systemic administration of pharmacologically and behaviorally relevant doses of ethanol or acetaldehyde. These points represent two critical and, up to now, still unanswered questions regarding the puzzle of acetaldehyde as neuroactive agent. Moreover, these questions will remain until (i) the analytical determination of acetaldehyde in the brain will become routine, so that acetaldehyde concentrations in the brain can be directly correlated with behavior, and until (ii) it will be possible to strictly control the genetic profiles of the whole enzymatic machinery involved in the production and disposal of acetaldehyde. This issue has been the topic of previous reviews on acetaldehyde that have given particular emphasis to such puzzling questions (for critical reviews on this topic see, for instance, Deitrich, 2004 and Quertemont and Tambour, 2004). In the last decades there have been many attempts to quantify acetaldehyde in blood and brain in order to correlate plasma levels with brain concentrations following the administration of either ethanol or acetaldehyde itself. Nevertheless, this line of research has generated conflicting and uncertain results. In fact, while some studies have reported detection of brain acetaldehyde after peripheral ethanol (Hamby-Mason et al., 1997; Kiessling, 1962; Eriksson and Sippel, 1977; Peana et al., 2010a; Sippel, 1974; Tabakoff et al., 1976; Westcott et al., 1980) and acetaldehyde (Heap et al., 1995; Quertemont et al., 2004; Ward et al., 1997) administration, others reported failure to detect acetaldehyde after administration of either ethanol (Eriksson and Sippel, 1977; Jamal et al., 2007; Sippel, 1974) or acetaldehyde (Peana et al., 2010b). Several areas of discrepancy and controversy are associated with these quantitative measures of brain acetaldehyde. Firstly, brain concentrations of detected acetaldehyde after peripheral acetaldehyde or ethanol administration are surprisingly very different. In fact these concentrations range between 0.05 ␮mol/g of tissue (i.e. ∼50 ␮M) 10 min after i.p. administration of 100 mg/kg acetaldehyde (Ward et al., 1997) and 0.40 mM 15 min after i.p. administration of 100 mg/kg acetaldehyde (Quertemont et al., 2004) and between 5 nmoles/g of tissue 60 min after ethanol 4 g/kg i.p. (Hamby-Mason et al., 1997) and 130 nmoles/g of tissue 90 min after ethanol 3 g/kg i.p. (Tabakoff et al., 1976). Secondly, since ALDH 2 rapidly removes acetaldehyde, measurements of acetaldehyde might be compromised by differences in the efficiency of this conversion to acetate (Deng and Deitrich, 2008; Deitrich, 2004). Therefore, the possibility that different rates of acetaldehyde oxidation may markedly affect the recovery of already-low acetaldehyde levels needs to be carefully addressed. Thirdly, although less importantly, since acetaldehyde can cross the alveolar-capillary membrane of the lungs, like other volatile compounds it can be eliminated by breathing (Tardif, 2007; Eriksson and Sippel, 1977). Fourthly, negative results obtained by brain microdialysis studies might be attributed to the possibility that acetaldehyde binds the polymers (mostly cellulose) that compose the dialysis membranes. This possibility is suggested by the work of Jamal and colleagues. In particular, it

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was shown that catalase critically contributes to the accumulation of acetaldehyde detected in the striatum by means of microdialysis following i.p. ethanol (1 g/kg), since in the absence of catalase inhibition acetaldehyde could not be detected, whereas catalase inhibition by ATZ or sodium azide allows its detection under the same experimental conditions (Jamal et al., 2007). The possibility that acetaldehyde binds to some extent the microdialysis membrane is further supported by the observation that in vitro recovery of acetaldehyde provides approximately identical recoveries (51 ± 6% and 49 ± 4%) from 125 and 250 ␮M solutions at the flow rate of 0.8 ␮l/min (Jamal et al., 2003c). In addition, in vivo measurements of interstitial acetaldehyde made with the push-pull perfusion technique, an earlier method for measuring chemicals in brain tissue that did not use dialysis membranes, yielded consistent acetaldehyde concentrations after i.g. administration of ethanol (4.5 g/kg), in a range between 5 and 20 ␮M (Westcott et al., 1980). In agreement with these findings, Peana and colleagues have recently reported a significant increase of acetaldehyde concentration in blood and brain after oral ethanol self-administration (Peana et al., 2010a), but failed to detect it in the brain of rats orally self-administering acetaldehyde (Peana et al., 2010b). This finding was interpreted as being due to the fact that acetaldehyde’s brain concentration was below detection limit, although a sensitive headspace gas chromatography (HS-GC-FID) procedure was applied which, nevertheless, allowed the determination of endogenous acetaldehyde in the blood (Peana et al., 2010a). An additional factor that should be taken into account to interpret the inability to detect acetaldehyde in the brain in the study by Peana et al. (2010b) is, however, the fact that acetaldehyde was orally ingested by rats over 30 min-long sessions, and not as a single bolus (Peana et al., 2010a). Overall, these observations further confirm the complexity of the determination of acetaldehyde levels, and suggest that other factors such as the timecourse, as well as the route and modality of administration, need to be simultaneously and strictly controlled in order to solve this issue. In this vein, finally, another aspect to be acknowledged, when considering factors that may affect acetaldehyde detection in the brain, is the observation that acetaldehyde is a highly reactive electrophilic chemical, and therefore is able to bind to nucleophilic structures and give condensation products (see also Section 7). In summary, many factors appear to contribute to the difficulties found in detecting acetaldehyde in the brain, and the discrepancies in acetaldehyde concentrations that are reported in the literature. Additional research will be necessary to clarify this important area of inquiry. 2.3. Acetaldehyde and the blood brain barrier The question whether acetaldehyde crosses the BBB represents one of the main issues raised against the idea that acetaldehyde has central effects following peripheral administration. The BBB is a highly specialized structure, localized in the blood vessels of the brain that functions, by virtue of the presence of tight junctions between endothelial cells of brain capillaries and of the oligodendrocytes it is made of, to prevent penetration and distribution of molecules with peculiar physical–chemical characteristics into the cerebral parenchyma. Thus, as a consequence of their polarity and size, basic pharmacokinetics explain why, in the absence of facilitated or carrier-mediated transport mechanisms, charged and/or large molecules cannot penetrate the BBB and therefore cannot exert direct effects on the brain. Exceptions to this principle are represented by structures such as the choroid plexus and/or pericysternal sites, where this highly specialized organization appears more loose. However, despite some local

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effects due to the actions of restricted molecules on a limited number of pericysternal/periventricular structures, this route does not offer a general avenue of penetrability into the brain. Interestingly, another efficient mechanism that makes BBB cells able to prevent substances from penetrating the brain is the presence of a “metabolic barrier” made by enzymes such as ALDH (Zimatkin, 1991). Thus, although the physical–chemical properties of acetaldehyde strongly suggest that this is a molecule that can easily penetrate the BBB, the high expression of ALDH within the BBB suggests otherwise. Indeed, as early as 1974, when brain ethanol metabolism had not been assessed yet, Sippel observed that, 30 min after i.p. administration of 65 mmol/kg (i.e. 3 g/kg) of ethanol, acetaldehyde could be found in significantly detectable concentrations in the brain only when blood acetaldehyde concentrations were greater than 250 nmoles/ml (Sippel, 1974). This observation led this author to predict (i) that cerebral capillary walls may contain ALDHs and (ii) that brain acetaldehyde would become detectable only once the capacity of such metabolic barrier would be saturated (Hoover and Brien, 1981; Westcott et al., 1980; Zimatkin, 1991). It appears clear, therefore, that at least two main concepts must be kept in mind when dealing with the issue of BBB penetrability by acetaldehyde. The first requires one to distinguish between determinations of brain acetaldehyde following peripheral administration of ethanol versus administration of acetaldehyde itself, since central ethanol metabolism may significantly contribute to acetaldehyde content within the brain; the second places emphasis on the fact that the “metabolic barrier” must be overridden before significant amounts of acetaldehyde accumulate in the brain and become detectable. A further, not less critical, point that must be taken into account is the time interval from ethanol and/or acetaldehyde peripheral administration. As a consequence of all this reasoning, therefore, those studies that report detectable acetaldehyde concentrations in the brain following intraperitoneal (Sippel, i.p. 1974; Tabakoff et al., i.p. 1976) or intragastric (Westcott et al., 1980) ethanol administration do not represent unequivocal proof of the fact that acetaldehyde, produced in the periphery from ethanol metabolism, has reached the brain. Based on this, the possibility that acetaldehyde may reach the brain following its administration through tobacco smoke inhalation has also been questioned (Seeman et al., 2002; Talhout et al., 2007). On the contrary, significantly detectable concentrations of acetaldehyde in the brain following its peripheral (i.p and i.v., respectively) administration, in a range of doses between 20 and 300 mg/kg, have been documented (Heap et al., 1995; Poso et al., 1981; Quertemont et al., 2004; Ward et al., 1997). Further, indirect evidence that acetaldehyde passes the BBB was offered by a recent study by Jamal et al. (2007). This study showed that acetaldehyde brain concentrations, as determined by in vivo brain microdialysis following ethanol (1 g/kg i.p.) administration, are decreased by peripheral (ADH) and central (catalase) ethanol metabolism inhibition, suggesting that both catalase and high levels of peripherally generated acetaldehyde are strongly involved in the accumulation of acetaldehyde in the brain (Jamal et al., 2007). Unfortunately, when ethanol (1 g/kg i.p.) was administered without any ALDH inhibitor, a near zero concentration of acetaldehyde in the striatum was reported while, in contrast, ethanol concentration was ≥20 mM (Jamal et al., 2007). Overall, although the acetaldehyde’s short elimination halflife and high reactivity make reliable analytical procedures for detecting it still highly desirable, it appears that at least at the pharmacologically and behaviorally significant doses used, blood concentrations would allow its penetration in the brain (Deng and Deitrich, 2008; Quertemont and Didone, 2006; Quertemont et al., 2005) and account for its central pharmacological actions.

2.4. Behavioral effects of endogenously formed acetaldehyde after ethanol administration Based upon the studies presented in the section below, it appears that many of the behavioral effects of ethanol administration are ultimately produced by acetaldehyde formed in the body, and more specifically in the brain. Over the last 20 years, the most common approach to this area has been to study the effects of manipulations that alter the enzymatic production and degradation of acetaldehyde, to determine how they influence the actions of ethanol (for a recent review see Hipólito et al., 2007). The blockade of ALDH activity, which results in an increase in acetaldehyde accumulation, was the first strategy used (Amit et al., 1976). However, the inhibition of ALDH can be difficult to interpret, since a systemic drug that targets ALDH 2 can affect both central and peripheral acetaldehyde metabolism. Thus, most studies that try to evaluate the impact of central ALDH 2 inhibition also administer an ADH 1 inhibitor. By inhibiting ADH 1 (isoenzyme that is not present in the brain) one avoids peripheral acetaldehyde accumulation, thus limiting the contribution of a source of acetaldehyde other than that centrally generated from ethanol metabolism. For example, in the presence of ethanol, the inhibition of ALDH 2 in liver and brain by cyanamide produces an increase in blood (Spivak et al., 1987a,b) and brain acetaldehyde levels (Jamal et al., 2007) respectively; however, such increase is prevented in blood when cyanamide is administered in combination with the ADH inhibitor 4-methylpyrazole (4MP) (Spivak et al., 1987a,b). Thus, 4MP suppresses the peripheral metabolism of ethanol and prevents high levels of peripherally synthesized acetaldehyde (Rydberg and Neri, 1972) from reaching the brain. However, a very important step in demonstrating the behavioral significance of centrally generated acetaldehyde has been to study the possible metabolic pathways that contribute to the formation of acetaldehyde directly into the brain. A key enzyme in this regard is catalase (Aragon et al., 1992; Hipólito et al., 2007), which is responsible for the highest proportion of central ethanol metabolism (Zimatkin et al., 2006). Thus, a decrease in central acetaldehyde formation, after peripheral ethanol administration and catalase inhibition, should be responsible for a reduction of ethanol-mediated behaviors. On the other hand, an increase in brain acetaldehyde production through increased catalase activity should potentiate ethanol effects on behavior. More recently, CYP2E1 also has been demonstrated to contribute to some degree to acetaldehyde central formation and effects (Zimatkin et al., 2006; Hipólito et al., 2007; Correa et al., 2009a). A number of drugs and genetic manipulations have targeted the enzymatic systems involved in ethanol and acetaldehyde central metabolism (for a recent review see Hipólito et al., 2007). The specificity of most of these drugs for the different enzymes is always a problematic aspect in this type of studies since most of such compounds can act on other cellular components, including other ethanol metabolizing enzymes. For this reason, any study that uses pharmacological compounds for altering enzymatic activity should have additional control experiments. Firstly, it should provide an evaluation of the enzymatic activity or of the enzymatic levels of the targeted enzyme in order to allow a correlation with the behavioral outcome induced by ethanol. Secondly, drugs other than ethanol should also be tested for potential interactions with the substance that modulates the enzymatic function. Thus, an interaction between a drug like cocaine and a pharmacological tool that modulates catalase activity, such as sodium azide, will indicate that the effect of sodium azide is not specific for ethanol and is probably affecting the monoaminergic systems that can ultimately be responsible for both cocaine and ethanol-induced effects on behavior. Finally, more than one agent able to inhibit or potentiate enzyme activity or expression should be used. These types of control experiments have been done in most of the studies

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presented in this section. A separate pharmacological strategy has been to assess the effect of the so-called “acetaldehyde sequestering agents” (Cederbaum and Rubin, 1976; Nagasawa et al., 1978) in modifying the behavioral actions of ethanol and acetaldehyde (see also Sections 2.4.1–2.4.4). These thiol compounds, such as l-cysteine and d-penicillamine, interact with acetaldehyde nonenzymatically to form stable adducts (Kera et al., 1985; Nagasawa et al., 1980) which have been detected in plasma, liver and brain after co-administration of these thiols with ethanol (Serrano et al., 2007), in this way reducing blood levels of acetaldehyde detected after ethanol administration (Nagasawa et al., 1978). Finally, the use of sub-strains of animals (mice and rats) which naturally differ in the activity or amount of the various ethanol metabolizing enzymes, or the use of KO mice for catalase, ALDH or CYP2E1, has been very useful. However, the interpretation of the results in KO mice is not always straightforward, since in many instances the lack of one enzyme type can lead to compensatory mechanisms and result in increases in other similar enzymes. Thus, ALDH 2 KO mice have significantly higher CYP2E1 protein expression levels than ALDH 2 WT mice (Oyama et al., 2005). Moreover, catalase levels are significantly higher in CYP2E1 KO mice compared to WT (Vasiliou et al., 2006; Correa et al., 2009a). This increase in catalase or CYP2E1 expression and activity are probably the result of a compensatory effect on such cellular detoxification systems (Terelius et al., 1991). In the following section we will review the impact of these pharmacological and genetic manipulations on ethanol consumption and ethanol-modulated behaviors mainly in the preclinical literature (for a extensive review on human data see Quertemont, 2004). 2.4.1. Ethanol consumption The relationship between ethanol or acetaldehyde accumulation and voluntary ethanol consumption has demonstrated to be very close. Clinical data suggest that acetaldehyde reaching or generated in the brain after ethanol consumption may be responsible for the reinforcing effect that sustains ethanol consumption (Wall et al., 1992; Hahn et al., 2006; Chen et al., 2009). However, high levels of blood acetaldehyde are clearly aversive, and in subjects with no previous experience with the drug, acetaldehyde can be a deterrent to future ethanol consumption (Chao, 1995). Thus, the balance between acetaldehyde generated in the periphery and that formed in the brain can determine the amount of ethanol intake. Some gene polymorphisms strongly protect against the development of alcoholism (Chen et al., 1999; for a review see Quertemont, 2004). A mutation in the gene encoding for the liver mitochondrial ALDH 2 (ALDH 2*2), present in some populations (Chen et al., 2009; Luo et al., 2006; Mulligan et al., 2003; Peng et al., 2007), lowers or abolishes the activity of this enzyme and results in elevations in blood acetaldehyde when consuming ethanol, thus resulting in a phenotype that greatly protects against ethanol abuse and alcoholism (for reviews see Eriksson, 2001; Quertemont et al., 2005; Tambour and Quertemont, 2007). In animals, ALDH 2 KO mice accumulate higher levels of acetaldehyde in several organs and show a reduction in their preference for ethanol relative to WT mice (Isse et al., 2002, 2005). Among the Wistar-derived rats bred as high (UChB) or low alcohol drinkers (UChA) in the University of Chile, the UChA rat line seems to be a good model for the human ALDH 2*2 mutation since these animals have a deficiency of the same isozyme (ALDH 2) due to a mutation in the encoding gene (Sapag et al., 2003; Quintanilla et al., 2005). Results of studies in rat lines bred in Finland (Eriksson, 1968) for their voluntary low and high alcohol consumption (Alko Non-Alcohol (ANA) and Alko Alcohol (AA) drinking, respectively) have shown that ethanol administration results in higher blood acetaldehyde concentrations in the ethanol-avoiding ANA rat line (Eriksson, 1973), as a consequence of genetically lower ALDH 2 activity, and this has been considered as the basis for the ethanol avoidance in this line

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(Eriksson, 1973; Koivisto et al., 1993; Koivisto and Eriksson, 1994). Also, low alcohol-preference (LAP) rats show higher blood acetaldehyde levels than high alcohol-preference (HAP) rats, respectively (Nishiguchi et al., 2002). However, between ANA and LAP rat lines there are no differences in low Km ALDH 2. Thus, in addition to the specific enzymatic mutation, blood acetaldehyde levels themselves seem to have a direct impact on ethanol consumption as they seem inversely related to the quantity of ethanol voluntarily consumed in humans and rodents (Eriksson, 2001; Quintanilla et al., 2005, 2007; Rivera-Meza et al., 2010). An increase in blood acetaldehyde levels produces a range of symptoms that, as a whole, are aversive (Eriksson, 2001). This peripheral effect of acetaldehyde is confirmed by the marked inhibition of ethanol intake in animals in which peripheral ALDH 2 activity is reduced and blood acetaldehyde levels are increased by antisense drugs that do not penetrate the BBB (Ocaranza et al., 2008). However, ALDH inhibitors such as disulfiram (Antabuse® ) and calcium carbimide (Abstem® , Temposil® ) have been used with mixed success to stop consumption and to prevent relapse in alcoholics. In animal studies it has been demonstrated that reductions in ethanol consumption induced by these drugs generally occur when rats do not have a long history of ethanol consumption, but these properties are not manifested when the animals have been consuming ethanol voluntarily for a long time (Tampier et al., 2008; Garver et al., 2000). These data, along with self reports in disulfiram treated patients and studies done in alcoholic populations with the ALDH 2*2 mutation (Hahn et al., 2006; Wall et al., 1992), suggest that the previous experience of consuming ethanol allows one to identify familiar internal stimuli that may be also detected even when other internal stimuli, aversive in this case, are present after the wave of blood acetaldehyde has occurred. These familiar stimuli may be related to the central effects of moderate levels of acetaldehyde formed after regular consumption of alcohol. Thus, it has been demonstrated that positive feelings and expectancies about alcohol consumption (i.e. physical and social pleasure as well feelings of relaxation) are higher while negative expectancies (social, emotional, cognitive and physical) are lower in alcoholics with the ALDH 2*2 mutation (Hahn et al., 2006; Wall et al., 1992). However, new genetic therapies targeting ALDH 2 are promising therapeutic approaches for reducing ethanol intake in alcohol-dependent patients. The administration of antisense phosphorothioate oligonucleotides (ASOs) can mimic the low-activity ALDH 2*2 phenotype increasing circulating plasma acetaldehyde levels after ethanol administration. Thus, this oligonucleotide delivered to rats by osmotic pumps led to aversion to ethanol (Garver et al., 2001). Moreover, a single i.v. administration of the anti-ALDH 2 antisense gene carried by an adenoviral vector reduced liver ALDH 2 activity by 85% and inhibited voluntary ethanol intake by 50% for 34 days in alcohol-dependent UChB rats compared to naïve UChB rats (Ocaranza et al., 2008). Another ethanol metabolizing enzyme that has been implicated in the consumption of alcohol is ADH 1. Individuals carrying an ADH allele (ADH 1B*2) that codes for an isoform that is one order of magnitude more active than that coded by the usual ADH 1B*1 are also protected against heavy ethanol use and alcoholism (Thomasson et al., 1991; Tu and Israel, 1995). However, since there have been no reports on acetaldehyde levels being elevated in ADH 1B*2 allele carriers, the mechanism of protection against alcoholism of the fast ADH is not clear (Peng et al., 2002). Among high alcohol consuming UChB rats, females show 70% higher hepatic ADH activity and consume 60% less ethanol than males. In this type of rat, females generated a transient blood acetaldehyde increase with levels that were 2.5 times greater than in males after ethanol administration. In this study, castration of males led to increased ADH activity, as well as the appearance of a transient increase in acetaldehyde, and a reduction in voluntary ethanol intake to levels comparable to

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naïve females (Quintanilla et al., 2007). Conversely, the competitive inhibitor of ADH, 4MP (10 mg/kg), blocked the appearance of arterial acetaldehyde and at the same time increased ethanol intake (Quintanilla et al., 2007). Thus, in general these studies suggest that increasing blood acetaldehyde levels, by increasing the amount of acetaldehyde production or reducing acetaldehyde metabolism, leads to a reduction in voluntary ethanol intake. Brain acetaldehyde levels seem also to be related to the quantity of ethanol voluntarily consumed. A positive correlation between brain ALDH activity and voluntary alcohol consumption has been observed in rats (Sinclair and Lindros, 1981; Socaransky et al., 1984), supporting the hypothesis that brain acetaldehyde formation and metabolism are critical factors regulating levels of locally formed acetaldehyde, which in turn is important for mediating ethanol consumption. Thus, fast local production and degradation of acetaldehyde seem to be the optimal conditions for sustaining ethanol consumption. In this sense, it has been demonstrated that in acatalasemic mice (Aragon and Amit, 1993), and in recombinant strains of mice with different levels of catalase activity (Gill et al., 1996b), alcohol drinking preference is genetically determined, in part, by the level of brain catalase activity which, in turn, regulates brain acetaldehyde concentrations. A positive correlation between catalase activity and voluntary ethanol consumption has been reported in humans (Amit et al., 1999; Koechling and Amit, 1992; Koechling et al., 1995) and rats (Amit and Aragon, 1988; Aragon et al., 1985b; Gill et al., 1996a). Further support for this notion has been provided by pharmacological studies employing catalase inhibitors, which have been shown to attenuate acquisition (Rotzinger et al., 1994) and maintenance (Aragon and Amit, 1992a; Koechling and Amit, 1994; Tampier et al., 1994) of voluntary ethanol consumption in rats and in mice (Aragon and Amit, 1992a; Koechling and Amit, 1994). Very recently, a study employing genetic therapies targeting central metabolism has demonstrated that ventral tegmental area (VTA) microinjections of the lentiviral vector encoding the anticatalase shRNA, which reduces catalase content, abolished voluntary consumption of alcohol by UChB rats, and conversely, that injection into the same brain nuclei of the lentiviral vector coding for ADH 1 stimulated ADH 1 synthesis and voluntary ethanol consumption (Karahanian et al., 2011, but see also in this regard Deitrich, 2011). The other enzyme that can mediate acetaldehyde formation in the brain, CYP2E1, seems to have little or no role in ethanol intake. In several human populations, polymorphisms of the CYP2E1 gene which resulted in a mutated allele (c2) with a 10folds higher transcriptional activity compared with the WT allele (c1) do not seem to modulate the amount of ethanol consumed in different ethnic populations of normal or alcoholic subjects (Hayashi et al., 1991; Watanabe et al., 1994). The reduction in enzymatic activity seems not to have major consequences for ethanol intake either. CYP2E1 KO mice only show a reduction in preference for voluntary consumption of low concentrations of ethanol (4–8%, v/v) compared with the WT animals, and no differences were observed after higher concentrations were introduced (Correa et al., 2009a). Finally, the use of acetaldehyde sequestering agents has led to interesting results, which support the hypothesis that acetaldehyde locally formed in the brain from ethanol is an important determinant of ethanol consumption. d-penicillamine administered to Long Evans rats that had been consuming stable amounts of ethanol by a non-operant two bottle procedure, reduced voluntary ethanol consumption (Font et al., 2006). Following cessation of the d-penicillamine treatments, animals returned to baseline levels of ethanol intake (Font et al., 2006). Moreover, l-cysteine, dose-dependently, reduced acquisition and maintenance of oral ethanol self-administration as well as reinstatement after ethanol extinction in Wistar rats (Peana et al., 2010a).

2.4.2. Anxiolytic effects It is well known that ethanol at moderate doses has anxiolytic effects in humans and rodents (Abrams et al., 2001; Boehm et al., 2002). However, very few studies have assessed the impact of acetaldehyde formed in the brain on this emotional response. In the elevated plus maze and in the dark/light box (the typical behavioral paradigms used to evaluate anxiety in rodents) mice receiving different doses of ethanol (0.5–1.5 g/kg i.p.) showed responses in both paradigms (Correa et al., 2008). However, pretreatment with catalase inhibitors such as aminotriazole (ATZ) or sodium azide, administered i.p., reduced or blocked the anxiolytic effect of ethanol found in control CD1 mice (Correa et al., 2008). The opposite effect was found when catalase activity was potentiated by lead acetate; animals showed an increase in time spent in the open arms compared to vehicle treated mice. These results, obtained in absence of motor effects, show that the anxiolytic properties of ethanol can be mediated by centrally formed acetaldehyde. Moreover, d-penicillamine blocked the anxiolytic response induced by ethanol (Correa et al., 2008), thus potentially inactivating central acetaldehyde formed after ethanol administration. Blockade of acetaldehyde removal by ALDH 2 inhibitors in humans and animals, as well as the ALDH 2 mutation in humans, has yielded the opposite pattern of results. In human populations with one inactive ALDH allele (ALDH 2*2) (Shibuya et al., 1989), acetaldehyde is elevated in blood after the consumption of alcohol, and produces the “alcohol flushing response” that is a cutaneous vasodilatation accompanied by other autonomic symptoms such as tachycardia, palpitation, dizziness, nausea (Chao, 1995; Eriksson, 2001; Von Wartburg, 1987). The autonomic symptoms produced by the interactions between ethanol and disulfiram also resemble some of the vegetative responses observed after an acute anxiety episode (Johnsen et al., 1992; Peachey et al., 1983). In CD1 mice, disulfiram at doses that were effective in inhibiting hepatic low Km ALDH 2 activity blocked the anxiolytic effects of alcohol in an elevated plus maze, reducing the number of entries into the open arms and the time spent there. Moreover, the highest doses of disulfiram, administered with an anxiolytic dose of ethanol triggered an anxiogenic response (Escrig et al., 2007). This latter set of results suggests that blocking acetaldehyde metabolism, which generates an accumulation in the entire body, can cause among other effects, anxiogenic responses. However, cyanamide (25 mg/kg), a well-known ALDH 2 inhibitor, had no effect on the anxiolytic effect of ethanol in CD1 and C57BL/6J mice tested in an elevated plus maze (Tambour et al., 2005). These authors used a dose of cyanamide (25 mg/kg) to inhibit hepatic ALDH 2 activity, thus potentially increasing accumulation of acetaldehyde in the periphery; however, since enzymatic ALDH activity was not assessed (Tambour et al., 2005), one cannot discard the possibility of a lack of effect on the enzyme. 2.4.3. Implicit learning: perception memory, conditioned taste and place avoidance and approach Ethanol at low doses enhances the social olfactory recognition memory of rats and mice (Thor and Holloway, 1982; Manrique et al., 2006) when administered immediately after the first presentation of a conspecific. This is a type of short-term memory that only lasts a few hours. In these studies, the exploration ratio (ER) is marker of the recognition capacity of the animal, a higher ER indicating less recognition. However, in mice pretreated with catalase inhibitors (ATZ or sodium azide), the improvement in recognition induced by ethanol (1.0 and 1.5 g/kg i.p.) was prevented. These data suggest that brain catalase activity, thus brain acetaldehyde, could mediate the memory-enhancing capacity of ethanol (Manrique et al., 2006). The association of a drug of abuse with a neutral stimulus such as a taste, a smell or a place produces a conditioned response to the later presentation of the paired neutral stimuli. The nature of that

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Table 1 CTA after ethanol administration and enzymatic manipulations (data are ordered by “rat strain”, “methodology” (CTA procedure) and “enzymatic manipulation” (ADH, ALDH and Catalase). Rat strain

CTA procedure

Enzymatic manipulation

CTA results

Reference

Sprague-Dawley rats

Pairing day = free choice between water and saccharin + enzymatic manipulation + conditioning agent ethanol (1–4 g/kg p.o.) Test day = free choice between water and saccharin Pairing day = enzymatic manipulation + saccharin + conditioning agent ethanol (0.4–1.2 mg/kg i.p.). Test day = only saccharin available

ADH inhibitor, 4MP (8 mg/kg i.p.)

NO change in CTA induced by ethanol (4 g/kg p.o.)

Hunt et al. (1987)

ADH inhibitor, 4MP (10 mg/kg i.p.)

NO change in CTA induced by ethanol (0.8 and 1.2 g/kg i.p.)

Spivak et al. (1987a)

ALDH inhibitor, cyanamide (25 mg/kg i.p.) 4MP + cyanamide

Potentiation of CTA by sub-threshold dose of ethanol (0.4 g/kg i.p.) Reduction of CTA induced by ethanol (1.2 g/kg i.p.) Reduction of CTA induced by ethanol (1.2 g/kg i.p.) Potentiation of CTA induced by ethanol (0.5 and 1 g/kg i.p.)

Escarabajal et al. (2003b)

Catalase inhibitor, ATZ (0.17–1 g/kg i.p.)

Potentiation of CTA induced by ethanol (1 g/kg i.p.)

Quertemont et al. (2003)

Catalase inhibitor, ATZ (1 g/kg i.p.)

Blockade of CTA induced by ethanol (1.2 g/kg i.p.)

Aragon et al. (1985a)

Long-Evans rats

Wistar rats

Wistar rats

Long-Evans rats

Pairing day = enzymatic manipulation + Free choice between water and saccharin + conditioning agent ethanol (0.5 or 1 g/kg i.p.) Test day = free choice between water and saccharin Pairing day = enzymatic manipulation + free choice between water and saccharin + conditioning agent ethanol (0.5 or 1 g/kg i.p.) Test day = Free choice between water and saccharin Pairing day = enzymatic manipulation + saccharin + conditioning agent ethanol (1.2 mg/kg i.p.). Test day = only saccharin available

ALDH inhibitor, cyanamide (25 mg/kg i.p.)

response in animals has led to an extensive debate, and it has been suggested that this response is either an emotional manifestation or an automatic pavlovian response. The difficulty of interpreting these experiments also comes from the fact that the nature of such response is highly dependent on the specific methodology used during the conditioning phase. There are two basic types of conditioned taste aversion procedure used in this area of research. With one procedure, subjects are trained to associate the drug with either an “aversive” state (produced by injections of lithium chloride) or a “neutral” state (saline injections) after consumption of

a flavored solution. On the test day another drug is given, to see if it generalizes to the lithium effect. In the other procedures (the more conventional ones) it is the drug itself (i.e. ethanol or acetaldehyde) that is used to produce the conditioned response if it reduces the consumption of the flavored food or solution. However, in the conventional “conditioned taste aversion” paradigm, aversive responses such as nausea and discomfort are not evaluated. In taste reactivity (TR) studies parameters such as gaping, head shaking or chin rubbing, more closely characterize the aversive nature of the response. Thus, it seems more appropriate to consider this behavior

Table 2 CTA as a discrimination procedure for the properties of acetaldehyde compared to ethanol. Rat strain

CTA procedure

CTA results

Reference

Long Evans rats

Pre-exposure = water + pre-exposure drug

Pre-exposure to acetaldehyde (200 and 300 mg/kg i.p.) attenuates or blocks the CTA to ethanol 1.2 g/kg i.p. Pre-exposure to ethanol (1.2 g/kg i.p.) attenuates or blocks the CTA to acetaldehyde (200 and 300 mg/kg i.p.)

Aragon et al. (1986, 1991a,b)

Acetaldehyde (300 mg/kg i.p.) Generalized to ethanol 0.8 g/kg + lithium Acetaldehyde (50–200 mg/kg i.p.) did not generalize to ethanol (0.8 g/kg) + lithium Ethanol (0.8–2 g/kg i.p.) generalized to acetaldehyde (300 mg/kg i.p.) + lithium Ethanol (1.2 and 1.6 g/kg i.p.) generalized to acetaldehyde (200 mg/kg i.p.) + lithium Ethanol (0.8 and 2 g/kg) did not generalize to acetaldehyde (200 mg/kg i.p.) + lithium No change in CTA induced by ethanol (0.8 g/kg) + lithium

Redila et al. (2000)

Pairing day = saccharin + generalization drug

Long Evans rats

Long Evans rats

Long Evans rats

Test day = saccharin Pairing day = ethanol (0.8 g/kg i.p.) + saccharin + lithium Cl or saline Test day = acetaldehyde (50–300 mg/kg i.p.) + saccharin Pairing day = acetaldehyde (200–300 mg/kg i.p.) + saccharin + lithium Cl or saline Test day = ethanol (0.8–2 g/kg i.p.) + saccharin

Pairing day = Ethanol (0.8 g/kg i.p.) + saccharin + lithium Cl or saline Test day = catalase inhibitor ATZ (1 g/kg i.p.) + ethanol (0.8 g/kg i.p.) + saccharin

Redila et al. (2002)

Redila et al. (2000)

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Table 3 CTA after direct acetaldehyde administration. Rat strain

CTA procedure

CTA results

Reference

Wistar rats

Pairing day = free choice between water and saccharin + acetaldehyde (200 or 300 mg/kg i.p.). Test day = free choice between water and saccharin Pairing day = saccharin + acetaldehyde (200 or 300 mg/kg i.p.). Test day = only saccharin available Pairing day = saccharin + acetaldehyde (200 or 300 mg/kg i.p.). Test day = Only saccharin available Pairing day = enzymatic manipulation + free choice between water and saccharin + acetaldehyde (100–300 mg/kg i.p.) or ethanol (0.5–2 g/kg i.p.) Test day = free choice between water and saccharin

Induction of CTA by acetaldehyde (200 and 300 mg/kg i.p.)

Kunin et al. (2000)

Induction of CTA by acetaldehyde (200 and 300 mg/kg i.p.)

Brown et al. (1978)

Induction of CTA by acetaldehyde (200 and 300 mg/kg i.p.)

Aragon et al. (1986, 1991a,b)

Induction of CTA by ethanol (1–2 g/kg i.p.)

Escarabajal et al. (2003b)

Wistar rats

Long Evans rats

Wistar rats

UChA and UChB rats

UChA and UChB rats

Sprague-Dawley rats Wistar rats

Pairing day = fruit-flavored solution + acetaldehyde (50–150 mg/kg i.p.) Test day = free choice between water or fruit-flavored solution

Pairing day = fruit-flavored solution + acetaldehyde (25–100 mg/kg i.p.) Test day = free choice between water or fruit-flavored solution Pairing day = saccharin + Ethanol (790 ␮g i.c.v.). Test day = free choice between water and saccharin Pairing day = saccharin + Acetaldehyde (64–800 ␮g i.c.v.) Test day = saccharin

as “conditioned taste avoidance” (CTA) instead of aversion (Parker, 1995). The CTA produced by drugs of abuse and lithium does not differ in the intensity of effects, but differs qualitatively when assessed by the TR test (Parker, 1995). Drugs of abuse paired with flavored solutions suppress ingestion of the solution, but the animal does not show aversive reactions like tongue protrusion and paw licking, and it does not have enhanced rejection responses. On the other hand, sucrose paired with lithium not only suppresses ingestion, but also elicits a pattern of enhanced rejection responses of chin rubbing and paw treading (Parker and Carvell, 1986). The lithium procedure has been used in the acetaldehyde field as the more common methodology to assess discrimination between acetaldehyde and other drugs, although any effects on reactivity measures have not been reported. Moreover, drugs of abuse that cross the BBB produce CTA via their action beyond the BBB, whereas lithium produces CTA via its action outside it (Parker and Carvell, 1986). A summary of these results and methodologies used is shown in Tables 1–3. Ethanol induces CTA in rats at doses that range from 0.8 to 2.0 g/kg i.p. using the conventional methodology (Aragon et al., 1985a; Escarabajal et al., 2003b; Parker, 1995; Quertemont et al., 2003; Quintanilla et al., 2001; Redila et al., 2000; Spivak et al., 1987b). The accumulation of acetaldehyde in the periphery induced by ALDH 2 inhibitors seems also to induce CTA (Spivak et al., 1987a; Escarabajal et al., 2003b). However, these results are difficult to interpret because some of these enzymatic manipulations also induced CTA on their own (Escarabajal et al., 2003b), and contradictory results have been found across different studies trying to assess the effects of acetaldehyde that is centrally formed via catalasemediated ethanol metabolism (Aragon et al., 1985a; Quertemont et al., 2003). These differences in results between studies can be due to differences in methodologies (i.e. reduction in saccharin intake is more difficult when is the only fluid available for the animals). Thus, after enzymatic manipulations, the involvement of centrally

Induction of CTA by acetaldehyde (300 mg/kg i.p.) NO effect of acetaldehyde (100–170 mg/kg i.p.) + cyanamide (25 mg/kg i.p.) UChA Induction of CTA by acetaldehyde (50, 100 and 150 mg/kg i.p.) when flavored fluid was the only choice Induction of CTA by acetaldehyde (100 and 150 mg/kg i.p.) when water and flavored fluid were present UChB No effect of acetaldehyde (50–150 mg/kg i.p.) No effect of Acetaldehyde (25 mg/kg) Induction of CTA by acetaldehyde (25 mg/kg i.p.) + cyanamide (10 mg/kg i.p.) Induction of CTP by ethanol (790 ␮g i.c.v.) Induction of CTP by acetaldehyde (320 ␮g i.c.v.) NO effect of acetaldehyde (64 or 800 ␮g i.c.v.)

Quintanilla et al. (2002)

Quintanilla and Tampier (2003a,b)

Crankshaw et al. (2003) Brown et al. (1978)

formed acetaldehyde on ethanol-induced CTA is not clear (for a summary see Table 1). Another conditioned response induced by many drugs of abuse is conditioned place preference (CPP) or avoidance (CPA). In these paradigms, the animal chooses to spend more or less time in one of the compartments of a multichamber box if that chamber has been previously associated with a drug. Thus, as is the case for the CTA paradigm (Redila et al., 2000), peripherally administered ethanol produces CPP when administered prior to the conditioning session (Cunningham et al., 2006) and CPA when administered after the animal has been in the chamber (Cunningham et al., 2006). Some researchers in this literature interpret the CPP results as a reliable measure for evaluating drug affective properties (Bardo and Bevins, 2000; Tzschentke, 1998). However, others have evaluated these results purely as a conditioned pavlovian response or as a drug discrimination paradigm that triggers an automatic response of approach or avoidance (Sanchis-Segura and Spanagel, 2006). The involvement of acetaldehyde in ethanol-induced CPP has been evaluated with different pharmacological tools. The ADH inhibitor 4MP (45 and 67.5 g/kg i.p.) decreased ethanol (1 g/kg i.g.) induced CPP in Wistar rats (Peana et al., 2008). However, this decrease can be interpreted either as a result of increasing peripheral accumulation of ethanol, or as a decrease of potentially synthesized acetaldehyde in the periphery, or even as an increase in acetaldehyde formed in the brain because more ethanol is reaching it. The results obtained after centrally sequestering acetaldehyde with thiol compounds (Serrano et al., 2007) are clearer, and demonstrate that these substances block ethanol effects on CPP. In the first of such studies it was shown, in CD1 mice, that while dpenicillamine blocked ethanol-induced CPP, it did not affect CPA (Font et al., 2006). This result suggests that when acetaldehyde is centrally formed it does not produce an avoidance response. These findings were supported by the efficacy of d-penicillamine and

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l-cysteine, to prevent ethanol (1 g/kg i.g.) induced CPP in Wistar rats (Peana et al., 2008, 2009). Variants of the CPP procedure have been used in rat pups (Petrov et al., 1997; Pautassi et al., 2011). Association of an odor after intracisternal (i.c.) administrations of 100 mg% ethanol in pups increases preference to a surrogate nipple providing water, as measured by time attached to the nipple. Pretreatment with i.c. administration of the catalase inhibitor, sodium azide, completely and selectively suppressed ethanol-induced CPP (Nizhnikov et al., 2007). Also in studies with preweanling rats it has been demonstrated that administration of d-penicillamine (i.p.) blocks ethanol (i.g.)-induced CPP for a tactile surface (Pautassi et al., 2011). Thus, after catalase-mediated metabolism, centrally formed acetaldehyde seems to be responsible for the increase in preference in pups (Nizhnikov et al., 2007; Pautassi et al., 2011). 2.4.4. Psychomotor studies: locomotion, locomotor sensitization and loss of righting reflex Since most of the behaviors described so far require the concurrence of an intact or minimally impaired motor performance, the impact of acetaldehyde on gross and fine motor parameters is a key factor to consider before reaching a conclusion about acetaldehyde effects on any behavior in general. Thus, it is useful to know the impact on horizontal and vertical locomotion or sedation of any manipulation in order to avoid confounds in paradigms used to assess anxiety or place approach studies. Large doses of ethanol induce locomotor suppression, motor incoordination and the loss of righting reflex or narcosis (Draski et al., 1992; Correa et al., 2001). In recombinant inbred mice from Long and Short Sleep mice, there is a correlation between narcosis time and the ability of the brain to oxidize ethanol to acetaldehyde in vitro (Zimatkin et al., 2001). In mice, acetaldehyde formed in the brain seems to counteract the narcosis induced by ethanol. There is an inverse relationship between brain catalase or CYP2E1 activity, and the duration of ethanol-produced loss of righting reflex. Thus, the behavioral phenotyping of strains with different levels of catalase expression has shown that acatalasemic mice have a longer duration of sleep time following ethanol administration than normal mice (Aragon and Amit, 1993; Vasiliou et al., 2006). Likewise, after an injection of ethanol, C57BL/6 mice display longer sleeping time as well as lower brain catalase activity than mice of the DBA/2 strain (Kiianmaa et al., 1983; Aragon and Amit, 1987). Moreover, ATZ and chronic lead acetate administration inhibit brain catalase activity and increase ethanol-induced narcosis in mice (Correa et al., 2001). Conversely, acute lead administration in doses that enhance brain catalase activity (Correa et al., 2001), increases the latency and reduces the duration of the loss of righting reflex after an acute ethanol injection (Correa et al., 2001; Swartzwelder, 1984). Studies done with CYP2E1 KO mice show that this enzyme has a smaller impact than catalase in ethanol-induced loss of righting reflex; in fact, while acatalasemic mice showed 65% increase in loss of righting reflex induced by high doses of ethanol, CYP2E1 KO mice showed only 12% increase both compared to their respective WT counterpart (Vasiliou et al., 2006). Moreover, in double mutant mice (catalaseCYP2E1) there was an almost perfect addition (75% more than their WT) of the two phenotypes in terms of ethanol-induced narcosis (Vasiliou et al., 2006). Conversely, in rats injected with systemic ethanol at doses that mainly produce suppression of locomotion (Chuck et al., 2006; Correa et al., 2003c), catalase inhibition with ATZ reduced that suppression but increased loss of righting reflex (Aragon et al., 1991b), suggesting a mirror effect between rats and mice in terms of acetaldehyde-mediated ethanol effects on motor behavior. The large number of studies that have assessed the locomotor effects of acetaldehyde formed and accumulated in the periphery or in the brain has led to the conclusion that acetaldehyde accumulated in the periphery after interfering with ethanol metabolism seems to mainly produce ataxic effects, while it is the

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central formation of acetaldehyde that can lead to the stimulating effects observed after ethanol consumption. Thus, in a recent study done in two populations of humans, one with the mutation ALDH 2*1 (active form) genotype and the other with the ALDH 2*2 (inactive form) genotype, it was demonstrated that peripherally accumulated acetaldehyde might be more important than ethanol in modulating psychomotor function and motor skills (Kim and Yoon, 2010). After the consumption of ethanol, the psychomotor performance of subjects with the inactive form was significantly poorer than that of subjects with the active form. Blood Ethanol Concentration (BEC) was comparable in the two genotype groups, whereas Blood Acetaldehyde Concentration (BAAC) was significantly higher in subjects with ALDH 2*2 than in those with ALDH 2*1. A linear regression analysis demonstrated that BAAC significantly predicted poorer psychomotor performance, whereas BEC did not (Kim and Yoon, 2010). That is also the case for blood ethanol and acetaldehyde levels studied in rodents after ADH 1 or ALDH 2 blockade. Blocking ADH with 4MP either does not affect locomotion induced by ethanol, or it produces a small increase (Escarabajal and Aragon, 2002a,b). On the other hand, after the administration of ALDH inhibitors, such as disulfiram, diethyl dithiocarbamate (DDTC), a metabolite of disulfiram, or cyanamide, ethanol-induced locomotor activity was reduced (Escrig et al., 2007; Escarabajal and Aragon, 2002a,b, 2003a; Sanchis-Segura et al., 1999b). The effect of DDTC and of cyanamide was prevented by the administration of 4MP, indicating the involvement of peripheral blood acetaldehyde accumulation, more than ethanol, in the suppressive effects observed after the administration of ethanol (Escarabajal and Aragon, 2002a,b). However, these results were not conclusive in terms of the implications for the peripheral or central accumulation of acetaldehyde, since ALDH 2 was blocked in the periphery but also in the brain. Moreover, inhibition of ALDH 2 in the BBB can increase acetaldehyde penetration in the brain (Jamal et al., 2003c). In addition, cyanamide also can act as a catalase inhibitor under the same doses and patterns of administration, thus blocking central acetaldehyde formation (Sanchis-Segura et al., 1999b,c). The role of centrally formed acetaldehyde on motor parameters seems to be clear (for a recent review see Hipólito et al., 2007). Sequestering centrally formed acetaldehyde with d-penicillamine was demonstrated to be effective in attenuating locomotion induced by ethanol, without altering spontaneous locomotor activity in mice (Font et al., 2005) and in preweanling rats (Pautassi et al., 2011). It has been suggested that the higher the activity of catalase, the higher the rate of acetaldehyde formation in the brain and the higher the increase of locomotion produced by ethanol. Thus, ethanol-induced locomotion is positively correlated with basal levels of brain catalase activity in different inbred, outbred, recombinant strains of mice (Gill et al., 1992; Correa et al., 2004), as well as in genetically acatalasemic mice (Aragon et al., 1992; Aragon and Amit, 1993). Pharmacological studies have demonstrated that mice treated with catalase inhibitors such as ATZ, sodium azide, cyanamide, and chronic lead acetate, have lower ethanol-induced locomotion than control animals (Aragon and Amit, 1993; Correa et al., 1999b, 2000; Sanchis-Segura et al., 1999a,c; Escarabajal et al., 2000). Conversely, acute lead or chronic cyanamide administration at doses that enhance brain catalase activity increase ethanol-induced locomotor activity (Correa et al., 1999a, 2000, 2004; Sanchis-Segura et al., 1999b). Additionally, since catalase uses as a substrate endogenous H2 O2 , conditions that increase brain H2 O2 levels result in an increase in ethanol-induced locomotion in mice (Pastor et al., 2002; Manrique et al., 2006), indicating that ethanol effects are not only related to the levels of brain catalase but also to the possible changes in brain H2 O2 levels. However, recent data indicate that CYP2E1 does not play a strong role in regulating ethanol-induced motor activity when ethanol is administered at low to medium doses in ethanol-naïve animals (Correa et al.,

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2009a). Acutely administered ethanol in mice increased locomotion to a similar extent in WT and in CYP2E1 KO mice (Correa et al., 2009a). This lack of robust difference between WT mice and CYP2E1 KO mice can be explained either by the lack of involvement of CYP2E1, or by the fact that catalase expression (Correa et al., 2009a) and activity (Vasiliou et al., 2006) is augmented in the CYP2E1 mice compared to the WT mice, possibly as a compensatory mechanism. On the other hand, repeated and intermittent administration of activating doses of ethanol, like other motor stimulating drugs of abuse, produces neural adaptations that are manifested as locomotor sensitization (Robinson and Berridge, 2001). As a result ethanol is more effective at inducing motor stimulation under these conditions. Ethanol-induced sensitization has been directly correlated with basal levels of brain catalase activity across different strains of mice (Correa et al., 2004). In relation to the involvement of CYP2E1 in the sensitization induced by ethanol, it was again demonstrated that ethanol produced sensitization both in WT mice and CYP2E1 KO mice to the same extent (Correa et al., 2009a). Repeated ALDH 2 inhibition with disulfiram at a dose (15 mg/kg i.p.) that does not alter the locomotor activity induced by acute ethanol, blocked the development of behavioral sensitization induced by repeated ethanol administration (Kim and Souza-Formigoni, 2010), seemingly indicating that high levels of acetaldehyde, both centrally formed and reaching the brain from periphery, counteract ethanolinduced neuroadaptations, or produce an effect that is different from the effect produced by the “physiological levels” of synthesized acetaldehyde. However, acutely administered disulfiram induced higher levels of locomotion in mice previously sensitized to ethanol (Kim and Souza-Formigoni, 2010). In summary, all these data indicate that acetaldehyde contributes to the motor stimulation and neuroadaptations produced by ethanol, but this effect depends on the amount of acetaldehyde formed and accumulated. 2.5. Behavioral effects after direct administration of acetaldehyde In the studies that will be summarized in this section, the behavioral effects of acetaldehyde have been assessed not with metabolic manipulations following ethanol administration, but rather with direct administration. Acetaldehyde itself has been administered through different routes, and several behavioral and physiological parameters have been assessed. In general it seems that ethanol and acetaldehyde have very similar effects. Both substances alter motor performance in several types of behaviors. Acetaldehyde, like ethanol, can act also as a substance that reinforces behavior, and this observation has implications for reinforcement learning but also for motivated behavior. Moreover, acetaldehyde has very potent and salient effects that can be associated with neutral stimuli, thus establishing pavlovian learning. However, these similarities depend highly on the route of administration, the dose, and the species, as the aversion and anxiety tests suggest. 2.5.1. Self-administration studies Acetaldehyde is self-administered in operant procedures peripherally (Myers et al., 1982a, 1984a,b; Takayama and Uyeno, 1985; Peana et al., 2010b) or centrally (Brown et al., 1979; RoddHenricks et al., 2002; Rodd et al., 2005). Fisher rats self-administer acetaldehyde (2, 6 and 18 ␮M/kg i.v.) in the jugular vein at doses lower than those needed for ethanol (18 ␮M/kg i.v.) selfadministration (Takayama and Uyeno, 1985). Moreover, in Long Evans rats i.v. self-infusions of acetaldehyde (10%) were reduced by administration of naloxone (Myers et al., 1984b). Thus, consistent with the role assigned to the opioid system in the effects of ethanol (see also Section 5), it appears that acetaldehyde selfadministration is modulated by the opioid system (Myers et al., 1984b). A recent study in Wistar rats has demonstrated that acetaldehyde can be orally self-administered within a limited dose

range (from 0.2% up to 1.6%) with lower (0.1%) and higher concentrations (3.2%) not being self-administered (Peana et al., 2010b). Furthermore, after extinction, nose-poking for acetaldehyde (0.2%) in rats was re-established to maintenance (pre-extinction) levels when acetaldehyde was reintroduced (Peana et al., 2010b). Moreover, acetaldehyde could be readily self-administered, in a concentration-dependent manner, directly in the brain. Nondependent Wistar rats exposed to the operant chambers for 24 h a day over 11 days would self-administer 2% and 5% (v/v) acetaldehyde into the lateral ventricles (i.c.v.) (Amit et al., 1977; Brown et al., 1979, 1980). However, ethanol (2% and 10%, v/v) or lower concentrations of acetaldehyde (1%, v/v) were not different from a vehicle solution in terms of operant responses leading to infusion (Brown et al., 1979). The reliability of acetaldehyde peripheral and central self-administration is supported by studies demonstrating that the propensity to self-administration relates to voluntary ethanol consumption. Thus, self-administration of 2% (v/v) acetaldehyde i.c.v. was related to the subsequent voluntary oral intake of ethanol at concentrations between 9% and 19% (v/v) (Amit and Smith, 1985). These results suggest that the central mechanisms mediating the reinforcing effects of acetaldehyde also subserve the reinforcing properties of ingested ethanol (Amit and Smith, 1985). Moreover, although it is well known that increases in peripheral acetaldehyde are associated with toxic or uncomfortable reactions, several decades ago, in Long Evans rats, it was demonstrated that i.v. selfinjections of acetaldehyde (1% or 2%, v/v) during 20 days increased voluntary oral consumption of ethanol (concentrations ranging from 3% to 30%, v/v) in free-choice situations (Myers et al., 1984a). On the other hand, the accumulation of high levels of acetaldehyde after the ingestion of ethanol has been suggested (Eriksson, 1973, 1980) to be a factor limiting the consumption of ethanol by selected sub-strains of rodents that exhibit low ethanol preference, such as ANA rats or UChA rats (Quintanilla and Tampier, 2003a,b) as well as certain strains of mice (Schlesinger, 1966; Schlesinger et al., 1966). For example, the UChA and UChB rat strains were developed for low or high preference, respectively, for 10% (v/v) ethanol solution versus water. In a priming experiment, when injected with 50 mg/kg i.p. of acetaldehyde and tested for voluntary oral ethanol consumption during 4 weeks, acetaldehyde induced a persistent and long-lasting enhancement of ethanol intake in UChB, but not in UChA rats (Tampier and Quintanilla, 2002; Quintanilla and Tampier, 2003a,b). Thus, it has been proposed that the aversive effects of acetaldehyde would contribute relatively less to the stimulus properties of ethanol in strains of animals displaying high preferences for ethanol. 2.5.2. Anxiety and disinhibition studies The anxiolytic and disinhibitory effects of ethanol are very robust across species, paradigms, and routes of administration (Correa et al., 2003a,b, 2005a, 2008). The enzymatic manipulations suggest that centrally formed acetaldehyde can play an important role in the anxiolytic effects of ethanol (Correa et al., 2008). Centrally infused acetaldehyde (30.8 ␮g i.c.v.) was more efficacious than ethanol at producing an anxiolytic effect in Sprague-Dawley rats in an open field, increasing exploration of the unprotected interior part of the arena (Correa et al., 2003c), an effect that often is interpreted as reflecting behavioral disinhibition or anxiolysis. These results were confirmed by assessing the anxiolytic effect in an elevated plus maze in the same strain of rats (Correa et al., 2005a). While acetaldehyde (61.7 ␮g i.c.v.) increased significantly the time and ratio of entries into the open arms compared to total entries, ethanol at the same dose was not capable of producing this effect (Correa et al., 2005a). In an operant schedule known as differential-reinforcement of low-rates-of-responding 30-s (DRL 30-s), the animal has to withhold responding for 30 s, and if it presses during that interval,

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the time is reset and it has to wait again. Thus, in well trained animals a very low rate of responding is optimal, as increases in responding generally cause the omission of reinforcers. An increase in response rate can be seen as reflecting the disinhibition of behavior, which has undesired consequences. The disinhibitory effect of i.c.v. ethanol was seen at a dose of 123.3 ␮g, while i.c.v. acetaldehyde produced a disinhibition in a broader range (31, 123.3 and 247 ␮g i.c.v.) of doses (Arizzi et al., 2003). A larger number of studies have evaluated the impact of peripherally administered acetaldehyde on anxiety using rats as well as mice. However, peripherally administered acetaldehyde at medium to high doses seems to affect anxiety measures in a different way than ethanol (Correa et al., 2005a; Escrig et al., 2007). In an early predecessor of the more recent anxiety studies, Long Evans rats, tested in a round open field with 3 concentric circles, showed that acetaldehyde produced an increase in the latency to leave the central circle at the highest (300 mg/kg i.p.) dose (Myers et al., 1987), thus indicating a potential anxiolytic effect of acetaldehyde. However, this high dose of acetaldehyde also reduced locomotion (Myers et al., 1987) and by slowing the animal it increased the latency to start moving. In a more recent study, i.v. administration of acetaldehyde at a dose (32 ␮g/kg) that did not affect locomotion in adult male SpragueDawley rats tested in an open field, also did not affect the time spent in the center part (Cao et al., 2007). These studies were limited in terms of the doses and anxiety measures used. Studies done in our laboratory have demonstrated that peripherally (i.p.) administered ethanol and acetaldehyde produce very different patterns of behavior in Sprague-Dawley rats in an elevated plus maze (Correa et al., 2005a). While ethanol (0.5 and 1.0 g/kg i.p.) significantly increased the time spent in the open arms and the ratio of open arm entries in relation to total arm entries, acetaldehyde at much lower doses (10 and 50 mg/kg i.p.) produced a significant decrease in the ratio of open arm entries and time spent in the open arms compared to saline treated animals, indicating that significant amounts of acetaldehyde accumulating in the periphery can induce anxiogenic effects. Studies done in mice have used a broader range of doses, some of which do not affect locomotion. However the results seem to lack consistency (Quertemont et al., 2004; Tambour et al., 2005; Escrig et al., 2007). Administration of acetaldehyde (30–170 mg/kg i.p.) to C57BL/6J mice did not affect the time spent in the open arms (Quertemont et al., 2004) or the percentage of open arm entries in C57BL/6J and CD1 mice (Tambour et al., 2005) tested in an elevated plus maze. However, in these studies some doses (56–170 mg/kg i.p.) significantly suppressed the total arm entries, indicating an effect on locomotion (Quertemont et al., 2004; Tambour et al., 2005). Recently, with CD1 mice tested in an elevated plus maze and in a dark-light box, it was demonstrated that peripherally administered acetaldehyde (25–100 mg/kg i.p.) at the highest dose used could reduce percentage of entries and time spent in the open arms, with no significant effect on total entries, indicating that it has anxiogenic actions independent of the locomotor effects (Escrig et al., 2007). Acetaldehyde (100 mg/kg i.p.) had an anxiogenic effect after 1, 6, 11 and 26 min in the elevated plus maze and/or in the dark-light box (Escrig et al., 2007). Furthermore, injections of d-penicillamine (50 or 75 mg/kg i.p.) at doses that reduced central levels of acetaldehyde formed from ethanol (Serrano et al., 2007) were not able to reverse the anxiogenic effect of this high dose (100 mg/kg i.p., injected 1, 6 or 11 min before test) of peripherally administered acetaldehyde (Escrig et al., 2007). The lack of effect of d-penicillamine on the anxiogenic response induced by this high dose of acetaldehyde contrasts with the blockade of the anxiolytic actions of ethanol (1 g/kg i.p.) (Correa et al., 2008), probably because this amount of acetaldehyde in the blood was greater than the amount potentially formed in the brain after ethanol administration in the previous study (Correa et al., 2008). In summary, although more work needs to be done in order to

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clarify discrepancies, the available data suggest that ethanol and acetaldehyde have a different pattern of effects that highly depend on the route of administration. Furthermore, these data suggest that acetaldehyde, whether centrally administered or enzymatically produced, can contribute to the anxiolytic effects observed after ethanol administration. On the other hand, elevated levels of acetaldehyde in blood can trigger an anxiogenic response, perhaps through vagal activation. In that case, any effect of acetaldehyde reaching the brain from the periphery will reduce the strength of the anxiogenic response. This latter point might explain the lack of effects in some studies (Quertemont et al., 2004; Tambour et al., 2005) in which blood and brain acetaldehyde’s levels detected after peripheral administration of 100–170 mg/kg i.p. (used in the anxiety studies) were in the same range in both tissues (Quertemont et al., 2004). Thus, it is possible that the lack of significant changes in the anxiety measures in that study was the result of acetaldehyde acting both in the periphery and also in the brain; both effects could be counteracting each other in terms of the overall outcome of the anxiety response generated. 2.5.3. Drug-discrimination studies Comparisons between the stimulus properties of ethanol and acetaldehyde have also been assessed in animals using different types of procedures such as CTA, operant procedures and T-maze navigation. For example, previous contact with one drug can reduce the impact of another drug, indicating that some of the novel interoceptive effects generalize (priming effect). On the other hand, even two drugs that generalize at some doses can produce very different effects at other doses, thus being easily discriminated from each other. Rats pre-exposed to acetaldehyde generalize not only to ethanol (summarized in Table 2), but also to morphine (Ng Cheong Ton and Amit, 1985) and nicotine (Kunin et al., 2000) in the CTA paradigm. These data indicate that acetaldehyde and ethanol have similar stimulus properties at certain doses when injected peripherally, although central acetaldehyde does not seem to be necessary for this discrimination (Redila et al., 2000, 2002). Similar results had been observed using a shock-motivated T maze discrimination task (York, 1981). In female ANA and AA rats, i.p. injections of vehicle or ethanol (1.0 g/kg) on alternate days were employed as discriminative stimuli signalling for the safety of right or left goal compartments, in the T-maze. Doses between 100 and 250 mg/kg of acetaldehyde generalized to ethanol in both sub-strains of rats but more rapidly and efficiently in low consuming ANA rats (York, 1981). Since ethanol administration results in higher blood acetaldehyde concentrations in ANA compared to AA rats (Koivisto and Eriksson, 1994), it may mean that ANA rats are more sensitive to the stimulus properties of acetaldehyde produced from ethanol. AA and ANA rats, however, did not differ in the impairment of motor performance in a rotarod produced by a broad range of ethanol doses, suggesting that differences in stimuli related to motor impairment do not contribute to the differences observed in the cue value of ethanol for AA and ANA rats (York, 1981). Drug-discrimination studies are more typically conducted in operant chambers fitted with two levers. An animal is trained to discriminate the presence of ethanol from vehicle. When ethanol is administered, the subject is trained to press a designated lever to receive a reinforcer (usually food pellets or some type of fluid). When the vehicle is administered the subject is trained to press the other lever to obtain the reinforcer. Once stimulus control has been achieved, generalization (administration of other drugs) or antagonism tests can be performed. Using this type of procedure, the results seem different. Acetaldehyde (56–300 mg/kg i.p.) administered to Long-Evans rats trained to discriminate water from ethanol (1.0 or 2.0 g/kg i.p.) did not substitute for the discriminative stimulus effects of either dose of ethanol. In addition, pretreatment with the catalase inhibitor ATZ did not affect the dose–response curves

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for ethanol discrimination (0–2.5 g/kg i.g.) (Quertemont and Grant, 2002). The authors concluded that neither exogenously administered acetaldehyde nor endogenously produced acetaldehyde have stimulus effects similar to those of ethanol. Thus, the operant procedure did not show the same general results as the other two drug-discrimination procedures. 2.5.4. Studies of conditioned effects: active and passive place or taste avoidance and approach As it is the case with pharmacological manipulations, the study of direct administration of acetaldehyde in learning and memory processes other than operant responses and pavlovian responses is quite limited. Acetaldehyde at high doses (100–300 mg/kg i.p.) administered to C57BL/6J mice immediately after an acquisition trial in the passive avoidance test impaired memory consolidation 24 h later (Quertemont et al., 2004). Thus, it seems that peripherally administered acetaldehyde impairs memory consolidation, whereas centrally formed acetaldehyde contributes to the establishment of short-term memory processes (Quertemont et al., 2004; Manrique et al., 2006). Acetaldehyde is more potent than ethanol at inducing CTA when both substances are administered peripherally (see Table 3). The lower dose of ethanol necessary to see this effect in outbred strains of rats is 1.0 g/kg i.p. while acetaldehyde results in a strong CTA at doses between 200 and 300 mg/kg i.p. (Brown et al., 1978; Aragon et al., 1986, 1991a; Kunin et al., 2000; Escarabajal et al., 2003b). However, selected strains of rats may be more sensitive. Low alcohol drinking UChA rats have blood acetaldehyde levels higher than the high alcohol drinking substrain (UChB rats), due to reduced activity of their mitochondrial ALDH 2 (Quintanilla et al., 2002). Thus, UChA rats are more sensitive and develop CTA after relatively low acetaldehyde doses (50–150 mg/kg i.p.; Quintanilla et al., 2002). This difference in sensitivity is also reflected by the fact that high alcohol drinking UChB rats only show CTA to high doses (2.0 g/kg i.p.) of ethanol (Quintanilla et al., 2001). Discrepancies in results regarding CTA induced by acetaldehyde are observed once again when different methodologies are used. One important difference is between forced versus free choice (the animal has only saccharine vs. it has a choice between multiple sources of fluid, such as saccharine and water). When the saccharin solution is the only available fluid at any time, reducing the volume consumed in the CTA results much more unlikely (see Table 3). In all the above mentioned experiments, relatively high doses of acetaldehyde have been used to produce avoidance (150–300 mg/kg i.p.). However, a lower range of doses (10–50 mg/kg i.p.) has been used to potentiate conditioned approach responses. In male Wistar rats, acetaldehyde at doses of 10 or 20 mg/kg i.p. paired to an odor cue produced CPP (Quertemont and De Witte, 2001). Higher doses (100–150 mg/kg i.p.) produced no effect or a tendency to get distant from the olfactory stimulus (CPA). In the UChA and UChB strain of rats 50 mg/kg i.p. of acetaldehyde paired with a specific location induced CPP in high drinkers UChB rats and CPA in low drinkers UChA rats (Quintanilla and Tampier, 2003a,b). Thus, the results indicate that there is a range of low doses of peripherally administered acetaldehyde that can increase the approach responses but, also, that this range depends on the susceptibility of the rat strain. It seems also that acetaldehyde, if administered at appropriate (high) doses, can produce CPA. In this regard it would be interesting to explore in the CPP paradigm the effect of higher doses of acetaldehyde (200–300 mg/kg i.p.) that had a clear effect in the CTA paradigms. The rationale for using small peripheral doses of acetaldehyde has been applied in the most recent studies that used i.g. as the main route of administration for acetaldehyde. Thus, among a range of acetaldehyde doses (10–40 mg/kg i.g.) only 20 mg/kg i.g. has been demonstrated to produce CPP in Wistar rats, although

there was also a non-significant tendency with 10 mg/kg i.g. (Peana et al., 2008). Moreover, the acetaldehyde sequestering agents dpenicillamine and l-cysteine prevented acetaldehyde (20 mg/kg i.g.)-induced CPP (Peana et al., 2008, 2009). Very few studies have assessed the impact of centrally administered acetaldehyde or ethanol on the CTA and CPP paradigms. With administration into the cerebrospinal cavities of the brain (ventricles and cisterna magna) it is unlikely that ethanol’s unconditioned properties are derived from its chemosensory attributes or its caloric value. Central administration also avoids the issue of brain penetrability, and therefore allows one to assess directly the intracerebral actions of ethanol and acetaldehyde on different aspects of behavior. When administered into the ventricles, acetaldehyde was more potent than ethanol at inducing CTP, and no dose induced CTA (see Table 3) (Brown et al., 1978; Crankshaw et al., 2003). In place conditioning paradigms it has been also demonstrated that acetaldehyde 640 ␮g i.c.v. during 5 pairing sessions, induced CPP in adult Sprague-Dawley rats (Smith et al., 1984). Results obtained using both paradigms when acetaldehyde was administered centrally (thus avoiding the periphery) indicate that centrally acting acetaldehyde does not induce avoidance responses and, at some doses, it induces approach responses. 2.5.5. Psychomotor studies: locomotion, loss of righting reflex and operant performance Several parameters of motor function are suppressed or impaired after peripheral acetaldehyde administration, a result that mimics ethanol effects at much higher peripherally administered doses. Thus, in one of the first studies in this area, peripheral (i.v.) acetaldehyde in mice was 300 times more potent than ethanol, at least during the first minute after administration, and the difference became smaller (acetaldehyde 50 times more potent) after that (Holtzman and Schneider, 1974). These conclusions about potency, speed and duration of action for peripherally administered acetaldehyde have been confirmed more recently using i.p. administration at doses ranging between 56 and 300 mg/kg, in different strains of mice and with different measures of motor activity (see Table 4) (Quertemont et al., 2004; Font et al., 2005; Tambour et al., 2005, 2006). The same range of acetaldehyde doses and times seem to be effective in rats, with females being more sensitive than males to the suppressive effects of peripherally administered (i.v or i.p.) acetaldehyde on motor parameters (Myers et al., 1987). Moreover, in agreement with the earlier studies in mice, peripherally administered acetaldehyde has been demonstrated to be more potent than ethanol for suppressing locomotion (0.5–2.0 g/kg i.p. for ethanol and 50–200 mg/kg i.p. for acetaldehyde; Chuck et al., 2006; Correa et al., 2003a,c). On the other hand, while ethanol produces a robust narcotic effect, acetaldehyde (170 and 300 mg/kg i.p.) induced a brief but significant loss of righting reflex (around 6 min for the highest dose; Quertemont et al., 2004; Tambour et al., 2006; Correa et al., 2001). Locomotion or narcosis studies among sub-strains of ethanol preferring and non-preferring rats are scarce. These studies indicate that increased sensitivity to the aversive effects of peripherally accumulated acetaldehyde and less voluntary consumption of ethanol correlates with increased sensitivity to loss of the righting reflex after acetaldehyde administration, which leads to reduced tolerance to the incoordinating effects of later administration of ethanol. Thus, in low preferring UChA rats, acetaldehyde at doses of 50 and 100 mg/kg i.p. produced a short-lasting loss of righting reflex (7.2 min for the highest dose) comparable to the effect in mice (Tampier and Quintanilla, 2002). However, in high preferring UChB rats, no loss of righting reflex was observed; instead, a slight motor stimulation was detected. In summary, in rats and mice acetaldehyde at doses ranging from 50 to 300 mg/kg i.p. mainly reduced locomotion in different types of locomotion paradigms

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Table 4 Effects of peripheral or central (i.c.v.) administration of acetaldehyde on motor parameters. Animal strain and route of administration

Motor paradigm

Results

Reference

CF1 mice, i.v.

Small activity cage

C57BL/6J, i.p.

Small activity cage

Swiss mice, i.p.

Small activity cage

Holtzman and Schneider (1974) Quertemont et al. (2004) and Tambour et al. (2006) Tambour et al. (2006)

Swis mice, i.p.

Open field

C57BL/6J and CD1 mice, i.p.

Total arm entries in elevated plus maze

Sprague Dawley rats, i.v. Long Evans rats, i.p.

Open field Open field

Sprague Dawley rats, i.p.

Stabilimeter cage

Wistar rats, i.p.

Small activity cage

UChA and UChB rats, i.p.

Open field

Long Evans rats, i.p.

Operant FR20 performance

Sprague Dawley rats, i.p.

Operant FR5 performance

C57BL/6J and Swiss mice, i.c.v.

Small activity cage

Wistar rats, i.c.v.

Home cage

Sprague Dawley rats, i.c.v.

Open field

Sprague Dawley rats i.c.v. Sprague Dawley rats, i.c.v.

Stabilimeter cage Operant FR5 performance

Acetaldehyde (3–100 mg/kg): suppression of locomotion: gross and fine motor parameters Acetaldehyde (100–300 mg/kg): suppression of locomotion Acetaldehyde (100–170 mg/kg): suppression of locomotion Acetaldehyde (200–300 mg/kg): suppression of locomotion d-Penicillamine: attenuation of suppression induced by acetaldehyde C57BL/6J: acetaldehyde (56–170 mg/kg): suppression of locomotion CD1: acetaldehyde (100–170 mg/kg): suppression of locomotion Acetaldehyde (0.032 mg/kg): no effect Acetaldehyde (300 mg/kg): suppression of locomotion and rearing in males Acetaldehyde (10–300 mg/kg): suppression of locomotion and rearing in females Acetaldehyde (50–100 mg/kg): suppression of locomotion Acetaldehyde (200 mg/kg): non significant suppression of total and horizontal locomotion Acetaldehyde (50–100 mg/kg): UChA: suppression of locomotion and rearing UChB: induction of locomotion and rearing Acetaldehyde (300 mg/kg): suppression of lever pressing Acetaldehyde (50–200 mg/kg): suppression of lever pressing, increase in pauses Acetaldehyde (155–309 ␮g): suppression of locomotion Acetaldehyde (800 ␮g): suppression of locomotion, induction of ataxia Acetaldehyde (31–123 ␮g): induction of locomotion and rearing Acetaldehyde (31–123 ␮g): induction of locomotion Acetaldehyde (31–776 ␮g): no effect

Sprague Dawley rats, i.c.v.

Operant DRL performance

Acetaldehyde (31–247 ␮g): induction of lever pressing

(Tampier and Quintanilla, 2002; Correa et al., 2003a,c; Quertemont et al., 2004; Font et al., 2005; Tambour et al., 2006). This effect was stronger during the first 5 min after acetaldehyde administration (Quertemont et al., 2004; Font et al., 2005; Tambour et al., 2006) and lasted up to 35 min after the highest dose (300 mg/kg) (Quertemont et al., 2004). However, the mild narcotic effects of acetaldehyde at high doses (100–300 mg/kg i.p.; Tampier and Quintanilla, 2002; Quertemont et al., 2004) were very weak when compared with the long duration of loss of righting reflex induced by narcotic doses of ethanol (4–4.5 g/kg i.p.) that can last for hours (Correa et al., 2001). The results after central administration of acetaldehyde are quite different. Early observations in rats indicated that i.c.v. infusions of a high dose of acetaldehyde (800 ␮g) produced ataxia and sedation 1 min after being administered, although after 3–5 min the animals recovered from the sedative effects and appeared to behave normally (Brown et al., 1978). In contrast, in the last few years, it has been demonstrated that injections of much lower doses of acetaldehyde (15–123 ␮g) into the lateral or third ventricle of rats increased locomotion in several paradigms (Correa et al., 2003a,b, 2009b). Ethanol and acetaldehyde injected into the lateral or third ventricles both showed a biphasic dose–response curve in a very similar dose range (increased locomotion at doses of 15–123 ␮g, while 246 ␮g had no effect; Correa et al., 2003a,b,c, 2009b; Pastor and Aragon, 2008). Thus, these studies show that the biphasic motor effects of ethanol and acetaldehyde in rats are present when the route of administration is central, and not peripheral. Moreover,

Font et al. (2005)

Quertemont et al. (2004) and Tambour et al. (2005)

Cao et al. (2007) Myers et al. (1987)

Correa et al. (2003c) Padilla-de la Torre et al. (2008) Tampier and Quintanilla (2002)

Quertemont and Grant (2002) McLaughlin et al. (2008) Tambour et al. (2006) Brown et al. (1978) Correa et al. (2003a) Correa et al. (2003c) Arizzi et al. (2003) and McLaughlin et al. (2008) Arizzi et al. (2003)

acetaldehyde is also clearly effective in acting as a locomotor stimulant when its action is restricted to the CNS. As is the case for gross motor parameters, it is important to know the effect of acetaldehyde on psychomotor performance in operant schedules reinforced by natural stimuli that generate different baseline rates of responding (i.e. rate dependent effects) to understand the stimulant or disruptive effect of the drug itself in order to eliminate motor artifacts during operant self-administration. Several studies using peripheral or central acetaldehyde administrations have characterized performance on operant tasks with food as a reinforcer. Different cognitive and motor components of the response have been observed, including the amount of lever pressing, the temporal distribution of the response (inter-response time intervals, pauses, etc.), the failure to withhold responses, etc. Peripherally administered ethanol decreased performance on different fixed ratio (FR) operant schedules of food reinforcement, and increased the latency to respond (Hiltunen and Järbe, 1988; Chuck et al., 2006; McLaughlin et al., 2008). The FR5 schedule typically generates a relatively high rate of responding and therefore is very sensitive to the motor suppressing effects of psychostimulant drugs like amphetamine, theofilline, caffeine (Wenger and Dews, 1976; Randall et al., 2011). Ethanol suppressed FR5 responding, and also increased pausing and fragmentation of the temporal pattern of responding at doses of 1.0–2.0 g/kg i.p. in Sprague-Dawley rats (Chuck et al., 2006; McLaughlin et al., 2008). Acetaldehyde (50–200 mg/kg i.p.) was demonstrated to be more

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potent than ethanol at reducing lever pressing, and increasing the inter-response time (IRT) on the FR5, thus slowing the response rate and increasing the number of pauses (McLaughlin et al., 2008). This last result is consistent with data from the previously described operant discrimination paradigm using Long Evans rats, in which acetaldehyde at the highest dose (300 mg/kg i.p.) reduced lever pressing for food on a FR20 schedule of reinforcement (Quertemont and Grant, 2002), thus interfering with the conclusions about generalization between ethanol and acetaldehyde. However, the total lever pressing and IRT distributions of ethanol and acetaldehyde treated rats were not significantly affected when these drugs were administered i.c.v. across a very broad range (31–776 ␮g) of doses (Arizzi et al., 2003; McLaughlin et al., 2008). On the other hand, the DRL 30 s schedule produces a low rate of responding and is sensitive to rate increasing effects of drugs. For example it has been shown to be extremely sensitive to the stimulant properties of amphetamine, caffeine and ephedrine (Michaelis et al., 1987). Ethanol i.c.v. produced an inverted “U” shaped dose–response curve (Arizzi et al., 2003). However, acetaldehyde increased lever pressing rate over a broader dose range (31–247 ␮g i.c.v.) than ethanol (Arizzi et al., 2003). As with ethanol, higher doses of acetaldehyde failed to have either rate-increasing or rate-decreasing effects on DRL responding (Arizzi et al., 2003). Thus, in contrast with what is found under a FR5 schedule when the drugs were injected peripherally (Chuck et al., 2006; McLaughlin et al., 2008), neither i.c.v. ethanol nor acetaldehyde had any suppressant effects on lever pressing in the dose range tested in the DRL or in the FR5 (Arizzi et al., 2003). In fact, both substances acted as stimulants. Thus, the route of administration is a key component of the motor effects for both ethanol and acetaldehyde; peripherally both substances suppress motor parameters and acetaldehyde is significantly more potent. However, centrally administered, acetaldehyde and its parent compound produce mainly stimulation, and they are more similar in potency. 3. Brain nuclei involved in acetaldehyde modulation of behavior The neuroanatomy of acetaldehyde mediated behavioral effects is largely unknown. The very few published studies that have assessed the impact of local modifications of the enzymatic systems involved in acetaldehyde formation or degradation so far have studied nuclei traditionally linked to ethanol effects. Thus, local administration of acetaldehyde has generally targeted nuclei related to the motor and motivationally activating effects of ethanol. Among the enzymatic studies, the cerebellum has been one of the nuclei that has received greater attention. It is well known that chronic ethanol consumption can cause degenerative changes in the cerebellum, especially in the cerebellar vermis, thus affecting cerebellar functions such as motor coordination or motor learning. More than 40% of alcoholic patients have some sort of cerebellar atrophy (Sullivan et al., 1995) and this damage has been linked to acetaldehyde formation in the brain (FornFrías and Sanchis-Segura, 2003). In patients with chronic ethanol intoxication an induction of ALDH 2 has been detected in Purkinje cells, basket neurons, and in the microvascular endothelium of cerebellar cortex (Konovko et al., 2004). As in humans, in rodents, after prolonged ethanol exposure, degenerative changes have also been found in the cerebellar cortex (Rintala et al., 1997). Purkinje cells contain the highest percentage of low-Km ALDH 2 in the rat brain (Zimatkin et al., 1992), and a significant formation of protein-acetaldehyde adducts has been detected in the granular (Upadhya and Ravindranath, 2002) and molecular layers of the cerebellum (Rintala et al., 2000), suggesting that acetaldehyde can be locally formed. Catalase also appears to be involved in this process. Accumulation of acetaldehyde produced from 50 mM ethanol

in rat brain homogenates seems to be maximal in the cerebral hemispheres and cerebellum, while inhibition of this process by the catalase inhibitor, ATZ, is maximal (57%) in the cerebellum (Zimatkin et al., 1998). In in vivo studies, chronic systemic acetaldehyde administration led to shortened time of ethanol induced narcosis, and to activation of catalase in the cerebellum and left hemisphere, which may indicate involvement of this enzyme in the development of metabolic tolerance (Bardina et al., 2003). Another correlate of local acetaldehyde formation in the cerebellum comes from studies of sub-strains of rodents with behavioral differences in response to ethanol or differential preferences for ethanol consumption. Thus, rats resistant to the motor incoordination effects of ethanol (alcohol-resistant or AT rats) have higher ALDH 2 activity in the cerebellar capillaries than alcohol-sensitive (ANT) rats (Zimatkin and Lindros, 1989), suggesting that faster elimination of acetaldehyde correlates with a better control of motor coordination. AA rats with high voluntary alcohol consumption have higher ALDH 2 activity in Purkinje cells and capillary endothelium of the cerebellum as compared to the corresponding structures from the alcohol avoiding ANA rats (Zimatkin and Lindros, 1989). However, in mice the opposite seems to be true. ALDH activity is greater in the cerebellum than in any other cerebral region (about 2-folds higher than in the cortex), and the ALDH 2 activity of the DBA/2 (alcohol avoiding) mice is higher than that of the C57BL/6J (alcohol preferring) mice in all brain regions, but especially in the cerebellum (Yamazaki et al., 1984). Thus, from the enzymatic as well as from the adduct studies, it seems that the cerebellum is a brain structure at which acetaldehyde can be produced from ethanol. However, although behavioral correlates of cerebellar involvement in acetaldehyde actions have not been assessed in detail, it can be hypothesized from the studies with phenotypically different strains of rodents, that fast cerebellar acetaldehyde production and degradation correlates with increased preference for ethanol and reduced motor incoordination and narcosis. More specifically, an increase in acetaldehyde production through catalase (Bardina et al., 2003) positively correlates with an increase in ethanol preference, and with a decrease in measures of sedation. On the other hand, an increase of acetaldehyde clearance mediated by an increase in ALDH 2 activity correlates with a reduced sensitivity to ethanol-induced motor incoordination (Zimatkin and Lindros, 1989) and with an increase in ethanol preference (Zimatkin and Lindros, 1989), although the opposite tendency seems to occur in mice in relation to ethanol preference (Yamazaki et al., 1984). Studies of the behavioral effects of direct acetaldehyde administration in specific nuclei started with experiments targeting the substantia nigra pars reticulata (SNr) (Arizzi-LaFrance et al., 2006). SNr is a station of the basal ganglia circuitry implicated in several types of motor activity, including muscle rigidity, lever pressing, tremor, catalepsy, circling, and locomotion (Correa et al., 2003d; Trevitt et al., 2001, 2002). SNr is one of the two major output nuclei of the basal ganglia (Scheel-Kruger et al., 1981) and it is a brain site at which several neurotransmitter systems interact to regulate motor activity (Scheel-Kruger et al. 1981; Trevitt et al., 2002). Ethanol has been demonstrated to affect the physiology and neurochemistry of SNr neurons (Criswell et al., 1993). This nucleus also is one of the brain areas with the highest concentration of catalase (Brannan et al., 1981), suggesting that SNr may be an important brain locus at which local acetaldehyde injections would modulate locomotor activity. In Sprague-Dawley rats it was found that infusions of ethanol or acetaldehyde (15.4–123.3 ␮g) directly into SNr resulted in a robust increase of locomotion as assessed in stabilimeter cages (Arizzi-LaFrance et al., 2006). Moreover, while ethanol produced a biphasic effect, the highest dose of acetaldehyde (123.3 ␮g) was the most effective one at inducing locomotion. The induction of locomotion produced by intranigral

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administration of ethanol (61.7 ␮g) was blocked by peripheral administration of sodium azide at a dose that inhibits catalase activity, suggesting that the transformation of ethanol by catalase in the SNr, and hence the presence of acetaldehyde, is a plausible mechanism for the induction of locomotion observed after central ethanol administration. Another brain region which has one of the highest levels of catalase expression (Moreno et al., 1995; Zimatkin and Lindros, 1996) and very low levels of ALDH 2 (Zimatkin et al., 1992), is the hypothalamic arcuate nucleus (ARH). Such enzymatic profile indicates that in this nucleus acetaldehyde accumulation from ethanol metabolism can take place in substantial amounts. The physiological relevance of the ARH comes from the fact that it is a nucleus with a critical location for integrating neural and endocrine signals, thus regulating homeostatic, motivationally and emotionally regulated sensorimotor functions (Chronwall, 1985). It has been demonstrated that ethanol-induced locomotor changes after either acute (Crabbe and Dorsa, 1986; Sanchis-Segura and Aragon, 2002; Sanchis-Segura et al., 2000) or repeated administration (Miquel et al., 2003) in rodents is clearly dependent on the integrity of the ARH. Moreover, catalase in the ARH seems to play a central role in mediating the behavioral effects of ethanol. Administration of the catalase inhibitor sodium azide directly into the ARH reduced the locomotor suppressant effects of peripherally administered ethanol (1.0 g/kg i.p.) in Sprague-Dawley rats (Sanchis-Segura et al., 2005). In addition, direct administration of ethanol into the ARH had a biphasic effect on rats locomotion in an open field (Pastor and Aragon, 2008). The lowest doses (64–128 ␮g) increase locomotion while the highest dose (256 ␮g) was not different from vehicle. Moreover, systemic inhibition of catalase activity with ATZ suppressed the locomotor stimulation induced by the local injection of ethanol (128 ␮g) into the ARH (Pastor and Aragon, 2008). In line with this last result it has recently been shown that local administration of acetaldehyde (15.4–30.8 ␮g) into the ARH induced locomotion and rearing in an open field also in SpragueDawley rats (Correa et al., 2009b). Acetaldehyde was shown to have a selective effect when injected into the ARH, as injections into a hypothalamic control site dorsal to the ARH did not affect locomotion (Correa et al., 2009b). Comparing these two studies with similar methodology and the same strain of rats (Pastor and Aragon, 2008; Correa et al., 2009b), acetaldehyde injected into the ARH seems to be more potent than ethanol. In fact, the lowest effective dose of ethanol was 64.0 ␮g, while the lowest effective dose of acetaldehyde was 15.4 ␮g. Moreover, ethanol induced locomotion only for the first 5 min after being administered (Pastor and Aragon, 2008), while acetaldehyde was effective at inducing locomotion for 25 min (Correa et al., 2009b). In the last study, acetaldehyde injected into the third ventricle also significantly induced locomotion but the effect lasted only for 5 min. It is likely that the rapid offset of the effects of acetaldehyde injected into the ventricle was due to the rapid diffusion of this substance away from the injection site. The ARH has direct projections to several brain areas, such as the Acb and the VTA (Chronwall, 1985; Herz, 1997), that are thought to be involved in the psychopharmacological effects of ethanol (Gianoulakis, 1990; Herz, 1997; Marinelli et al., 2004; Melis et al., 2007; Rodd et al., 2005; Rodd-Henricks et al., 2002). Moreover, since the ARH is a major site for the synthesis of ␤-endorphins in the telencephalon (Finley et al., 1981; Herz, 1997), which is regulated not only by ethanol but also by acetaldehyde (Reddy and Sarkar, 1993; Reddy et al., 1995; Pastorcic et al., 1994; Marinelli et al., 2004), it has been suggested that acetaldehyde in the ARH can promote release of ␤-endorphins, which would stimulate locomotion through the activation of the mesolimbic dopamine (DA) system (Sanchis-Segura et al., 2005). DA containing neurons originate in the VTA and project, among other structures, to the Acb (Ford et al., 2006; Herz, 1997). Thus, the VTA is a very relevant site

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for the regulation of many components of motor and motivated behaviors. VTA is also rich in catalase (Zimatkin and Lindros, 1996; Hung and Lee, 1998). Thus, ethanol (3.3–61.7 ␮g) and acetaldehyde (11.0 ␮g) have both been demonstrated to increase locomotion in Sprague-Dawley and Wistar rats when injected into the posterior VTA (Correa et al., 2005b; Sanchez-Catalan et al., 2009; MartíPrats et al., 2010). Moreover the induction of locomotion produced by 6.6 ␮g of ethanol or 11.0 ␮g of acetaldehyde was blocked by pre-infusions into the posterior VTA of the non-selective opioid receptor antagonist naltrexone or the selective receptor antagonist ␤-funaltrexamine (Sanchez-Catalan et al., 2009). Stimulation of locomotion by intra VTA administration of ethanol (6.6 ␮g) was also suppressed by d-penicillamine administered i.p. (Martí-Prats et al., 2010). Considering all these data in terms of the locomotion effects, it can be concluded that acetaldehyde administered in the ventricles (lateral or third) induces locomotion, although the minimum doses required to do so are higher (30.8 ␮g) than the minimum doses (1 1.0 ␮g) that need to be injected into discrete brain nuclei such as the SNr, the ARH or the VTA to produce comparable results (Arizzi et al., 2003; Arizzi-LaFrance et al., 2006; Correa et al., 2009b; Sanchez-Catalan et al., 2009). Thus, it seems plausible that acetaldehyde injected into the ventricles is dissolved and transported by the ventricular fluid, rapidly diffusing away from the injection site, and spreading to multiple brain areas through the ventricular system, with only a portion of its content entering into active nuclei. Self-administration studies with direct infusion of acetaldehyde into the VTA have demonstrated that acetaldehyde is a more potent reinforcer than ethanol when injected into the posterior VTA of Alcohol Preferring (P) rats (McBride et al., 2002; Rodd-Henricks et al., 2002; Rodd et al., 2005). Interestingly, Wistar and P rats self-administer ethanol (17–66 mM) in the posterior but not in the anterior VTA (Gatto et al., 1994; RoddHenricks et al., 2002; Rodd et al., 2005). Acetaldehyde injected into the posterior VTA maintains self-administration during 8 sessions with an inverted U-shaped dose–response curve and at lower concentrations (6–90 ␮M) than ethanol (Rodd-Henricks et al., 2002). The animals discriminated between the active and inactive levers and showed extinction when acetaldehyde 90 ␮M was substituted by artificial cerebrospinal fluid (aCSF), and gradually reinstated active lever responding when acetaldehyde was reintroduced. However, self-administration of 33 mM ethanol was not altered by co-infusion of the catalase inhibitor ATZ (Rodd et al., 2005). Nevertheless, in that study ATZ was co-administered with ethanol and this may represent a potential methodological confound since ATZ is a noncompetitive inhibitor that requires 3–5 h to produce its effects on catalase. Thus, although the self-administration sessions lasted 4 h it is possible that the inhibition did not occur early enough to have significant cumulative effects on blocking ethanol conversion into acetaldehyde. Ethanol and acetaldehyde, injected into the VTA, seem to have mechanisms for promoting self-administration that are somehow independent since co-infusion of a 5-HT3 receptor antagonist only decreased ethanol self-administration but not acetaldehyde, while co-infusion of a DA D2 /D3 receptor agonist produced a decrease in self-administration of both drugs (Rodd et al., 2005). 4. Modulation of neurotransmitter release by acetaldehyde Since the mid ’80 there has been an exponential growth in brain microdialysis studies aimed at exploring the wide array of effects that drugs can have on neurotransmitter release in vivo (thoroughly reviewed by Di Chiara et al., 1996a). Acetaldehyde has not escaped this fate and a significant number of studies aimed at addressing the role of acetaldehyde in modulating neurotransmitter release are present in the literature. In the present review, we will restrict our analysis mainly to the studies on the effects of acetaldehyde

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on DA neurotransmission (i) because of the vast literature on the effects of ethanol on this measure; (ii) because a great deal of evidence comes from experiments in which the role of acetaldehyde or ethanol metabolism was assessed using the DA-mediated effects of ethanol; and (iii) because DA is a neurotransmitter that many researchers think is critically involved in the motivational properties of drugs. The first report on the effect of acetaldehyde on DA transmission in the Acb in vivo was published by Ward et al. (1997) in a study that presented a detailed analysis of the effects of i.p. administered acetaldehyde (20 and 100 mg/kg) on DA, serotonin, GABA, glutamate, aspartate and taurine release in rats. Unfortunately, this study fails to convincingly demonstrate clear effects of acetaldehyde on neurotransmitter release, mostly as a consequence of the inconsistent time-course of the effects on these neurotransmitters. Extracellular levels of DA were significantly affected at 20, 80 and 120 min after the dose of 20 mg/kg i.p., whereas after the dose of 100 mg/kg i.p. significance was reached at 40 and 80 min; similarly, serotonin release was significantly decreased after the lower dose at 80 and 120 min and at 40, 60 and 120 min after the higher dose. Therefore, these results appear inconsistent firstly from a methodological point of view since, given the short half-life of acetaldehyde, one would reasonably expect that its effects on DA and serotonin release would have been restricted to the initial time points of their time course. In addition, the observation of decreases in extracellular DA and serotonin after acetaldehyde administration are in sharp contrast with the time-course of the effects of ethanol on Acb DA, which reportedly causes significant increases in extracellular DA at least 20 and 40 min after ethanol i.p. (Di Chiara and Imperato, 1986; Yan, 1999; Yoshimoto et al., 1992, 2000) or i.v. (Howard et al., 2008) administration. Interestingly, the observations reported by Ward et al. (1997) have been partially confirmed, to our knowledge, only by one study reporting that Acb DA neurotransmission is decreased when the administration of acetaldehyde (0.16 mg/kg i.p.) follows 180 min after injection of 0.3 mg/kg i.p. nicotine (Sershen et al., 2009). However, considering nicotine’s short half-life, one might suspect that in the study by Sershen et al. (2009) acetaldehyde was administered when nicotine was largely absent. Furthermore, these measurements of DA neurotransmission were obtained by pooling four, five and six 30 min samples, respectively, as pre-drug baseline before nicotine, as after nicotine and as after acetaldehyde samples (Sershen et al., 2009). Unfortunately, this sampling procedure has certainly resulted in blunting temporal resolution, which is highly desirable in microdialysis experiments, thus reducing any potential impact of the study. In contrast to the Ward et al. (1997) and Sershen et al. (2009) studies, in which no distinction was made between the anatomically and functionally diverse shell and core regions of the Acb (Heimer et al., 1991; Di Chiara, 2002), Melis et al. (2007) and Enrico et al. (2009) have found that i.g. administration of acetaldehyde increased AcbSh DA transmission. In particular, DA transmission was increased significantly at the first (15 min) and second (30 min) samples after acetaldehyde (20 mg/kg i.g.) administration, and returned to baseline within 1 h. Further insights into the mechanism by which acetaldehyde stimulates DA transmission in the AcbSh is provided by the observation that focal application by reverse dialysis of acetaldehyde (75 ␮M for 15 min) into the VTA increased DA transmission in the AcbSh in a manner similar to that after its i.g. administration (Melis et al., 2007). This latter observation is in agreement with previous work from the same group reporting that i.v. administration of cumulative doses of acetaldehyde (5, 10 and 20 mg/kg) to urethane anesthetized rats increased the firing rate and spike frequency of identified DA neurons in the VTA (Foddai et al., 2004). When these authors compared the effects of i.v. acetaldehyde with those of i.v. ethanol on firing properties of DA neurons (Foddai et al., 2004; Enrico et al., 2009; Gessa et al., 1985), they found striking similarities. Moreover, the increases of

firing rate, burst firing and spike/bursts induced by ethanol could be prevented by systemic pre-treatment with 4MP and with dpenicillamine or l-cysteine (Foddai et al., 2004; Enrico et al., 2009; Sirca et al., 2011). Thus, these studies provide a clear demonstration that the stimulatory effects of acetaldehyde on DA transmission in the AcbSh are mediated through the activation of firing properties of DA neurons in the VTA (Foddai et al., 2004; Melis et al., 2007; Enrico et al., 2009). Interestingly, the characteristic property of stimulating DA transmission preferentially in the AcbSh compared to the core (AcbC) by addictive drugs (Pontieri et al., 1995; Howard et al., 2008) has been suggested as the common neurochemical trait that distinguishes drugs with from drugs without addictive potential (Di Chiara, 2002). In this regard it is unfortunate that the studies by Melis et al. (2007) and Enrico et al. (2009) lack of investigating the effects of acetaldehyde on AcbC DA as well as on other extended amygdala nuclei. Finally, although the differences between the studies by Ward et al. (1997) and Sershen et al. (2009), on the one hand, and those by Melis et al. (2007) and Enrico et al. (2009) on the other, appear contradictory one might remember that sampling DA from the Acb with no distinction between shell and core may provide very different, possibly contradictory, results. Overall, the results of these studies indicate that acetaldehyde modulates DAergic function in the mesolimbic pathway and this may be highly relevant for the motivational properties of acetaldehyde. In agreement with this observation, we recently reported that acetaldehyde (20 mg/kg i.g.) elicits CPP and that this is prevented by blockade of DA D1 receptors (Spina et al., 2010). Furthermore, the involvement of DA transmission in the effects of acetaldehyde is strongly suggested by the evidence provided by intracranial self-administration studies for at least two main reasons. First, P rats self-administered acetaldehyde in the posterior portion of the VTA (Rodd-Henricks et al., 2002), the region of origin of DA projections to the shell of the Acb (Ford et al., 2006). Second, the involvement of DA has been directly demonstrated with the use of the DA D2 /D3 receptor agonist, quinpirole, coinfused with acetaldehyde or ethanol in the posterior VTA (Rodd et al., 2005) of P rats. Administered locally into the VTA, quinpirole activates somatodendritic autoreceptors and reduces neuronal activity of DAergic neurons (Centonze et al., 2002). Interestingly, co-infusions of 23 ␮M acetaldehyde with 100 ␮M quinpirole significantly reduced the responses on the active lever (Rodd et al., 2005). As mentioned above, the studies on in vivo neurotransmitter release elicited by acetaldehyde also focused on excitatory (glutamate and aspartate) and inhibitory (GABA and taurine) aminoacids. Ward et al. (1997) reported that two doses of acetaldehyde (20 and 100 mg/kg i.p.) did not affect glutamate, aspartate and GABA in the Acb, while they could briefly (only at the first sample) increase taurine neurotransmission. However, Kashkin and De Witte (2004) in a recent study examined the effects of acetaldehyde (20 and 100 mg/kg i.p.) on glutamate and taurine neurotransmission in the Acb but found no effects. This latter study also compared the effects of ethanol administered with or without ATZ pre-treatment on glutamate and taurine transmission in the Acb and, in contrast with the effect of acetaldehyde, found that acetaldehyde’s parent compound increased it in both conditions (Kashkin and De Witte, 2004). Finally, acetaldehyde (20 and 100 mg/kg i.p.) was reported to decrease (at both doses) glutamate and to increase (at the higher dose) taurine, but failed to affect GABA transmission assessed in the rat anterior cingulate cortex (Zuo et al., 2007). In summary, studies of the effects of acetaldehyde on neurotransmitter release in vivo suffer because of the inconsistency of the results on one hand, and because of methodological limitations on the other. The most clear-cut evidence originates from the studies that investigated the effects of acetaldehyde, administered systemically (i.g.) or into the VTA, on DA transmission specifically on AcbSh. This evidence

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indicates that acetaldehyde increases AcbSh DA transmission, and that at least some of the actions of ethanol on DA VTA neurons and on DA release in the AcbSh are mediated by acetaldehyde. 5. Acetaldehyde and the opioid system A large number of studies suggest that the endogenous opioid system plays a key role in the effects of ethanol (Di Chiara et al., 1996b; Herz, 1997; Gianoulakis, 2009) and this seems also to apply to acetaldehyde. Already more than 30 years ago Smith (1975) reported that acetaldehyde competitively inhibits the oxidation of ALDH substrates. As a consequence biogenic amines can be converted into increasing quantities of aldehydes, which in condensation reactions with intact amines may yield tetrahydropapaverolines (THPs). These compounds are closely related to precursors of opioids and this evidence was seen as a link between ethanol abuse and the opioid system (Gianoulakis, 2009). In this regard, it was suggested that ethanol may act at the enkephalinergic receptor level also through condensation by-products such as salsolinol (see also below section 7), the product of a direct cyclization between DA and acetaldehyde (Lucchi et al., 1982). In particular, the changes induced by chronic ethanol and salsolinol on the enkephalinergic system could be attributed to a decrease of the affinity of the receptor for its ligand and to a down-regulation process due to the continuous opiate receptor stimulation that might occur after ethanol administration (Lucchi et al., 1982). Interestingly, more robust evidence for a possible role of the opioid system in the effects of acetaldehyde was provided in Myers’ laboratory (Myers et al., 1984b) by showing that the opioid antagonist, naloxone, could decrease acetaldehyde i.v. self-administration without having any effect on rats’ spontaneous activity. On the other hand, buprenorphine, the mixed agonist–antagonist derived from the opium alkaloid thebaine, also produced a significant decrease in acetaldehyde self-administration, but this effect on barpressing could not be dissociated from a possible involvement of buprenorphine’s effects on motor responding (Myers et al., 1984b). Thus, although these findings are consistent with the hypothesis of an involvement of the opioid system in acetaldehyde selfadministration, the authors used some caution in their conclusions about the participation of endogenous opiates in this acetaldehydemediated behavior (Myers et al., 1984b). More recently, Reddy et al. (1995) reported that low doses of ethanol and acetaldehyde enhanced immunoreactive ␤-endorphin secretion from fetal hypothalamic neurons in primary culture. Pretreatment of these cultures with the catalase inhibitors, 3-ATZ or sodium azide, caused an inhibition of ethanol-stimulated immunoreactive ␤-endorphin secretion. These blockers could prevent the production of acetaldehyde from ethanol, and also ethanol-induced immunoreactive ␤-endorphin secretion strongly supporting the suggestion that acetaldehyde mediates part of the ethanol’s stimulatory effect on this parameter. This evidence derived by the action of catalase in ethanol-activated opioid neurotransmission in vitro was a novel finding suggesting that this system is operational in vivo (Reddy et al., 1995). In this regard, it is highly relevant that 10 years later, Sanchis-Segura et al. (2005) proposed a model in which ethanol oxidation via catalase may indeed produce acetaldehyde in the ARH and promote ␤-endorphins release which in turn can be responsible of ethanol-induced behavioral changes and opioid receptors-mediated locomotion (Sanchis-Segura et al., 2005). Accordingly, Pastor and Aragon (2008), more recently, reported that naltrexone and ATZ, while failing to affect spontaneous activity, could prevent intra ARH ethanol-induced locomotor stimulation (Pastor and Aragon, 2008). These results, overall, sustain earlier evidence indicating that the ARH and the ␤-endorphinergic neurons therein are necessary for ethanol to induce stimulation and suggest that brain structures, like the ARH, that are rich in

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catalase may support the formation of ethanol-derived acetaldehyde, at pharmacologically relevant concentrations and, therefore may be of critical relevance for the behavioral effects of ethanol (Zimatkin and Lindros, 1996). In fact, increases of hypothalamic ␤-endorphin release are dependent on the catalasemic conversion of ethanol into acetaldehyde (Zimatkin and Lindros, 1996; Pastor and Aragon, 2008). Interestingly, the ARH is the main site of ␤-endorphin synthesis in the brain and one of the regions with higher levels of catalase expression (Khatchaturian et al., 1985; Zimatkin and Lindros, 1996). More recently, Sánchez-Catalán and colleagues (2009) reported that the posterior VTA is another brain region involved in the opioid-mediated locomotor activation after the intra posterior VTA administration of ethanol or acetaldehyde (Sanchez-Catalan et al., 2009). These data indicate that ␮ opioid receptors could be the target of the actions of these compounds in the VTA (Sanchez-Catalan et al., 2009). Furthermore, Hipólito et al. (2010) hypothesized that salsolinol could be responsible of these effects. In keeping with this possibility, in fact, salsolinolinduced locomotor activity after intra-VTA administration could be decreased by treatment with naltrexone or with the more selective antagonist of ␮ opioid receptors, ␤-funaltrexamine (Hipólito et al., 2010). Finally, a link has been observed between gene expression alterations and selective epigenetic modulation in the pro-dynorphin promoter region demonstrating a specificity of the changes induced by ethanol and acetaldehyde (D’Addario et al., 2010). In fact, these authors, in particular, reported that ethanol and acetaldehyde affect transcription of opioid system genes in human SH-SY5Y neuroblastoma cells suggesting that acetaldehyde could be responsible for the mediation of ethanol effects at the genomic level (D’Addario et al., 2008, 2010). While this review was under revision, we published a study showing a critical role of opioid receptors in the reinforcing effects of acetaldehyde (Peana et al., 2011). This study demonstrates suppressive effects of naltrexone and/or naloxonazine on oral selfadministration of acetaldehyde, but not saccharin. In particular, we found that pretreatment with naltrexone could disrupt acetaldehyde deprivation effects and responding for acetaldehyde under a progressive ratio of reinforcement. In addition, we also found that naltrexone could reduce ERK phosphorylation in the Acb following non-contingent administration of acetaldehyde (20 mg/kg i.g.) (Vinci et al., 2010). These findings further emphasize the critical role of ERK mediated modulation of accumbal function in acetaldehyde’s effects, and provide a set of new data that represent a straightforward demonstration of the opioidergic involvement in acetaldehyde’s self-administration behavior and reinforcing properties (Peana et al., 2011). 6. Intracellular actions of acetaldehyde Based upon the studies reviewed above, it appears that acetaldehyde has mainly been studied for its own behavioral and neurochemical effects, and for its role in mediating the behavioral and neurochemical effects of ethanol. Nevertheless, recent studies have begun to clarify the molecular actions of this compound in the brain. To our knowledge these studies mainly have focused on the role of Extracellular signal regulated kinase (ERK) and DA D1 receptors in the molecular and motivational actions of acetaldehyde and, at the electrophysiological level, on the mechanism by which acetaldehyde excites DA neurons in the posterior VTA. Abundant evidence, accumulated in the last few years, suggests that ERK play a critical role in the central effects of psychoactive compounds. ERK kinases are members of the mitogen activated protein kinases (MAPKs) family that are abundantly present in discrete brain regions and in particular in the DA mesolimbic system and in other nuclei of the extended amygdala (Alheid and Heimer, 1988; Heimer et al., 1991) where they have been related to the

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mechanism of action of addictive drugs (Valjent et al., 2004; Girault et al., 2007). The mechanism by which addictive drugs activate ERK involves both DA D1 and NMDA receptors. Also, the activation by dual phosphorylation of ERK results in cytoplasmic and nuclear events that might regulate behavioral outcomes (Girault et al., 2007). One such behavioral outcome is the ability to elicit CPP (Beninger and Gerdjikov, 2004). Indeed, blockade of ERK phosphorylation by compounds able to inhibit the mitogen activated ERK kinases (MEK), the kinases responsible of ERK phosphorylation, prevents the acquisition of drug-elicited CPP (Valjent et al., 2000; Gerdjikov et al., 2004; Salzmann et al., 2003). As previously discussed, the CPP method has been applied to characterize the motivational properties of acetaldehyde, as well as ethanol metabolism, and recent advances demonstrated that i.g. administration of acetaldehyde resulted in a significant CPP effect (Peana et al., 2008, 2009; Spina et al., 2010). Interestingly, when rats were pre-treated with the MEK inhibitor PD98059 before i.g. administration of acetaldehyde, the acquisition of acetaldehyde-elicited CPP was prevented in a dose- and time-related manner (Spina et al., 2010). These results appear to be fully in agreement with previous studies reporting that blockade of MEK impairs drug (ecstasy, d-amphetamine and cocaine)-elicited CPP (Salzmann et al., 2003; Gerdjikov et al., 2004; Valjent et al., 2000), and suggest that, following acetaldehyde administration, the phosphorylation of ERK takes place in brain regions critical for the acquisition of such conditioned responses. In this regard, we recently demonstrated that after i.g. administration, acetaldehyde (20 mg/kg) induces ERK phosphorylation (Vinci et al., 2010). This activation takes place in the same brain areas, Acb, BSTL and CeA, as following i.g. administration of ethanol (1 g/kg) (Ibba et al., 2009). Interestingly, when rats were pretreated with 4MP or with d-penicillamine, ethanol could not induce ERK activation, suggesting that the metabolic conversion into acetaldehyde is necessary for this action of ethanol (Vinci et al., 2010). Finally, either acetaldehyde (20 mg/kg i.g.)-elicited ERK and acetaldehyde (20 mg/kg i.g.)-elicited CPP appear to be dependent on DA D1 receptors stimulation since blockade of these receptors results in prevention of ERK phosphorylation (Vinci et al., 2010) and acetaldehyde-elicited CPP (Spina et al., 2010). Blockade of DA D1 receptors, however, also reduces the number of pERK positive neurons in the Acb and CeA (Ibba et al., 2009; Vinci et al., 2010) and this observation leaves open the question of whether the prevention of ERK phosphorylation represents the consequence of a functional antagonism rather than the consequence of blockade of postsynaptic D1 receptors in response to increased DA transmission, at least in the AcbSh as the studies by Melis et al. (2007) and Enrico et al. (2009) would suggest. The mechanism of action of acetaldehyde has also been investigated at the cellular level in the posterior VTA with an in vitro approach that addressed both the role of acetaldehyde in the effect of ethanol on electrophysiological properties of DA neurons and, also, its possible mechanism of action. Identified DA neurons in the posterior region of the VTA represent a critical target for addressing the issue of the mechanism of action of acetaldehyde for a number of reasons, extensively discussed earlier in Sections 2.4, 2.5, and 3), related to the enzymatic distribution and behavioral effects of focal administration of acetaldehyde in this area. In addition, since these neurons have been identified as the site of origin of DA projections to the shell region of the Acb (Ford et al., 2006), the effects of acetaldehyde on DA neurons in this area may be related to the neurochemical evidence on the role of acetaldehyde on DA neurotransmission in the AcbSh (Melis et al., 2007; Enrico et al., 2009), and to the behavioral evidence on the role that the DA D1 receptors/ERK pathway plays on the motivational properties of acetaldehyde (Spina et al., 2010; Vinci et al., 2010). In fact, in whole-cell patch-clamp recordings from DA neurons in the rat posterior VTA, ethanol (100 ␮M) stimulates

DAergic firing, and this effect is prevented by bath application of the catalase inhibitor ATZ (1 ␮M) (Melis et al., 2007). Perfusion of the slices with acetaldehyde (0.01–1 ␮M) yields similar results and DA neurons’ spontaneous activity is readily increased up to 237% from baseline (Melis et al., 2007). In addition, the action of acetaldehyde on neuronal excitability was found dependent on IA (A-type) and Ih (hyperpolarization-activated inward) K+ currents. Thus, since both the reduction of A-type and the increase of hyperpolarization-activated K+ (Ih ) currents were prevented by ZD7288 and 4-aminopyridine, respectively, (Melis et al., 2007), these observations strongly point to these ionic mechanisms as potential sites of the cellular actions of acetaldehyde on DA neurons in the VTA. In addition, these experiments further corroborate the in vivo evidence of the action of acetaldehyde on DA neurons in the VTA (Foddai et al., 2004), and converge to indicate that the motivational properties of acetaldehyde may be due to its direct action on DA mesolimbic neurons both at the pre-synaptic (in vivo and in vitro, electrophysiology and microdialysis) and post-synaptic (ERK phosphorylation in target neurons) levels. Acetaldehyde has also been shown to increase c-fos and c-jun gene expression in rat fat-storing cell culture via protein kinase C regulatory mechanisms (Casini et al., 1994). The induction of Fos/Jun families of transcription factors has been widely used as a tool to show activation of neurons and neuronal pathways in response to a wide range of stimuli (Curran and Morgan, 1995). Ethanol exposure throughout different routes of administration induces early-gene protein expression in several brain regions (Ogilvie et al., 1998; Bachtell et al., 1999; Thiele et al., 2000; Knapp et al., 2001; Crankshaw et al., 2003), and such expression reflects specific activation of brain pathways (Curran and Morgan, 1995; Thiele et al., 2000). Inhibition of brain catalase activity with ATZ (1 g/kg i.p.) was demonstrated not to alter ethanol (1.0, 2.5 and 4.0 g/kg i.p.)-evoked dose-dependent increases of c-fos expression in several brain regions of Sprague-Dawley rats, such as the nucleus of the solitary tract (NTS), the parabrachial nucleus (PBN), the paraventricular/parafascicular nuclei of thalamus (ThPV/PF), the Acb and the CeA (Canales, 2004). This lack of effects after blockade of centrally generated acetaldehyde suggests that ethanol rather than acetaldehyde triggers these neuronal changes. However, these results seem to be different when blood acetaldehyde is accumulated after the co-administration of ethanol and the ALDH 2 inhibitor cyanamide in rats (Kinoshita et al., 2002). A low dose of ethanol (1 g/kg i.p.) alone did not increase c-fos expression in the paraventricular nucleus of the hypothalamus (HPV). However, the combination of cyanamide (50 mg/kg i.p.) and this low dose of ethanol resulted in a significant increase in c-fos mRNA in this hypothalamic nucleus. The high dose of ethanol (3 g/kg i.p.) resulted in a significant increase in c-fos mRNA, and this stimulation appeared to be maximal as there was no further increase in c-fos expression in the presence of cyanamide (Kinoshita et al., 2002). Studies of direct administration of acetaldehyde (32 mg/kg i.v.) in young male (P27) Sprague-Dawley rats did not find a significant change in c-fos expression in the HPV, CeA, AcbSh, superior colliculus (SC) or BSTL. Only ThPV c-fos mRNA expression was increased by this dose of acetaldehyde (Cao et al., 2007). The authors suggested that such induction was possible because this dorsal thalamic region is minimally protected by the BBB (Ueno et al., 2000) (see Section 2.3). Studies of central i.c.v. acetaldehyde administration (Segovia et al., 2009) have yielded a clearer picture of on c-fos expression. Ethanol and acetaldehyde produce a general pattern of c-fos induction at doses able to stimulate motor behaviors that were similar in magnitude for both compounds. Thus, a dose of 2.8 ␮moles i.c.v. of either ethanol or acetaldehyde significantly increased c-fos expression to the same extent in VTA, AcbSh and Ventral Pallidum (VP), although acetaldehyde produced a greater increase than ethanol in substantia nigra pars compacta (SNc),

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dorsomedial (DMS) and ventrolateral (VLS) striatum, AcbC, and motor cortex (Segovia et al., 2009). Peripherally administered acetaldehyde (0.1 and 0.5 g/kg i.p.) was more potent than ethanol (0.5 and 2.5 g/kg i.p.) at inducing Fos in all the above mentioned structures (Segovia et al., 2009). In summary, it seems that some nuclei are sensitive to central and peripheral acetaldehyde administration and accumulation by ALDH inhibitors, although the absence of centrally formed acetaldehyde seems not to change c-fos expression induced by ethanol. 7. Beyond acetaldehyde: acetaldehyde’s adducts Acetaldehyde has been reported to interfere with monoamines metabolism through its in vivo and in vitro inhibitory actions on ALDH (Lahti and Majchrowicz, 1967, 1969; Walsh et al., 1970), on monoamine-oxidases (Nakahara et al., 1994; Naoi et al., 2004) and on cathecol-O-methyl transferases (Giovine et al., 1976). These properties result in an interference with the mechanisms of disposition of the intermediate oxidative by-products of endogenous monoamines and, on the other hand, determine the production of tetrahydroisoquinoline alkaloids such as tetrahydropapaveroline (THP) or norlaudanosoline obtained by condensation between DA and its oxidation product, dopaldehyde (3,4-dihydroxyphenilacetadehyde) (DOPAL) (Davis et al., 1970). The condensation between ␤-aryl-ethyl-amines and carbonyl compounds, known as Pictet-Spengler condensation, a reaction that spontaneously takes place also in plants, is particularly relevant when acetaldehyde condenses with DA to produce salsolinol. This condensation, which is an example of the Mannich reaction, has also been used in the past to histochemically detect monoamines in the nervous tissue following exposure to vapors of formaldehyde. As previously discussed (see Section 5) the discovery of salsolinol (Yamanaka et al., 1970) led to the suggestion in the early ’70s that this alkaloid might be at the basis of alcohol addiction (Davis and Walsh, 1970; Davis et al., 1970), a suggestion further corroborated, in subsequent years, by the discovery that salsolinol is also present in beers and other alcoholic (and non-alcoholic) beverages (Duncan and Smythe, 1982; Carlson et al., 1985). Intriguingly, the presence of salsolinol in the brain can be derived independently from the non-enzymatic condensation source mentioned above, since it can also be enantio-specifically synthesized as R-salsolinol by the enzyme salsolinol synthase in mammalian organisms (Naoi et al., 1996, 2004). In this regard it is noteworthy that significant concentrations of R-salsolinol have been found in plasma (Baum and Rommelspacher, 1994), cerebrospinal fluid, and brains of alcoholic and non-alcoholic individuals (Moser and Kompf, 1992; Ung-Chhun et al., 1985). Salsolinol and THP thus might be regarded as direct and indirect acetaldehyde condensation products, respectively, and the improvements in modern analytical methods together with a body of experimental evidence indicate that both molecules represent useful lines of research. In this regard, one line of evidence originated from the observations that salsolinol and THP can be detected, respectively, in the rat brain after contingently self-administered acetaldehyde (Myers et al., 1985a,b; Cashaw, 1993) and noncontingently administered ethanol. In the Myers et al. (1985b) study, significant concentrations of salsolinol were detectable after i.v. self-administration of acetaldehyde (2.32 mg/kg/injection), but not ethanol (44.33 mg/kg/infusion), although these authors found detectable salsolinol concentrations in the brain of rats chronically treated with ethanol in another study (Myers et al., 1985a). Interestingly, acetaldehyde, but not ethanol, was reported to be self-administered i.c.v. (Brown et al., 1979); however, since a number of reasons may help explain these contrasting results between studies, as has been thoroughly discussed in this review, it is reasonable to suggest that ethanol also can determine a rise of salsolinol concentrations in the Acb

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following its acute administration (Sällström Baum et al., 1999). In fact, differential effects have been reported on salsolinol and THP concentrations in the Acb following acute ethanol (2 g/kg i.p.) administration (Sällström Baum et al., 1999). Thus, while THP, Rsalsolinol and S-salsolinol basal dialysate concentrations could be detected, ethanol administration significantly increased Acb THP dialysate both in AA and ANA rats, but failed to affect salsolinol (both enantiomers) concentrations (Sällström Baum et al., 1999). These results are partially in agreement with studies reporting that salsolinol concentrations could be detected in the dialysates only when ethanol was co-administered with the ALDH 2 inhibitor cyanamide (Jamal et al., 2003a,b). Interestingly, though, when acetaldehyde was locally applied in the striatum by reverse dialysis at high (1000 ␮M) but not low (250–500 ␮M) concentrations, salsolinol concentration was significantly raised, while the DA signal was dose-dependently reduced (Wang et al., 2007). A second line of evidence originates from a different approach that circumvents answering the question of how much salsolinol is detectable in the body and brain following ethanol or acetaldehyde administration. In a recent study Rodd et al. (2008) determined whether exogenously self-administered salsolinol would be able to exert any motivational effect. These authors demonstrated that ethanolnaïve Wistar rats learn to self-administer salsolinol (0.03–0.3 ␮M) into the posterior VTA. Thus, while from the above studies it might appear questionable whether or not salsolinol is detectable in the brain following ethanol or acetaldehyde administration, it is clear that salsolinol per se is able, when administered locally in the posterior VTA (Rodd et al., 2008), and also in the AcbSh of alcohol preferring P rats (Rodd et al., 2003), to support the acquisition and maintenance of self-administration behavior. This property of (racemic) salsolinol, applied locally by reverse dialysis, might be related to the ability of stimulating DA transmission in the striatum (Nakahara et al., 1994; Maruyama et al., 1992) and of depressing monoamine metabolism (Antikiewicz-Michaluk et al., 2000). Such interpretation, on the other hand, is hampered by the recent observation that local application of salsolinol (0.1–25 ␮M) by reverse dialysis in the AcbSh and AcbC resulted in differential effects on DA transmission (Hipólito et al., 2009). In particular, this study reported that DA neurotransmission is increased in the AcbC but decreased in the AcbSh following local application of salsolinol. This observation is apparently in contrast to the role attributed to shell DA in the motivational properties of drugs (Di Chiara, 2002), and suggests that local mechanisms in the AcbSh may have an opposite control on salsolinol-mediated DA transmission with respect to intra-VTA or systemic acetaldehyde administration (Melis et al., 2007). However, Hipólito et al. (2009) suggested that the mechanism by which salsolinol exerts such differential effects on DA transmission in the shell and core of the Acb could be related to an action on ␮ opioid receptors in these Acb subregions (Hipólito et al., 2008). This possibility might be in agreement with other studies demonstrating a role for ␮ opiod receptors in salsolinol-elicited CPP (Matsuzawa et al., 2000) and locomotor stimulant effects (Hipólito et al., 2010). In conclusion, while it seems unequivocal that acetaldehyde adducts (salsolinol and THP, in particular) exert relevant behavioral and neurochemical actions, and that these effects might be related to acetaldehyde formation and presence in active sites within discrete brain regions, this research avenue still awaits new studies with advanced methods to clarify the relationship between acetaldehyde, salsolinol and THP, their reciprocal influences, and their respective behavioral effects. 8. Beyond acetaldehyde: the role of ALDH in addiction The hypothesis that THP may contribute to ethanol consumption and addiction, which was questioned (Halushka and Hoffman,

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1970) shortly after its appearance (Davis and Walsh, 1970), has been evaluated several times since (Cashaw and Geraghty, 1991; Cashaw, 1993; McCoy et al., 2003; Myers, 1990; Privette and Myers, 1989). Clear cut evidence, however, on the role of this adduct has never been reached. Indeed, the question whether THP plays a role in ethanol consumption has remained unanswered since either a favourable effect on ethanol consumption (McCoy et al., 2003; Myers et al., 1982b) and a preventive effect on ethanol intake (Smith et al., 1980; McCoy et al., 2003) have been documented. However, despite such uncertainty on the role of THP in ethanol intake, a new and somewhat unexpected role for this adduct has recently emerged. In the present review we have being discussing so far the role of ALDH in light of acetaldehyde’s contribution to ethanol effects, but recent evidence indicates a critical role for THP and ALDH inhibition in cocaine self-administration (Yao et al., 2010) and in cocaine dependence (Carroll et al., 2004). In fact, besides being primarily involved in ethanol metabolism, ALDH also plays an important role in the conversion of DOPAL, a DA metabolite, into dihydroxyphenilacetic acid (DOPAC) (Marchitti et al., 2007); DOPAL, after ALDH inhibition, accumulates and can condensate with DA to form THP. Interestingly, THP is a tyrosine hydroxylase (TH) inhibitor (Kim et al., 2005) even more potent than the classical TH inhibitor, ␣-methylp-tyrosine, with half-maximal inhibitory concentrations of 3.8 ␮M for the unphosphorylated form of TH and of 50 nM for the phosphorylated (activated) one (Yao et al., 2010). Thus, the finding that CVT-10216, a selective ALDH inhibitor, could reduce i.v cocaine selfadministration and methamphetamine-induced reinstatement and decrease cocaine-elicited DA production (Yao et al., 2010) was interpreted to mean that increasing THP formation would in turn decrease state-dependent TH activity, and therefore prevent DAmediated behaviors related to addiction. Although this is not conclusive (see, in this regard, the commentary by Weinshenker, 2010) the evidence provided by the study of Yao et al. (2010), together with the finding that ALDH inhibition prevents ethanol seeking also in the absence of acetaldehyde (Arolfo et al., 2009; Keung et al., 1995), opens new and exciting avenues of research on therapeutic approaches to addiction, and places THP and ALDH inhibitors at the crossroads between alcoholism (Arolfo et al., 2009) and cocaine dependence (Carroll et al., 2004; Gaval-Cruz and Weinshenker, 2009) treatment.

of methodologies that may allow convergence towards a common set of conclusions. In considering all these results, it is important to distinguish between the central versus the peripheral effects of acetaldehyde. While peripheral administration of acetaldehyde induces effects that resemble the results of peripheral inhibition of ethanol metabolism by blockade of ALDH, the central effects of acetaldehyde can be quite different, and produce actions that are consistent with studies involving manipulation of central ethanol metabolism by affecting catalase activity. This important distinction between the central and the peripheral effects of acetaldehyde lays the groundwork for considering that many of the putative central effects of ethanol administration could in fact depend upon the actions of its first metabolite, acetaldehyde. Thus, the seemingly contradictory results observed among the clinical literature on human populations with the less active ALDH 2*2 enzyme, or those treated with ALDH inhibitors, can be understood by looking through a different prism. Although peripherally accumulated acetaldehyde is a potential toxic and deterrent substance, high levels of this substance then can reach the brain and generate perceived positive effects that can promote later consumption. Those subjects in whom the aversive peripheral physiological response overrides the central mood enhancing effects will be protected from the development of alcoholism. However, if the positive central effects are more salient, those subjects with less active ALDH 2 not only may lack protection, but they also may be at risk of excessive alcohol consumption. Acknowledgements This work was supported by grants to M. Correa from Fundació Bancaixa/U. Jaume I. (P1A2007-15) and Plan Nacional de Drogas (2010I024) and to E. Acquas from the Italian Ministero dell’Istruzione, Università e Ricerca (PRIN 2006057754 002), Fondazione Compagnia di San Paolo (Turin, Italy) – Bando Neuroscienze 2008, and Fondazione Banco di Sardegna (Sassari, Italy). Authors gratefully thank Prof. M.G. Corda (Department of Toxicology, University of Cagliari, Italy) and Prof. G. Zernig (Department of General Psychiatry and Social Psychiatry, Medical University Innsbruck, Austria) for critical reading and helpful suggestions on an early draft of the manuscript.

9. Summary

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The present review summarizes 40 years of preclinical studies focusing on the behavioral impact of the ethanol metabolite acetaldehyde, and its possible mechanism of action in the brain. The “acetaldehyde hypothesis” has been continuously questioned because of lingering concerns about the measurement of brain acetaldehyde levels, but mostly due to several persistent ideas in the field related to the toxic nature of this compound, the lack of a feasible enzymatic machinery capable of transforming ethanol into acetaldehyde in the brain, and the inability of peripheral acetaldehyde to cross the BBB. This review attempts to summarize the evidence gathered by many groups from different countries that support the idea that acetaldehyde is indeed a centrally active and behaviorally relevant metabolite of ethanol. This conclusion is based partly on studies involving enzymatic manipulations of the ethanol and acetaldehyde metabolizing systems, and also on those involving the effects of direct administration of acetaldehyde. These two basic methodological approaches are very different, and there are laboratories that reject the data obtained with one or the other. One of the goals of the present review is to make clear what type of results these approaches have achieved and to demonstrate that both of them have strengths and weaknesses. Fortunately, recent evidence from several laboratories integrates both types

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