Mutations in mitochondrial aldehyde dehydrogenase (ALDH2) change cofactor affinity and segregate with voluntary alcohol consumption in rats

Sapag, Amalia; Tampier, Lutske; Valle-Prieto, Araceli; Quintanilla, Marı́a Elena; Moncada, Claudio; Israel, Yedy

doi:10.1097/00008571-200308000-00009

Cited by 22 publications

(11 citation statements)

References 24 publications

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“…Thus, Aldh2 2 and Aldh2 3 are specific for low and high drinkers, respectively, in these lines. The Aldh2 3 allele codes for arginine-67 but also contains a second point mutation that changes glutamic-479 into lysine-479 (17). These point mutations in rat Aldh2 are different from those in human ALDH2 (Glu-487 into Lys-487) (18,19).…”

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confidence: 98%

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Complex I regulates mutant mitochondrial aldehyde dehydrogenase activity and voluntary ethanol consumption in rats

et al. 2005

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Animals selectively bred for a desirable trait retain wanted genes but exclude genes that may counteract the expression of the former. The possible interactions between selected and excluded genes cannot be readily studied in transgenic or knockout animals but may be addressed by crossing animals bred for opposite traits and studying the F2 offspring. Ninety-seven percent of Wistar-derived rats selectively bred for their voluntary low-alcohol consumption display a mutated nuclear allele of aldehyde dehydrogenase Aldh22 that encodes an enzyme with a low affinity for NAD+, whereas rats bred for high-alcohol consumption do not present the Aldh22 allele. This enzyme is inserted into mitochondria, where NADH-ubiquinone oxidoreductase (complex I) regenerates NAD+. The possible influence of complex I on ALDH2 activity and voluntary ethanol intake was investigated. Homozygous Aldh22/Aldh22 rats derived from a line of high-drinker F0 females (and low-drinker F0 males) showed a markedly higher ethanol consumption (3.9=/-0.5 g x kg(-1) x day(-1)) than homozygous animals derived from a line of low-drinker F0 females (and high-drinker F0 males) (1.8+/-0.4 g x kg(-1) x day(-1)). Mitochondria of F2 rats derived from high alcohol-consuming females were more active in oxidizing substrates that generate NADH for complex I than were mitochondria derived from low alcohol-consuming females, leading in the former to higher rates of acetaldehyde metabolism and to a reduced aversion to ethanol. This is the first demonstration that maternally derived genes can either allow or counteract the phenotypic expression of a mutated gene in the context of alcohol abuse or alcoholism

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“…Recently, a mutation in the Aldh2 gene (lower case nomenclature used for rodents) was shown to strongly segregate with voluntary ethanol consumption in Wistar-derived rats (17). Low alcohol-consuming (UChA) rats display a point mutation in the Aldh2 gene that changes glutamine-67 (Aldh2 1 allele) into arginine-67 (Aldh2 2 allele) in the enzyme coded.…”

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confidence: 99%

Complex I regulates mutant mitochondrial aldehyde dehydrogenase activity and voluntary ethanol consumption in rats

et al. 2005

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“…Rats of the UChA line (virtually Abstainer) display a mutation in the aldh2 gene (Sapag et al, 2003; see Quintanilla et al, 2006), which codes for an enzyme with a higher K m for NAD + and a lower Vmax that the ALDH2 of heavy drinker animals (UChB; Bibulous). Further, the levels of arterial acetaldehyde display a large “acetaldehyde burst,” reaching 40–50 μM (vs. 10–20 μM for controls), which deters their alcohol intake (Quintanilla et al, 2005b).…”

Section: Aversive Effects Of Liver-generated Acetaldehydementioning

confidence: 99%

Gene specific modifications unravel ethanol and acetaldehyde actions

Israel¹,

Rivera-Meza²,

Karahanian³

et al. 2013

Front. Behav. Neurosci.

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Ethanol is metabolized into acetaldehyde mainly by the action of alcohol dehydrogenase in the liver, while mainly by the action of catalase in the brain. Aldehyde dehydrogenase-2 metabolizes acetaldehyde into acetate in both organs. Gene specific modifications reviewed here show that an increased liver generation of acetaldehyde (by transduction of a gene coding for a high-activity liver alcohol dehydrogenase ADH1*B2) leads to increased blood acetaldehyde levels and aversion to ethanol in animals. Similarly aversive is an increased acetaldehyde level resulting from the inhibition of liver aldehyde dehydrogenase-2 (ALDH2) synthesis (by an antisense coding gene against aldh2 mRNA). The situation is diametrically different when acetaldehyde is generated in the brain. When the brain ventral tegmental area (VTA) is endowed with an increased ability to generate acetaldehyde (by transfection of liver rADH) the reinforcing effects of ethanol are increased, while a highly specific inhibition of catalase synthesis (by transduction of a shRNA anti catalase mRNA) virtually abolishes the reinforcing effects of ethanol as seen by a complete abolition of ethanol intake in rats bred for generations as high ethanol drinkers. Data shows two divergent effects of increases in acetaldehyde generation: aversive in the periphery but reinforcing in the brain.

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“…The mechanisms leading to alcohol rejection in the virtually abstainer UChA line are mainly related to polymorphisms in nuclear and mitochondrial genes that lead to a slow metabolism of acetaldehyde and to high blood acetaldehyde levels. These UChA studies have been previously described (Sapag et al, 2003; Quintanilla et al, 2005, 2006; Israel et al, 2013) and thus not covered in the present review. Studies conducted in UChB rats are indicated in the text.…”

Section: Introductionmentioning

confidence: 98%

Acquisition, Maintenance and Relapse-Like Alcohol Drinking: Lessons from the UChB Rat Line

Israel

Karahanian

Ezquer

et al. 2017

Front. Behav. Neurosci.

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This review article addresses the biological factors that influence: (i) the acquisition of alcohol intake; (ii) the maintenance of chronic alcohol intake; and (iii) alcohol relapse-like drinking behavior in animals bred for their high-ethanol intake. Data from several rat strains/lines strongly suggest that catalase-mediated brain oxidation of ethanol into acetaldehyde is an absolute requirement (up 80%–95%) for rats to display ethanol’s reinforcing effects and to initiate chronic ethanol intake. Acetaldehyde binds non-enzymatically to dopamine forming salsolinol, a compound that is self-administered. In UChB rats, salsolinol: (a) generates marked sensitization to the motivational effects of ethanol; and (b) strongly promotes binge-like drinking. The specificity of salsolinol actions is shown by the finding that only the R-salsolinol enantiomer but not S-salsolinol accounted for the latter effects. Inhibition of brain acetaldehyde synthesis does not influence the maintenance of chronic ethanol intake. However, a prolonged ethanol withdrawal partly returns the requirement for acetaldehyde synthesis/levels both on chronic ethanol intake and on alcohol relapse-like drinking. Chronic ethanol intake, involving the action of lipopolysaccharide diffusing from the gut, and likely oxygen radical generated upon catechol/salsolinol oxidation, leads to oxidative stress and neuro-inflammation, known to potentiate each other. Data show that the administration of N-acetyl cysteine (NAC) a strong antioxidant inhibits chronic ethanol maintenance by 60%–70%, without inhibiting its initial intake. Intra-cerebroventricular administration of mesenchymal stem cells (MSCs), known to release anti-inflammatory cytokines, to elevate superoxide dismutase levels and to reverse ethanol-induced hippocampal injury and cognitive deficits, also inhibited chronic ethanol maintenance; further, relapse-like ethanol drinking was inhibited up to 85% for 40 days following intracerebral stem cell administration. Thus: (i) ethanol must be metabolized intracerebrally into acetaldehyde, and further into salsolinol, which appear responsible for promoting the acquisition of the early reinforcing effects of ethanol; (ii) acetaldehyde is not responsible for the maintenance of chronic ethanol intake, while other mechanisms are indicated; (iii) the systemic administration of NAC, a strong antioxidant markedly inhibits the maintenance of chronic ethanol intake; and (iv) the intra-cerebroventricular administration of anti-inflammatory and antioxidant MSCs inhibit both the maintenance of chronic ethanol intake and relapse-like drinking.

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Mutations in mitochondrial aldehyde dehydrogenase (ALDH2) change cofactor affinity and segregate with voluntary alcohol consumption in rats

Cited by 22 publications

References 24 publications

Complex I regulates mutant mitochondrial aldehyde dehydrogenase activity and voluntary ethanol consumption in rats

Complex I regulates mutant mitochondrial aldehyde dehydrogenase activity and voluntary ethanol consumption in rats

Gene specific modifications unravel ethanol and acetaldehyde actions

Acquisition, Maintenance and Relapse-Like Alcohol Drinking: Lessons from the UChB Rat Line

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