Monoamine metabolism and behavioral responses to ethanol in mitochondrial aldehyde dehydrogenase knockout mice.

BACKGROUND It is widely accepted that, in addition to removing acetaldehyde produced during the metabolism of ethanol, mitochondrial aldehyde dehydrogenase (ALDH2) functions in the pathway by which aldehyde metabolites of the monoamines dopamine (DA) and serotonin (5-HT) are converted to their acidic metabolites. Moreover, studies of ALDH2 inhibitors used for treating alcoholism suggest that their antidipsotropic effects may be related to inhibition of monoamine metabolism. Therefore, we examined the hypothesis that altered brain monoamine metabolism is related to the influence of ALDH2 on behavioral responses to ethanol. METHODS Mice were generated with a gene-trap mutation of the ALDH2 gene. ALDH2 mRNA was absent in ALDH2-/- mice. Western blot analysis of liver mitochondria confirmed the absence of ALDH2 protein in the ALDH2-/- mice. Wild-type and ALDH2-deficient mice were tested for the effects of different doses of ethanol on locomotor activity, ataxia, and a 2-bottle ethanol-water preference test. RESULTS Wild-type and ALDH2+/- mice preferred ethanol to water. However, ALDH2-/- mice drank significantly less ethanol than wild-type or ALDH2+/- mice. Locomotor activity and ataxia were significantly more affected by ethanol in ALDH2-/- mice than in wild-type or ALDH2+/- mice. There was no effect of genotype on levels of 5-HT, DA, or their precursors or metabolites in several brain regions, as measured by HPLCec. CONCLUSIONS The results indicate that: (1) the effect of the mutant genotype on behavioral responses to ethanol is unrelated to altered brain monoamine metabolism and (2) ALDH2 is not required for the metabolism of brain monoamines in vivo.

[1]  J. Salamone,et al.  Motor Stimulant Effects of Ethanol Injected into the Substantia Nigra Pars Reticulata: Importance of Catalase-Mediated Metabolism and the Role of Acetaldehyde , 2006, Neuropsychopharmacology.

[2]  J. Costentin,et al.  Semi‐chronic increase in striatal level of 3,4‐dihydroxyphenylacetaldehyde does not result in alteration of nigrostriatal dopaminergic neurones , 2004, Journal of neuroscience research.

[3]  H. de Wit,et al.  Biological and behavioral markers of alcohol sensitivity. , 2004, Alcoholism, clinical and experimental research.

[4]  K. Lesch,et al.  Alcohol intake after serotonin transporter inactivation in mice. , 2003, Alcohol and alcoholism.

[5]  M. Low,et al.  Effects of a Drd2 Deletion Mutation on Ethanol-Induced Locomotor Stimulation and Sensitization Suggest a Role for Epistasis , 2003, Behavior genetics.

[6]  P. Chambon,et al.  Retinaldehyde dehydrogenase 2 (RALDH2)- independent patterns of retinoic acid synthesis in the mouse embryo , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[7]  A. Bachmanov,et al.  Influence of test duration on the sensitivity of the two-bottle choice test. , 2002, Chemical senses.

[8]  K. Kitagawa,et al.  Diminished alcohol preference in transgenic mice lacking aldehyde dehydrogenase activity. , 2002, Pharmacogenetics.

[9]  M. Caron,et al.  Decreased ethanol preference and consumption in dopamine transporter female knock-out mice. , 2002, Alcoholism, clinical and experimental research.

[10]  T. Wall,et al.  Genetic risk for alcoholism relates to level of response to alcohol in Asian-American men and women. , 2002, Journal of studies on alcohol.

[11]  U. Dräger,et al.  Retinoic acid synthesis for the developing telencephalon. , 2001, Cerebral cortex.

[12]  E. Quertemont,et al.  Conditioned stimulus preference after acetaldehyde but not ethanol injections , 2001, Pharmacology Biochemistry and Behavior.

[13]  W. Keung.  Biogenic aldehyde(s) derived from the action of monoamine oxidase may mediate the antidipsotropic effect of daidzin. , 2001, Chemico-biological interactions.

[14]  M. Low,et al.  Ethanol-conditioned place preference is reduced in dopamine D2 receptor-deficient mice , 2000, Pharmacology Biochemistry and Behavior.

[15]  W. Keung,et al.  The mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway: a potential site of action of daidzin. , 2000, Journal of medicinal chemistry.

[16]  M. Low,et al.  Lack of operant ethanol self-administration in dopamine D2 receptor knockout mice , 2000, Psychopharmacology.

[17]  K. Kitagawa,et al.  Aldehyde dehydrogenase (ALDH) 2 associates with oxidation of methoxyacetaldehyde; in vitro analysis with liver subcellular fraction derived from human and Aldh2 gene targeting mouse , 2000, FEBS letters.

[18]  R. C. Lin,et al.  Effects of isoflavones on alcohol pharmacokinetics and alcohol-drinking behavior in rats. , 1998, The American journal of clinical nutrition.

[19]  C. Hoppel,et al.  The Malonyl-CoA-sensitive Form of Carnitine Palmitoyltransferase Is Not Localized Exclusively in the Outer Membrane of Rat Liver Mitochondria* , 1998, The Journal of Biological Chemistry.

[20]  Christophe Person,et al.  Disruption and sequence identification of 2,000 genes in mouse embryonic stem cells , 1998, Nature.

[21]  B. Vallee,et al.  Daidzin and its antidipsotropic analogs inhibit serotonin and dopamine metabolism in isolated mitochondria. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[22]  L A Herzenberg,et al.  Disruption of overlapping transcripts in the ROSA beta geo 26 gene trap strain leads to widespread expression of beta-galactosidase in mouse embryos and hematopoietic cells. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  G. Beauchamp,et al.  Intake of ethanol, sodium chloride, sucrose, citric acid, and quinine hydrochloride solutions by mice: A genetic analysis , 1996, Behavior genetics.

[24]  R. C. Lin,et al.  Isoflavonoid compounds extracted from Pueraria lobata suppress alcohol preference in a pharmacogenetic rat model of alcoholism. , 1996, Alcoholism, clinical and experimental research.

[25]  E. Sellers,et al.  Low doses of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH DPAT) increase ethanol intake , 1994, Psychopharmacology.

[26]  C. Fahlke,et al.  Involvement of the serotonergic system in ethanol intake in the rat. , 1993, Alcohol.

[27]  C. Ehlers,et al.  Subjective feelings of alcohol intoxication in Asians with genetic variations of ALDH2 alleles. , 1992, Alcoholism, clinical and experimental research.

[28]  A. Yoshida.  Molecular genetics of human aldehyde dehydrogenase. , 1992, Pharmacogenetics.

[29]  A. Helander,et al.  Metabolism of biogenic aldehydes in isolated human blood cells, platelets and in plasma. , 1987, Biochemical pharmacology.

[30]  R. Deitrich,et al.  Effects of induction of rat liver cytosolic aldehyde dehydrogenase on the oxidation of biogenic aldehydes. , 1986, Biochemical pharmacology.

[31]  A. W. Tank,et al.  Enzymology and subcellular localization of aldehyde oxidation in rat liver. Oxidation of 3,4-dihydroxyphenylacetaldehyde derived from dopamine to 3,4-dihydroxyphenylacetic acid. , 1981, Biochemical pharmacology.

[32]  R. D. Myers,et al.  Disulfiram alters dopamine metabolism at sites in rat's forebrain as detected by push-pull perfusions , 1978, Brain Research Bulletin.

[33]  L. L. Coughenour,et al.  A new device for the rapid measurement of impaired motor function in mice , 1977, Pharmacology Biochemistry and Behavior.

[34]  D. Crabb,et al.  Distribution of messenger RNAs for aldehyde dehydrogenase 1, aldehyde dehydrogenase 2, and aldehyde dehydrogenase 5 in human tissues. , 1996, Journal of investigative medicine : the official publication of the American Federation for Clinical Research.

[35]  H J Edenberg,et al.  Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant. , 1989, The Journal of clinical investigation.