Monoamine Metabolism and Behavioral Responses to Ethanol in Mitochondrial Aldehyde Dehydrogenase Knockout Mice

Oct 3, 2006Alcoholism, clinical and experimental research

Brain chemical changes and behavior after alcohol in mice missing a key mitochondrial enzyme

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Abstract

ALDH2-deficient mice drank significantly less ethanol than wild-type or ALDH2+/- mice.

Wild-type and ALDH2+/- mice preferred ethanol over water.
Locomotor activity and ataxia were significantly more affected by ethanol in ALDH2-/- mice.
There was no observed effect of genotype on levels of serotonin, dopamine, or their precursors and metabolites in multiple brain regions.
The altered behavioral responses to ethanol in ALDH2-/- mice are not linked to changes in brain monoamine metabolism.
ALDH2 is not necessary for the metabolism of brain monoamines in living organisms.

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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.

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Monoamine Metabolism and Behavioral Responses to Ethanol in Mitochondrial Aldehyde Dehydrogenase Knockout Mice

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