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.
Fernandez
Elizabeth
E
Research Service and Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas, USA.
Koek
Wouter
W
Ran
Qitao
Q
Gerhardt
Greg A
GA
France
Charles P
CP
Strong
Randy
R
D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004247:DNA / Q000032:analysis; D004298:Dopamine / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*
D002492:Central Nervous System Depressants; D012333:RNA, Messenger; D012701:Serotonin; D000431:Ethanol; D004247:DNA; D000444:Aldehyde Dehydrogenase; D004298:Dopamine