Increased ethanol consumption despite taste aversion in mice with a human tryptophan hydroxylase 2 loss of function mutation

Tph2 Gene Expression Defines Ethanol Drinking Behavior in Mice

“…The finding of enhanced ethanol drinking in Tph2 −/− mice is in line with previous studies showing that mice expressing the hypofunctional R439H allele for the Tph2 gene consumed more ethanol–sucrose solution, had increased preference for ethanol, and reduced sensitivity to ethanol compared to the wild-type animals [ 50 ]. However, another study found that the R439H Tph2 knock-in mice exhibited no change in ethanol intake relative to the control animals, but, only under aversive conditions, motivation for ethanol consumption increased [ 51 ]. While the methodological differences (e.g., the use of sucrose-fading procedure [ 50 ]; or the introduction of a 4-day withdrawal phase [ 51 ]) may account for the observed inconsistencies in studies of R439H Tph2 mutant mice, the variability in drinking-related outcomes between these animals and Tph2 −/− mice is likely to be related to the extent of the brain 5-HT depletion.…”

“…However, another study found that the R439H Tph2 knock-in mice exhibited no change in ethanol intake relative to the control animals, but, only under aversive conditions, motivation for ethanol consumption increased [ 51 ]. While the methodological differences (e.g., the use of sucrose-fading procedure [ 50 ]; or the introduction of a 4-day withdrawal phase [ 51 ]) may account for the observed inconsistencies in studies of R439H Tph2 mutant mice, the variability in drinking-related outcomes between these animals and Tph2 −/− mice is likely to be related to the extent of the brain 5-HT depletion. Indeed, R439H mutation in Tph2 gene resulted in partial (60–80%) reduction in 5-HT levels in the frontal cortex, amygdala, striatum, and hippocampus [ 46 , 47 , 48 , 49 ].…”

“…For example, mice with a hypofunctional R439H polymorphism in Tph2 gene (analogous to a human R441H variant), leading to a partial (60–80%) deficiency in 5-HT level in the brain [ 46 , 47 , 48 , 49 ], drank more ethanol–sucrose solution compared to wild-type mice [ 50 ]. In another study, the R439H Tph2 knock-in mice drank amounts of ethanol comparable to wild-type animals; however, under aversive conditions, displayed enhanced motivation for ethanol [ 51 ]. Low preference for ethanol was reported in two mouse strains, BALB/cJ and DBA/2A, that carry another polymorphism, C1473G (P447R) in the Tph2 gene, leading to reduction in Tph2 mRNA and protein levels and about a 15% decrease in 5-HT content in the brain [ 52 , 53 , 54 , 55 ].…”