Indirect evidence supports a link between disrupted serotonin (5-hydroxytryptamine;
5-HT) signaling in the brain and addictive behaviors. However, the effects of hyposerotonergia on
ethanol drinking behavior are contradictory. In this study, mice deficient in tryptophan hydroxylase
2 (Tph2 -/-), the rate-limiting enzyme of 5-HT synthesis in the brain, were used to assess the role
of central 5-HT in alcohol drinking behavior. Life-long 5-HT depletion in these mice led to an
increased ethanol consumption in comparison to wild-type animals in a two-bottle choice test. Water
consumption was increased in naïve 5-HT-depleted mice. However, exposure of Tph2 -/- animals to
ethanol resulted in the normalization of water intake to the level of wild-type mice. Tph2 deficiency
in mice did not interfere with ethanol-evoked antidepressant response in the forced swim test. Gene
expression analysis in wild-type animals revealed no change in Tph2 expression in the brain of mice
consuming ethanol compared to control mice drinking water. However, within the alcohol-drinking
group, inter-individual differences in chronic ethanol intake correlated with Tph2 transcript levels.
Taken together, central 5-HT is an important modulator of drinking behavior in mice but is not
required for the antidepressant effects of ethanol.

DOI:https://doi.org/10.3390/cells11050874