Tph2 Gene Expression Defines Ethanol Drinking Behavior in Mice

Magdalena Zaniewska,Natalia Alenina,Michael Bader,Valentina Mosienko

doi:10.3390/cells11050874

Abstract

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.

Highlights

Alcoholism is a chronic relapsing brain disorder defined by a loss of control over drinking despite known health consequences
ANOVA analyses revealed that the effect of Tph2 deficiency on ethanol consumption with a two-bottle choice paradigm did not change according to drinking days (no effect of genotype x day interaction (F(13,312) = 1.40, p = 0.16, ηp2 = 0.055); Figure 1A)
On the final day of ethanol drinking, liquid intake was measured after 24 h, and mice were introduced to the forced swim test (FST)

Summary

Introduction

Alcoholism is a chronic relapsing brain disorder defined by a loss of control over drinking despite known health consequences. Disulfiram, which is an inhibitor of the acetaldehyde dehydrogenase, an enzyme responsible for ethanol metabolism, is a second-line treatment option [1]. The efficacy of these therapies is low, potentially due to the high diversity in treatment response between alcoholic individuals (for review [2]). Depressive symptoms commonly occur in the period preceding the development of alcohol dependence and very often initiate drug-taking behavior for selfmedication, a behavior called autotherapy. The comorbidity of depression and alcohol abuse further hampers the researchers’ ability to explain the molecular mechanisms underlying these brain disorders and to find effective pharmacotherapy

Methods

Results

Conclusion