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No effect of sex on ethanol intake and preference after dopamine transporter (DAT) knockdown in adult mice

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Abstract

Rationale

Dopamine levels are controlled in part by transport across the cell membrane by the dopamine transporter (DAT), and recent evidence showed that a polymorphism in the gene encoding DAT is associated with alcoholism. However, research in animal models using DAT knockout mice has yielded conflicting results.

Objectives

The present study was planned to evaluate the effects of DAT knockdown in the nucleus accumbens (Nacc) on voluntary ethanol consumption and preference in male and female C57BL/6J mice.

Methods

For this purpose, animals were stereotaxically injected with DAT siRNA-expressing lentiviral vectors in the Nacc, and using a voluntary, continuous access two-bottle choice model of alcohol, we investigated the importance of accumbal DAT expression in voluntary alcohol intake and preference. We also investigated the effects of DAT knockdown on saccharin and quinine consumption and ethanol metabolism.

Results

We show that females consumed more alcohol than males. Interestingly, DAT knockdown in the Nacc significantly decreased alcohol intake and preference in both groups, but no significant sex by group interaction was observed. Also, DAT knockdown did not alter total fluid consumption, saccharin or quinine consumption, or blood ethanol concentrations. Using Pearson correlation, results indicated a strong positive relationship between DAT mRNA expression and ethanol consumption and preference.

Conclusions

Taken together, these data provide further evidence that DAT plays an important role in controlling ethanol intake and that accumbal DAT contributes in the modulation of the reinforcing effects of ethanol. Overall, the results suggest that DAT inhibitors may be valuable in the pharmacotherapy of alcoholism.

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Abbreviations

BEC:

Blood ethanol concentration

DAT:

Dopamine transporter

LV:

Lentiviral vectors

Nacc:

Nucleus accumbens

shRNA:

Short hairpin RNA

TBC:

Two-bottle choice

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Acknowledgments

The authors would like to acknowledge Mrs. Christine Deforel-Poncet and Dr. Frederic Boyer for their technical assistance with the lentiviral vectors’ preparation. The authors are also grateful to Mr. Mohamed Shafiullah and Dr. Mahmoud Hag Ali from the Central Animal Facility for their advice on animal care and welfare.

Funding

AB was supported by grants from the UAE University (No. NP/13/05) and the National Research foundation (No. 31M082). JLD received grants from the Swiss National Science Foundation 3100-059350 and 3100AO-100686. The funders had no further role in study design, analysis, writing of the report, or in the decision to submit the paper for publication.

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AB designed the study and wrote the protocol. AB and JLD managed the literature searches and analyses. AB undertook the statistical analysis, and AB and JLD wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

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Correspondence to Amine Bahi.

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Bahi, A., Dreyer, JL. No effect of sex on ethanol intake and preference after dopamine transporter (DAT) knockdown in adult mice. Psychopharmacology 236, 1349–1365 (2019). https://doi.org/10.1007/s00213-018-5144-9

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