**Acknowledgements**

agent. It has been shown that varenicline reduce alcohol intake and alcohol‐seeking behaviour in long‐term drinking rats [205] and modulate NAc dopamine after systemic administrations

*2.6.2. Clinical evidence for the use of indirect modulation of dopamine for the treatment of alcohol*

Albeit the preclinical data look promising regarding the glycine transporter‐1 inhibitor Org25935, the multicenter randomized clinical trial produced a negative outcome on alcohol intake, but did not discard the potential importance of the mechanism [207]. More promis‐ ing clinical studies with varenicline show that this agent decreased alcohol consumption and craving in an experimental setting in heavy‐drinking smokers [208–210]. Moreover, data from a randomized clinical trial in alcohol‐dependent individuals show that the smoking cessa‐ tion agent reduced the weekly percent heavy drinking days drinks, decreased the drinks per drinking day as well as prevented alcohol craving [211]. It should, however, be noted that recent clinical trials in alcohol‐dependent individuals were unable to find a beneficial effect of varenicline based on self‐reported alcohol consumption [212, 213]. Nevertheless, when also monitoring the selective alcohol biomarker phosphatidylethanol (PEth) in the blood of the subjects in the above‐mentioned clinical trial [212], it was found that varenicline indeed had effect on this objective measure of alcohol consumption [214] strengthening the potential of varenicline as potential novel medication for alcohol dependence. Besides glycine receptors and nAChR, there are various signalling systems indirectly targeting the mesolimbic dopamine system with promising preclinical findings on alcohol‐mediated behaviours. Collectively, these data indicate that indirect modulation of dopamine signalling might be a potential target for novel treatment strategies for alcohol dependence and that these targets should be investigated in more detail in human laboratory studies as well as randomized

Extensive preclinical and clinical research support the hypothesis that alcohol's acute rein‐ forcing effects are mediated through a dopamine surge in the mesocorticolimbic dopamine system and that the chronic and excessive alcohol consumption, in contrast, induces a dopamine deficient state driving the processes of craving and relapse. In addition, it is well substantiated that alcohol affects dopamine directly via the NAc and VTA as well as through indirect activation of the mesolimbic pathway via interaction with other reward‐related brain regions and neurotransmitters. These complex relationships need to be investigated further. Given dopamine's pivotal role in the development and maintenance of alcohol dependence, medications targeting dopamine does constitute an important area of research. Although promising preclinical results, the majority of results from the clinical studies with dopamine‐ acting medications have thus far been discouraging. The side effects profile of many of the evaluated compounds, including typical antipsychotic drugs, render them clinically unfav‐

of alcohol alone and in combination with nicotine [206].

96 Recent Advances in Drug Addiction Research and Clinical Applications

*dependence*

clinical trials.

**3. Conclusion**

The study is supported by grants from the Swedish Research Council (2009‐2782, 2014‐3887 and 2015‐03219), Swedish Society for Medical Research, Swedish Alcohol Monopoly Founda‐ tion for Alcohol Research.
