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Hadar R1, Vengeliene V2, Barroeta Hlusicke E1, Canals S3, Noori HR2, Wieske F1, Rummel J1, Harnack D4, Heinz A5, Spanagel R2, Winter C1

1 Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
2 Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
3 Cellular and Systems Neurobiology Unit, Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, Sant Joan d’Alacant, Spain.
4 Department of Neurology, Charité Universitätsmedizin Berlin, Germany.
5 Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Germany.

The lack of controlled clinical trials of DBS as a treatment method for alcohol dependent patients as well as the scarce human evidence motivated us into a preclinical investigation. For that we used the alcohol deprivation (ADE) rodent model which allows to study compulsive alcohol drinking and relapse-like behavior. To mimic the human situation stimulation was carried out in a chronic-continuous fashion into the nucleus accumbens (Nacc), following the existing case reports, but also to other brain sites. To determine the network effects of deep brain stimulation in alcohol dependent rats we combined electrical stimulation in the Nacc with functional magnetic resonance imaging and studied neurotransmitter levels in Nacc stimulated animals vs. sham-stimulated rats. To our surprise, DBS of the Nacc led to augmented relapse behavior in the ADE model. We furthered our investigation and based on our associated fMRI data we also applied chronic-continuous DBS to the medial prefrontal cortex and caudate putamen, related regions which were shown to be activated upon Nacc stimulation. However, stimulation applied to these areas did not affect relapse behaviour, confirming that the nucleus accumbens is critical for generating this paradoxical effect. Neurochemical analysis of the major activated brain sites of the network revealed that the effect of stimulation may depend on accumbal dopamine levels. This was supported by the finding that brain stimulation treated rats exhibited augmented alcohol-induced dopamine release compared to sham stimulated animals. Our data suggest that deep brain stimulation in the nucleus accumbens can produce incentive salience to alcohol consumption probably via enhanced dopamine release and can thereby promote relapse.