Dynamical ventral tegmental area circuit mechanisms of alcohol‐dependent dopamine release

dc.contributor.authordi Volo, Matteo
dc.contributor.authorMorozova, Ekaterina O.
dc.contributor.authorLapish, Christopher C.
dc.contributor.authorKuznetsov, Alexey
dc.contributor.authorGutkin, Boris
dc.contributor.departmentPsychology, School of Scienceen_US
dc.date.accessioned2019-02-22T15:48:00Z
dc.date.available2019-02-22T15:48:00Z
dc.date.issued2019
dc.description.abstractA large body of data has identified numerous molecular targets through which ethanol (EtOH) acts on brain circuits. Yet how these multiple mechanisms interact to result in dysregulated dopamine (DA) release under the influence of alcohol in vivo remains unclear. In this manuscript, we delineate potential circuit‐level mechanisms responsible for EtOH‐dependent dysregulation of DA release from the ventral tegmental area (VTA) into its projection areas. For this purpose, we constructed a circuit model of the VTA that integrates realistic Glutamatergic (Glu) inputs and reproduces DA release observed experimentally. We modelled the concentration‐dependent effects of EtOH on its principal VTA targets. We calibrated the model to reproduce the inverted U‐shape dose dependence of DA neuron activity on EtOH concentration. The model suggests a primary role of EtOH‐induced boost in the Ih and AMPA currents in the DA firing‐rate/bursting increase. This is counteracted by potentiated GABA transmission that decreases DA neuron activity at higher EtOH concentrations. Thus, the model connects well‐established in vitro pharmacological EtOH targets with its in vivo influence on neuronal activity. Furthermore, we predict that increases in VTA activity produced by moderate EtOH doses require partial synchrony and relatively low rates of the Glu afferents. We propose that the increased frequency of transient (phasic) DA peaks evoked by EtOH results from synchronous population bursts in VTA DA neurons. Our model predicts that the impact of acute ETOH on dopamine release is critically shaped by the structure of the cortical inputs to the VTA.en_US
dc.eprint.versionAuthor's manuscripten_US
dc.identifier.citationdi Volo, M., Morozova, E. O., Lapish, C. C., Kuznetsov, A., & Gutkin, B. (2019). Dynamical ventral tegmental area circuit mechanisms of alcohol-dependent dopamine release. European Journal of Neuroscience, 0(0). https://doi.org/10.1111/ejn.14147en_US
dc.identifier.urihttps://hdl.handle.net/1805/18440
dc.language.isoenen_US
dc.publisherWileyen_US
dc.relation.isversionof10.1111/ejn.14147en_US
dc.relation.journalEuropean Journal of Neuroscienceen_US
dc.rightsPublisher Policyen_US
dc.sourceAuthoren_US
dc.subjectalcoholen_US
dc.subjectcomputational modelingen_US
dc.subjectcortical synchronyen_US
dc.titleDynamical ventral tegmental area circuit mechanisms of alcohol‐dependent dopamine releaseen_US
dc.typeArticleen_US
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