Summary: Researchers have identified how alcohol influences dopaminergic and inhibitory neurons in the ventral tegmental area. The findings could help develop new treatments for alcohol dependence.
Source: National Research University Higher School of Economics.
Scientists of the Higher School of Economics, Indiana University, and École normale supérieure clarified how alcohol influences the dopamine and inhibitory cells in the midbrain that are involved in the reward system and the formation of dependency on addictive drugs. The results of the study were published in the article ‘Dynamical ventral tegmental area circuit mechanisms of alcohol-dependent dopamine release.’
Let’s say you drink some coffee to get an energy boost. At the same moment, a burst of dopamine is released in your midbrain that acts as positive reinforcement of your action. Over time, the brain becomes conditioned to the stimulus and raises the dopamine level in advance – as soon as you simply smell the coffee or approach a coffee shop. This is how the body learns through reinforcement. The ventral tegmental area (VTA) – over 50 percent of which is composed of dopaminergic neurons – plays a decisive role in this process.
Neurotransmitter dopamine is a biologically active chemical that transmits signals from one nerve cell to another. Dopamine acts on the brain’s ‘motivation centre’, eliciting either a sense of anticipation of pleasure from a particular action, or the pleasure sensation itself if the pleasurable event occurs unexpectedly. But there is a particular link between dopamine and a number of addictive substances. In particular, alcohol directly affects the activity of dopamine nuclei and triggers the release of a burst of dopamine. This means that, regardless of how alcohol affects the rest of the body, the brain responds to it with positive reinforcement.
Alcohol has another characteristic as well: it influences how gamma-aminobutyric acid (GABA) receptors carry out their normal function of inhibiting cells from releasing dopamine. The mathematical model developed by researchers at HSE and Indiana University provides an accurate representation of the way alcohol, dopamine, and GABA cells interact.
The structure of the inhibitory network’s activity – that is, how that activity arises and functions – determines the effect that GABA cells have on dopamine neurons. From 30 to 60 GABA cells in the VTA are connected to every dopamine cell. (This is generally true for GABA cells in the VTA, from outside the VTA this is a much larger number.) When all of those inhibitory cells function asynchronously, they inhibit dopamine activity. According to computational modelling, the reverse is also true: when inhibitory cells synchronize, the dopamine level increases. Researchers found that alcohol helps change the inhibitory network from an asynchronous to a synchronous state – that is, it ceases to inhibit dopamine and stimulates its release instead.
This discovery could help in the treatment of alcohol dependence. ‘Our model suggests that targeted pharmacological work with dopamine is possible,’ said Boris Gutkin, a co-author of the article and a leading research fellow with the HSE Centre for Cognition and Decision Making. ‘By blocking the synchronization of the inhibitory GABA network, we can influence the dopamine reactions alcohol causes.’
Source: Liudmila Mezentseva – National Research University Higher School of Economics
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Original Research: Abstract for “Dynamical ventral tegmental area circuit mechanisms of alcohol‐dependent dopamine release” by Matteo di Volo, Ekaterina O. Morozova, Christopher C. Lapish, Alexey Kuznetsov, and Boris Gutkin in European Journal of Neuroscience. Published September 14 2018.
Dynamical ventral tegmental area circuit mechanisms of alcohol‐dependent dopamine release
A 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.