After being conditioned to drink alcohol, 15% of rats continue to seek alcohol after being given the choice of switching to sweetened water. This group of rats shows a high motivation to pursue alcohol even when it is paired with a negative stimulus such as an electric shock, mimicking the compulsion as well as the frequency of alcohol-related problems in humans. Further examination of this group revealed the GAT-3 γ-aminobutyric acid transporter protein was significantly downregulated in the amygdalas of these rats, leading to decreased clearance of γ-aminobutyric acid (GABA) from synapses in this region.
To confirm this model, the Heilig group of the Linköping University in Sweden then downregulated GAT-3 in the amygdala in rats which until that point showed no preference for alcohol. As the injected vector began to downregulate GAT-3, the rats showed a stronger and stronger preference for alcohol over sweetened water.
This model also seems to hold true for humans: postmortem examination of human subjects showed lower GAT-3 expression in the amygdalas of those with alcohol dependence.
The study is being lauded not only for proceeding from basic research to translational significance in humans, but also for its addition of choice to the basic experimental design. Allowing the research animals to choose between self-administering alcohol or switching to another reward after the conditioning period required a more lengthy and larger scale project (over 600 rats), but it revealed how the animals should be grouped together for further analysis.
While this study indicates a causal relationship between a GABA transporter and alcohol dependence, it may not point directly to the best drug target for addiction therapy. Increasing GABA transport back into neurons in the amygdala may prove more difficult than other ways of controlling GABA levels in the region.
The Heilig group of the Linköping University in Sweden presented the results at the Research Society on Alcoholism meeting in San Diego and subsequently in the journal Science:
A molecular mechanism for choosing alcohol over an alternative reward
Science 22 Jun 2018: Vol. 360, Issue 6395, pp. 1321-1326, DOI: 10.1126/science.aao1157