The dynamics of synaptic dopamine clearance: relevance to alcohol use disorder

Alcohol misuse is a leading cause of preventable death, yet the neurochemical changes governing its addictive properties remain elusive. Ethanol, the psychoactive component of alcoholic beverages, interacts with many neurotransmitter systems, including dopamine. Dopamine is a key modulator of reward and its dysregulation represents one mechanism behind ethanol’s reinforcing effects. After release, dopamine is cleared from the synapse by uptake, diffusion, and enzymatic degradation. These processes maintain dopamine homeostasis and thus modulate neural activity. Proteins which aid in the removal of dopamine from the synaptic cleft are associated with maladaptive ethanol-seeking behaviours. However, studies investigating whether ethanol administration directly affects dopamine clearance mechanisms are unclear. Deciphering how ethanol modulates synaptic dopamine clearance will provide insight into the mechanism of action of ethanol, and reveal new drug targets for alcohol use disorder. This review deciphers whether ethanol modulates dopamine clearance, and considers potential mechanisms regarding ethanol-induced changes in dopamine clearance, with a focus on dopamine uptake and degradation. Finally, this review highlights existing gaps and controversies in the literature, and emphasizes the use of neurogenetic approaches in Drosophila melanogaster to resolve outstanding questions.