Figure 3: A representation of possible neurochemical/molecular sites of interaction between ethanol and caffeine. The MCL DA system includes afferent projections from DAneurons in the VTA to several projections regions, including the mPFC and NAc. Neurons of the mPFC are primarily glutamatergic, whereas the majority of neurons in the NAc are GABAergic medium spiny neurons. While evidence for the effects of caffeinated ethanol in this system is limited, it may be hypothesized that caffeine enhances EtOH’s effects, increasing DA and glutamate neurotransmission, while disinhibiting release of these transmitters through reductions in NAc GABA signaling. Taken together, co-administration of caffeine and ethanol may increase the rewarding and reinforcing properties associated with either drug alone. Repeated experience with this drug combination may initiate neural and/or behavioral adaptations. This may have important implications for the transition from recreational alcohol drinking to alcoholism, particularly in populations that exhibit greater vulnerability or predisposition to develop alcohol use disorders.