Activation by Alcohol of Prefrontal Layer 5 Pyramidal Neurons Depends on Ascending Dopaminergic Input

Short-term alcohol exposure modulates activity in reward-related regions such as the ventral tegmental area (VTA) and executive cortical regions such as the prefrontal cortex (PFC), potentially contributing to alcohol use disorders. Although alcohol induces dopamine release from VTA projection neurons, how dopamine signaling contributes to the acute effects of alcohol in the PFC at the cellular level remains unclear. Using in vivo Ca²⁺ imaging and in vitro slice electrophysiology in mice of either sex, we found that moderate-to-high doses of alcohol increased the activity of layer 5 (L5) pyramidal neurons in the PFC in a D1/D5 receptor-dependent manner. We further identified the VTA as a major source of this dopaminergic input by showing that alcohol increased activity in VTA dopaminergic axons within the PFC and that chemogenetic inhibition of VTA projection neurons prevented the excitatory effects of alcohol on L5 pyramidal neurons. These findings demonstrate that acute alcohol activates PFC L5 pyramidal neurons via ascending dopaminergic input from the VTA, which may contribute to the behavioral effects of alcohol intoxication.