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 in executive cortical regions such as the prefrontal cortex (PFC), potentially contributing to alcohol use disorders. Although alcohol induces dopamine release from the VTA, how dopamine signaling interacts with acute alcohol exposure 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.Significance statement Understanding the initial actions of alcohol on brain circuits can reveal mechanisms that drive the transition from controlled drinking to addiction. Although alcohol increases dopamine release in midbrain reward regions such as the ventral tegmental area (VTA), it remains unclear how executive cortical regions such as the prefrontal cortex (PFC) are modulated by dopamine during acute alcohol exposure. Here, using mice, we show that alcohol activates PFC pyramidal neurons and that this activation requires dopaminergic signaling from the VTA. This dopaminergic modulation of PFC activity provides insight into early circuit-level vulnerabilities and suggests potential therapeutic targets relevant to alcohol addiction.