VTA dopamine inputs activate accumbal D1 receptors to promote alcohol seeking

Summary The mesolimbic dopamine system is central to cue-induced alcohol craving, but the role of D1 receptors (D1R) in the nucleus accumbens (NAc) remains unclear. Here, we show that cue-induced, but not context-elicited, alcohol seeking selectively upregulates NAc D1R protein expression in mice, which positively correlates with craving intensity. Systemic D1R antagonist SCH23390 suppresses cue-induced seeking and reverses c-Fos activation in the NAc and ventral pallidum. Chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons attenuates craving, an effect fully rescued by intra-NAc D1R agonist SKF38393 without affecting locomotion. These findings establish that dopaminergic projections from the VTA to the NAc drive cue-specific alcohol seeking through D1 receptor-dependent manner.