Context can influence reactions to environmental cues and this elemental process has implications for substance use disorder. Using an animal model, we show that an alcohol-associated context elevates entry into a fluid port triggered by a conditioned stimulus (CS) that predicted alcohol (CS-triggered alcohol-seeking). This effect persists across multiple sessions and, after it diminishes in extinction, the alcohol context retains the capacity to augment reinstatement. Systemically administered eticlopride and chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons reduce CS-triggered alcohol-seeking. Chemogenetically silencing VTA dopamine terminals in the nucleus accumbens (NAc) core reduces CS-triggered alcohol-seeking, irrespective of context, whereas silencing VTA dopamine terminals in the NAc shell selectively reduces the elevation of CS-triggered alcohol-seeking in an alcohol context. This dissociation reveals new roles for divergent mesolimbic dopamine circuits in the control of responding to a discrete cue for alcohol and in the amplification of this behaviour in an alcohol context.

Discrete and contextual cues that predict alcohol trigger alcohol-seeking. However, the extent to which context influences alcohol-seeking triggered by discrete cues, and the neural mechanisms underlying these responses, are not well known. We show that, relative to a neutral context, a context associated with alcohol persistently elevated alcohol-seeking triggered by a discrete cue, and supported higher levels of priming-induced reinstatement. Alcohol-seeking triggered by a discrete cue in a neutral context was reduced by designer receptor-mediated inhibition of ventral tegmental area (VTA) dopamine neurons in TH::Cre rats. Inhibiting terminals of VTA dopamine neurons in the nucleus accumbens (NAc) core reduced alcohol-seeking triggered by a discrete cue, irrespective of context, whereas inhibiting VTA dopamine terminals in the NAc shell selectively reduced the elevation of alcohol-seeking triggered by a discrete cue in an alcohol context. This dissociation highlights unique roles for divergent mesolimbic dopamine circuits in alcohol-seeking driven by discrete and contextual environmental cues.