The ventral tegmental area dopamine to lateral amygdala projection supports cocaine cue associative learning

Learning and memory mechanisms are critically involved in drug craving and relapse. Environmental cues paired with repeated drug use acquire incentive value such that exposure to the cues alone can trigger craving and relapse. The amygdala, particularly the lateral amygdala (LA), underlies cue-related learning processes that assign valence to environmental stimuli including drug-paired cues. Evidence suggests that the ventral tegmental area (VTA) dopamine (DA) projection to the LA participates in encoding reinforcing effects that act as a US in conditioned cue reward-seeking as DA released in the amygdala is important for emotional and behavioral functions. Here we used chemogenetics to manipulate these VTA DA inputs to the LA to determine the role of this projection for acquisition of drug-cue associations and reinstatement of drug-seeking. We found inhibiting DA input to the LA during cocaine self-administration slowed acquisition and weakened the ability of the previously cocaine-paired cue to elicit cocaine-seeking. Conversely, exciting the projection during self-administration boosted the salience of the cocaine-paired cue as indicated by enhanced responding during cue-induced reinstatement. Importantly, interfering with DA input to the LA had no impact on the ability of cocaine to elicit a place preference or induce reinstatement in response to a priming cocaine injection. Overall, we show that manipulation of projections underlying DA signaling in the LA may be useful for developing therapeutic interventions for substance use disorders.