Methamphetamine potentiates the use of outcome-specific associations via a hypothalamic-dopamine circuit

Drug cues strongly influence drug seeking and relapse to addiction. However, it is unclear how drug cues do this. We reveal that a novel pathway from ventral tegmental area dopamine (VTA_DA) neurons to the lateral hypothalamus (LH) is necessary and sufficient to govern learning about associations between cues and specific outcomes and the use of such associations to govern decision making. We found that prior methamphetamine self-administration enhanced the control that reward cues have over behavior in this same manner, which was correlated with bidirectional strengthening of the LH-VTA circuit. We characterized dopamine release in LH to reward cues across learning and found that this learning signal was augmented following methamphetamine experience. These data demonstrate that cues exert greater, specific control over decision making after repeated drug use, concomitant with drug-induced changes in the LH-VTA circuit. This contrasts with habit theories of addiction that assert behavior becomes automatic, without thought of possible outcomes.