Midbrain endocannabinoids actuate dopamine-based action selection

Summary: Quickly adapting behavior to changing environments is key for survival. Brain dopamine signals reinforce actions that procure rewards and avoid adverse outcomes. However, the molecular mechanisms within the circuits that actuate these signals at subsecond timescales remain unexplored. We show that midbrain endocannabinoid mobilization is the conditio sine qua non for behavioral invigoration evoked by external cues. Reward- and punishment-predictive signals require intact retrograde release of the endocannabinoid 2-arachidonoylglycerol (2-AG) from ventral tegmental area dopamine neurons. Moreover, we show that genetic deletion of presynaptic cannabinoid type-1 receptors (CB1Rs), the target for 2-AG, recapitulates behavioral and dopaminergic deficits. Exploiting causal inference tools to interpret continuous brain signals, we describe that 2-AG/CB1R communication is essential for striatal dopamine release to signal salient cues and propel conditioned responding. These findings reveal an endocannabinoid-mediated disinhibition mechanism exploited by dopamine neurons to orchestrate striatal dopamine release events, enabling adaptive action selection informed by cues.