Endocannabinoid modulation of dopamine release during reward seeking, interval timing, and avoidance

Endocannabinoids (eCBs) are neuromodulators that influence a wide range of neural systems and behaviors. In the current review, we describe our recent research showing how eCBs, particularly 2-arachidonoylglycerol (2-AG), concurrently shape mesolimbic dopamine (DA) release and associated behavior. We will restrict our discussion by emphasizing three distinct behaviors: reward seeking, interval timing, and active avoidance. During reward seeking we find that 2-AG is necessary to observe cue-evoked DA release events that are thought to represent the value of a rewarding outcome. We then describe data showing that 2-AG modulates unique patterns of DA release and behavior observed under conditions of periodic reinforcement. These data are discussed within the context of interval timing and adjunctive behavior. eCB modulation of DA release is also implicated in defensive behavior, including the avoidance of harm. As in reward seeking, our data suggest that the concentration of DA that is evoked by a warning signal can represent the value of an avoidance outcome. And, disrupting eCB signaling concomitantly reduces the concentration of the avoidance value signal and active avoidance. Disruptions in reward seeking, interval timing, and defensive behavior are commonly observed in a variety of movement disorders (e.g., Parkinson's and Huntington's disease) and disorders of motivation (e.g., addiction). We believe our data on eCB-DA interactions have implications for the development of novel pharmacotherapies to treat these disorders. Thus, we conclude by discussing how eCB pharmacology might be harnessed to treat disorders of movement and motivation.