Tales from the dark side: Do neuromodulators of drug withdrawal require changes in endocannabinoid tone?

• All drugs of abuse produce some form of withdrawal.
• Withdrawal-associated stimuli begin to motivate drug seeking.
• Conditioned withdrawal shares parallels with conditioned avoidance.
• Subsecond dopamine release is involved in conditioned avoidance.
• Endocannabinoids have the potential to modulate subsecond dopamine release during drug withdrawal.

Environmental and interoceptive cues are theorized to serve as ‘signals’ that motivate drug seeking and effects that may be augmented in the withdrawn state. Phasic dopamine release events are observed in the nucleus accumbens in response to such motivational salient stimuli and are thought to be necessary for drug-associated cues to trigger craving. We recently demonstrated how dopamine neurons encode stimuli conditioned to a negative event, as might occur during conditioned withdrawal, and stimuli predicting the avoidance of negative events, as might occur as an addict seeks out drugs to prevent withdrawal. In this review we first discuss how the subsecond dopamine release events might process conditioned withdrawal and drug seeking driven by negative reinforcement processes within the context of our dopamine data obtained during conditioned avoidance procedures. We next describe how the endocannabinoid system modulates phasic dopamine release events and how it might be harnessed to treat negative affective states in addiction. Specifically, we have demonstrated that endocannabinoids in the ventral tegmentum sculpt cue-induced accumbal surges in dopamine release and, therefore, may also be mobilized during drug withdrawal.