Endocannabinoids and dopamine drive incentive learning processes underlying addiction vulnerability

Abstract

Phenotypic behavioral differences termed sign-tracking (ST) and goal-tracking (GT) differentially predict vulnerability to addiction and relapse. ST rats show enhanced cue sensitivity prior to drug experience that predicts greater discrete cue-driven drug-seeking compared to GT rats. Cue-evoked dopamine in the nucleus Accumbens (NAc) is a neurobiological signature of sign-, but not goal-tracking. Here, we examine an important regulator of the dopamine system; endocannabinoids, which primarily bind to the cannabinoid receptor-1 (CB1) in the central nervous system. We use pharmacological, optogenetic, and fiber photometry approaches to test the hypothesis that ventral tegmental area (VTA) CB1 receptor activation regulates extracellular concentrations of NAc dopamine to control sign-tracking. Rats are first trained in a Pavlovian lever autoshaping procedure to determine tracking group. We demonstrate that optogenetic inhibition of dopamine terminals in the NAc selectively reduce lever-directed behaviors, whereas intra-VTA CB1 receptor blockade both decreases lever-directed while increasing foodcup-directed behaviors. This change in response profile was coincident with increased dopamine levels in the NAc shell during the reward delivery period. These findings implicate VTA CB1 receptor signaling in maintaining Pavlovian cue-reward relationships in sign-tracking rats.