Decreased ventral tegmental area CB1R signaling reduces sign-tracking and shifts cue-outcome dynamics in rat nucleus accumbens

Sign-tracking rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug-seeking compared to goal-tracking or intermediate- rats. Cue-evoked dopamine in the nucleus Accumbens (NAc) is a neurobiological signature of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system; endocannabinoids, which bind the cannabinoid receptor-1 (CB1R) in the Ventral Tegmental Area (VTA) to control cue-evoked striatal dopamine levels. We use cell-type specific optogenetics, intra-VTA pharmacology and fiber photometry to test the hypothesis that VTA CB1R receptor signaling regulates NAc dopamine levels to control sign-tracking. We trained rats in a Pavlovian lever autoshaping task (PLA) to determine their tracking groups before testing the effect of VTAèNAc dopamine inhibition. We found this circuit is critical for mediating the vigor of the ST response. Upstream of this circuit, intra-VTA infusions of rimonabant, a CB1R inverse agonist, during PLA decrease lever and increase foodcup approach in sign-tracking rats. Using fiber photometry to measure fluorescent signals from dopamine sensor, GRABDA, we tested the effects of intra-VTA rimonabant on NAc dopamine dynamics during autoshaping. We found that intra-VTA rimonabant-induced decreases in sign-tracking behaviors are not associated with changes to phasic cue(CS)-evoked NAc dopamine activity. Instead, intra-VTA rimonabant increases NAc shell, but not core, dopamine levels during reward delivery (US). Our results suggest that CB1R signaling in the VTA influences the balance between the CS- and US-evoked dopamine responses in the NAc shell and biases behavioral responding to cues in sign-tracking rats. SIGNIFICANCE STATEMENT Substance Use Disorder is a chronically relapsing neurobiological disorder that affects a subset of individuals that engage in drug use. Recent research suggests that there are individual behavioral and neurobiological differences prior to drug experience that predict addiction and relapse vulnerabilities. Here, we investigate how midbrain endocannabinoids regulate a brain pathway that is exclusively involved in driving cue- motivated behaviors of sign-tracking rats. This work contributes to our mechanistic understanding of individual vulnerabilities to cue-triggered natural reward seeking that have relevance for drug motivated behaviors. ### Competing Interest Statement The authors have declared no competing interest.