A multivariate regressor of patterned dopamine release predicts relapse to cocaine

Understanding mesolimbic dopamine adaptations underlying vulnerability to drug relapse is essential to inform prognostic tools for effective treatment strategies. However, technical limitations have hindered the direct measurement of sub-second dopamine release in vivo for prolonged periods of time, making it difficult to gauge the weight that these dopamine abnormalities have in determining future relapse incidence. Here, we use the fluorescent sensor GrabDA to record, with millisecond resolution, every single cocaine-evoked dopamine transient in the nucleus accumbens (NAc) of freely moving mice during self-administration. We reveal low-dimensional features of patterned dopamine release that are strong predictors of cue-induced reinstatement of cocaine seeking. Additionally, we report sex-specific differences in cocaine-related dopa-mine responses related to a greater resistance to extinction in males compared with females. These findings provide important insights into the sufficiency of NAc dopamine signaling dynamics-in interaction with sex-for recapitulating persistent cocaine seeking and future relapse vulnerability.

Automated summary

Understanding mesolimbic dopamine adaptations underlying vulnerability to drug relapse is crucial but challenging due to technical limitations. In this study, the fluorescent sensor GrabDA was used to measure sub-second dopamine release in the nucleus accumbens of mice during self-administration. The findings reveal predictors of cue-induced reinstatement of cocaine seeking and sex-specific differences in cocaine-related dopamine responses. These insights shed light on the role of NAc dopamine signaling dynamics and sex in persistent cocaine seeking and relapse vulnerability.