But how relapse relates to activity in specific VTA and accumbens compartments, whether this is the same for different forms of relapse, and how relapse-associated activity relates to activity during self-administration or extinction/abstinence are unknown. Relapse is presumably assembled from activity across the mesolimbic dopamine system. In turn, there are distinct profiles of dopamine release across compartments of the ventral striatum giving rise to different functions ( de Jong et al., 2019 Mohebi et al., 2019). VTA dopamine neurons form distinct channels linked to differences in behavioral and motivational function ( Cohen et al., 2012 de Jong et al., 2019 Heymann et al., 2019 Lammel et al., 2008 Lammel et al., 2011 Lammel et al., 2013 Saunders et al., 2018 Tian et al., 2016 Watabe-Uchida et al., 2012). However, the mesolimbic dopamine system has a complex architecture. In animal models, dopamine mediates various forms of relapse to drug seeking (cue-, stress-, priming, context/renewal reinstatement) because these can be prevented by systemic or local manipulation of ventral tegmental area (VTA) and nucleus accumbens (Acb) ( Bossert et al., 2013 Bossert et al., 2007 Chaudhri et al., 2009 Gibson et al., 2018 Hamlin et al., 2007 Mahler et al., 2014 McFarland and Kalivas, 2001 Schmidt et al., 2005). A persistent propensity to relapse is a diagnostic feature of drug addiction and remains a primary impediment to successful long-term treatment (Association, 2013 Jonas et al., 2014).

Chief among these is how dopamine contributes to relapse. Much remains to be learned about these roles of dopamine in addiction. Moreover, exposure to drugs of addiction can profoundly alter these functions ( Volkow et al., 2017). Dopamine mediates the reinforcing effects of drugs of abuse, instructs learning about behavioral as well as environmental antecedents to these effects, and contributes to action selection controlling drug seeking and drug taking ( Everitt et al., 2008 Luscher, 2015 Nutt et al., 2015). It is axiomatic that the actions of dopamine are critical to drug addiction. We show that signatures of relapse can be identified from heterogeneous activity profiles across the mesolimbic dopamine system and that these signatures differ for different forms of relapse. Finally, we use dissimilarity matrices to identify mesolimbic dopamine signatures of self-administration, extinction, and relapse. Using a variety of interventions, we show that this activity is causal to both forms of relapse. Using gCaMP and dLight fibre photometry, we show that self-administration and two forms of relapse (renewal/context-induced reinstatement and reacquisition) are associated with recruitment across the mesolimbic dopamine system. Here we show how different forms of relapse to alcohol-seeking are assembled from activity across the ventral tegmental area and the nucleus accumbens. Less well understood is how complex addiction-related behaviors emerge from activity patterns across these compartments. The mesolimbic dopamine system comprises distinct compartments supporting different functions in learning and motivation.

Dlight dopamine sensor