br Author contributions br Financial disclosures

Author contributions
Financial disclosures
Acknowledgements We thank Ms. Eva So for the editorial assistance. This work was supported by grants from the National Natural Science Foundation of China (No. 81622015, 81571042 and 81501143) and the National Basic Research Program of China (No. 2014CB548100) to ZD, and the Canadian Institutes of Health Research (FDN-154286) to YTW. YTW is the holder of Heart and Stroke Foundation of British Columbia and Yukon Chair in Stroke Research.
Introduction Vulnerability to relapse is a hallmark of cocaine addiction in humans, yet current interventions remain largely ineffective (Kampman, 2005, Kampman, 2010). Animal models of cocaine addiction suggest that the persistent risk of relapse involves experience-dependent synaptic plasticity in mesocorticolimbic circuitry including the nucleus accumbens (NAc), a major limbic-motor interface critical for directing motivated behavior (Lüscher and Malenka, 2011). For example, forced abstinence from either chronic passive or actively self-administered cocaine results in strengthening of excitatory synapses onto gamma-aminobutyric A 350619 hydrochloride (GABAergic) medium spiny neurons (MSNs) in the NAc shell (NAcSh) – a phenomenon that is largely driven by enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated neurotransmission (Thomas, 2001, Boudreau and Wolf, 2005, Kourrich et al., 2007, Ma et al., 2014, Pascoli et al., 2014, Dong, 2016). Several studies have indicated that this plasticity is necessary for driving cocaine-related behavior, including the expression cocaine sensitization in mice exposed to passive cocaine injections (Pascoli et al., 2011, Terrier et al., 2016) as well cocaine-seeking or incubation of cocaine craving elicited by exposure to cocaine-associated contexts and/or cocaine-associated cues in animals with a chronic history of volitional, active cocaine self-administration (Ma et al., 2014, Pascoli et al., 2014, Terrier et al., 2016). While these findings strongly implicate potentiation at NAcSh MSNs in driving relapse-related behavior, studies looking at cocaine-seeking behavior in self-administering mice typically do so using forced abstinence/relapse models of self-administration (Venniro et al., 2016). Thus, it is unclear whether findings generalize to mice that have undergone extinction training during a drug-free period, or if maintains after exposure to different types of relapse-promoting stimuli. Relapse-related behavior during drug-free periods can be induced by exposure to various triggers including exposure to contextual cues (e.g., drug-associated environment), discrete cues (e.g., drug-associated objects in the environment), acute drug re-exposure, or stress. Interestingly, previous work using locomotor sensitization procedures have found that while chronic cocaine exposure followed by a drug-free period potentiates NAcSh synapses, exposure to cocaine or forced swim stress during drug-free periods has the opposite effect and instead reduces excitatory synaptic strength at NAcSh MSNs relative to unchallenged animals (Boudreau et al., 2007, Kourrich et al., 2007, Ferrario et al., 2010, Rothwell et al., 2011, Pascoli et al., 2011, Jedynak et al., 2016). These findings suggest that transient reductions in synaptic strength may also be important for relapse in response to these stimuli. However, it is unclear if such bidirectional plasticity also occurs in animals with a history of chronic volitional cocaine self-administration or how it may relate to relapse-related behavior induced by different stimuli. Therefore, we investigated relationships between NAcSh plasticity and relapse-related cocaine-seeking behavior using an extinction/reinstatement model of cocaine self-administration (de Wit and Stewart, 1981). This model differs from forced abstinence/relapse procedures in that it employs daily exposure to the cocaine-associated context during the drug-free period. Under these conditions, cocaine-seeking behavior in the drug-associated context becomes extinguished, but can then be reinstated by exposure to cocaine-associated cues, cocaine, or stress. We chose this approach as it is a different model than is typically used to examine relapse-related plasticity, and it also allowed us to selectively examine relapse-related plasticity at NAcSh MSNs across multiple independent modalities. These models also have important behavioral and neurological parallels to extinction training approaches used to reduce craving in humans (Bowers et al., 2010, Bossert et al., 2013).