Previous studies in our laboratory have highlighted the importance of the setting in which drug is taken. We used an in vivo animal model in which one group of rats is transferred to the self-administration (SA) chambers during the 3 hour test sessions (Non Resident rats) and a second group literally lives in the SA chambers (Resident rats). Using this model we have seen that the setting modulates heroin self-administration (Caprioli et al. 2008), the choice between heroin and cocaine (Caprioli et al., 2009), the relapse (Montanari et al., 2015), as well as the internal state of the rats (Avvisati et al., 2016). Also the neurobiological effects of heroin are a function of the setting as previously demonstrated (Paolone et al. 2007; Celentano et al. 2009) using in situ hybridization and immunohistochemistry experiments. Thus, in the present study we have hypothesized the setting may influence also the synaptic plasticity in the cortico-accumbens circuit, areas involved in the impaired ability of addicts to regulate drug seeking, taking and relapse (Jentsch and Taylor, 1999; Luscher and Malenka, 2011; Nestler 2001; Kalivas and Volkow, 2011; Kalivas and O’Brien, 2008; Kalivas et al., 2004; Self et al., 2004). We trained independent groups of rats self administering heroin (25?g/kg/infusion) and saline for 10 sessions (3 hour each). After 14 days of abstinence rats underwent a cue induced reinstatement test. We also exposed single housed rats (IH) to Residence and Non Residence condition and we compared these rats with grouped house rats (GH). Using ex vivo field recordings on parasagittal slice we found that Heroin SA Resident rats showed an impairment in the capability to induce LTP (fEPSP amplitude 140% of baseline) when compared to Heroin SA Non Resident rats (fEPSP amplitude about 160% of baseline). Moreover saline SA, as well, single housed rats showed an impairment in the capability to induce LTP (fEPSP amplitude about 120% of baseline) when compared with grouped house rats (fEPS amplitude about 160%). This suggests that 1) cortico-accumbens synaptic plasticity is impaired in isolated rats and 2) heroin produces a recovering in the LTP response in both Non Resident and Resident rats even if Resident rats showed a non complete LTP recovering maybe due to the more rewarding effect of the drug in this environment. Further elucidations on how drugs of abuse alter cortico-accumbens plasticity will be necessary for the development of new therapies especially studies based on the use of heroin administration since most of the articles in literature have used cocaine.