Introduction
Chronic cocaine produces persistent neuroadaptations in brain networks that underlie long-term risks of relapse and incubation of drug craving (van Huijstee and Mansvelder, 2015). Rewarding properties of psychostimulants such as cocaine are associated with hyperdopaminergic state (Wise and Hoffman, 1992) whereas acute withdrawal from acute and chronic psychostimulants leads to a hypodopaminergic state, specifically in the mesolimbic system (Shen et al., 2007; Belujon et al., 2016; Salin et al., 2021), leading to hedonic deficits (Wise, 2008; Belujon and Grace, 2017). Reduction of DA activity is also observed after long abstinence (Diana et al., 1996; Salin et al., 2021); this reduction could be involved in dysphoria described after protracted abstinence (Haake et al., 2019).
DA activity is regulated by different afferent circuits. In particular, the basolateral nucleus of the amygdala (BLA)-ventral pallidum (VP) pathway has been shown to inhibit VTA DA activity (Chang and Grace, 2014). The BLA is a crucial brain structure involved in emotional processes (LeDoux, 2000; Adhikari et al., 2015; Janak and Tye, 2015) and in reward-associated learning and memory (Murray, 2007; Wassum and Izquierdo, 2015). In drug addiction, the BLA is a major brain substrate for drug-associated cue memory and imaging studies in humans report increased activity in the amygdala in cocaine craving addicts exposed to drug-cues (Maas et al., 1998; Childress et al., 1999; Garavan et al., 2000). In rodents, increased activity of BLA neurons have been described during abstinence from chronic cocaine (Munshi et al., 2019) and exposure to drug-related environmental cues triggers drug-seeking behavior which is alleviated by lesion of the BLA (Meil and See, 1997). The VP is a central site for limbic reward signals (Smith et al., 2009) and is involved in drug-seeking behavior after long-term abstinence (Farrell et al., 2019), in particular its projections to the VTA (Mahler et al., 2014). Importantly, the BLA-dependent decrease in VTA activity found in psychiatric disorders such as major depressive disorders appears to be regulated by the VP (Chang and Grace, 2014). However, it is not known whether the same circuit plays a role in DA hypoactivity that characterize prolonged abstinence.
In this work, we investigated the potential involvement of the BLA and the VP in VTA hypodopaminergic activity during withdrawal from chronic cocaine, using a model of cocaine self-administration, in vivoelectrophysiological recordings of DA VTA neurons and BLA putative projections neurons from anesthetized rats during early and protracted abstinence.