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.