is mediated in part by a reduction in cysteine containing GSH in human alcoholic brain and in binge drinking mice (Marballi et al., 2016; Wrona et al., 1997). In addition, increased glutamatergic excitatory signaling within corticostriatal pathways is associated with craving in humans and is necessary for reinstatement in rodents. The cystine-glutamate antiporter (xCT) exchanges extracellular cysteine for intracellular glutamate and functions as the primary regulator of extracellular glutamate in many brain regions. N-acetylcysteine is a l-cysteine prodrug and is known to act by normalizing dependence-induced extra-synaptic glutamate through the activation of the cystine-glutamate exchanger (Massie et al., 2015). Indeed, repeated N-acetyl cysteine reduces drug seeking in rodents and craving in humans (Amen et al., 2011). Therefore, it is intriguing to speculate that genetic variation in CARS may be related to functional alterations in cysteine containing proteins, alterations in oxidative stress, and dysfunction of the cystine-glutamate exchange system. Collectively, these alterations in cysteine biology could be hypothesized to impose significant dysfunction to corticostriatal circuits associated with drug abstinence and craving relevant to the preoccupation-anticipation addiction domain.
