As discussed earlier, excessive glutamate in the synapse (e.g., the addiction-related hyperglutamatergic state) can lead to excitotoxicity and neuronal death. Thus, glutamate uptake/transport from the synapse and perisynapse is required to prevent the plasticity associated with addiction to become excitotoxicity.34,38 There are several transporters that regulate extracellular glutamate levels including the EAAT1 (glutamate aspartate transporter: GLAST or Slc1a3), EAAT2 (GLT1), EAAT3 (excitatory amino acid carrier 1: EAAC1 or Slc1a1), EAAT4 (Slc1a6), and EAAT5; where EAAT indicates the human homolog.55–57 There are also intracellular vesicular glutamate transporters (VGLUT1–3 of the Slc17 family of genes) that mediate the uptake of glutamate into synaptic vesicles. Intracellular glutamate carriers, other than the vGLUTs, include the Slc25a family of genes. Since the NMDAR NR1 subunit contains the glycine-binding site, it is important to recognize the role of bidirectional glycine transporters (GlyT1 which is primarily glial and GlyT2 which is primarily neuronal) at the excitatory synapse (GlyTs are represented by gene families Slc6a and Slc7a). Given the increased interest in N-acetyl-cysteine’s role in mental health, it is equally important to recognize the cystine–glutamate exchanger’s (xCT =
