Figure 2.

The tripartite synapse and glutamate homeostasis. When glutamate homeostasis is maintained, GLT-1 removes glutamate from the synaptic cleft, and the glial system X_c⁻ releases glutamate to the extrasynaptic location, which activates the inhibitory metabotropic glutamate receptors 2 and 3 (mGluR2/3) which inhibits synaptic glutamate release. Drugs of abuse alter glutamate homeostasis by increasing the levels of oxidative stress, which impair GLT-1 activity and reduce the activity of system X_c⁻. Both effects potentiate cued-induced increases in post-synaptic glutamate tone. Drugs of abuse also strengthen glutamatergic transmission by promoting the recruitment of Ca²⁺ permeable AMPA receptors (CP-AMPAR). Antioxidants like N-acetylcysteine (NAC) normalize glutamate homeostasis by increasing the levels of cystine, activating both the system X_c⁻ and mGluR2/3, also increasing GSH and reducing oxidative stress, which recovers GLT-1 activity. Administration of secretome derived from mesenchymal stem cells (MSCs) also reduces drug consumption by reducing oxidative stress and recovering GLT-1 activity.