Figure 1.

Model of the tetrapartite synapse and how it is altered after withdrawal from addictive drugs. A) Drug-naïve synaptic glutamate release probability is regulated by mGluR2/3 inhibitory autoreceptors, while the cystine-glutamate exchanger (Xc-) and glutamate transporter (GLT-1) expressed largely on astroglial cells, regulate the elimination of glutamate and determine how much glutamate spills out of the synapse. The extracellular matrix maintains synaptic structure and mediates synaptic plasticity by activating MMPs and signaling to the postsynapse via integrins. B) After drug self-administration and extinction training, presentation of the cues previously associated with the drug during acquisition of drug use induces a strong release of glutamate originating from prelimbic cortical afferents. Decreased function of mGluR2/3 and GLT-1, and withdrawal of astroglial end feet impair glutamate homeostasis and allow spillover of glutamate from the synaptic cleft. Extrasynaptic glutamate stimulates mGluR5 on nNOS interneurons (not shown), which activates matrix metalloproteases via nitrosylation. Catalytic signal transduction in the extracellular matrix by MMPs stimulates the expansion of postsynaptic spines and the insertion of AMPA receptors. AMPA-R: α-Amino-3-hydroxy-5-Methyl-4-isoxazole Propionic Acid Receptor

ECM: Extracellular Matrix GLT-1: Glutamate Transporter 1

Glu: Glutamate

MMP: Matrix Metalloprotease

MSN: Medium Spiny Neuron

NMDA-R: N-Methyl-D-Aspartate Receptor

Xc-: Cysteine/glutamate exchanger