Extracellular Matrix Signaling Through β3 Integrin Mediates Cocaine Cue-induced Transient Synaptic Plasticity and Relapse

Background: Cue-induced relapse to drug use is a primary symptom of cocaine addiction. Cue-induced transient excitatory synaptic potentiation (t-SP) induced in nucleus accumbens mediates cued cocaine seeking in rat models of relapse. Cue-induced t-SP depends on extracellular signaling by matrix metalloproteases (MMPs), but it is unknown how this catalytic activity communicates with accumbens neurons to induce t-SP and cocaine seeking. Methods: Male Sprague-Dawley rats (n=125) were trained to self-administer cocaine, extinguished and reinstated by cocaine-conditioned cues. We used a morpholino antisense strategy to knock-down the β1- or β3-integrin subunit, or inhibitors to prevent phosphorylation of integrin signaling kinases focal adhesion kinase (FAK) or integrin-linked kinase (ILK). We quantified protein changes with immunoblotting, and t-SP by measuring dendritic spine morphology and AMPA/NMDA glutamate currents. Integrin signaling was stimulated by microinjecting an MMP activator or integrin peptide ligand into the accumbens. Results: Knock-down of β3-integrin or FAK inhibitor, but not β1-integrin or ILK inhibitor, prevented cue-induced cocaine seeking, but not sucrose seeking. β3-integrin knock-down prevented t-SP as measured by preventing the cue-induced increases in both AMPA/NMDA ratio and spine head diameter. Activating MMP gelatinases with tissue plasminogen activator potentiated cue-induced reinstatement, which was prevented by β3-integrin knock-down and FAK inhibition. Stimulating integrin receptors with the RGD ligand liberated by MMP gelatinase activity also potentiated cued cocaine seeking. Conclusions: Activation of MMP gelatinase in the extracellular space is necessary for and potentiates cued cocaine seeking. This extracellular catalysis stimulates β3-integrins and activates FAK to induce t-SP and promote cue-induced cocaine seeking.