Background: Cue-induced relapse to drug use is a primary symptom of cocaine addiction. Cue-induced transient excitatory synaptic potentiation (t-SP) induced in the 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 nucleus accumbens neurons to induce t-SP and cocaine seeking. Methods: Male Sprague Dawley rats (N = 125) were trained to self-administer cocaine, after which self-administration was extinguished and then reinstated by cocaine-conditioned cues. We used a morpholino antisense strategy to knock down the β1 or β3 integrin subunits or inhibitors to prevent phosphorylation of the integrin signaling kinases focal adhesion kinase (FAK) or integrin-linked kinase. We quantified protein changes with immunoblotting and t-SP by measuring dendritic spine morphology and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate glutamate currents. Integrin signaling was stimulated by microinjecting an MMP activator or integrin peptide ligand into the accumbens. Results: Knockdown of β3 integrin or FAK inhibitor, but not β1 integrin or integrin-linked kinase inhibitor, prevented cue-induced cocaine seeking but not sucrose seeking. β3 integrin knockdown prevented t-SP as measured by preventing the cue-induced increases in both alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate glutamate ratio and spine head diameter. Activating MMP gelatinases with tissue plasminogen activator potentiated cue-induced reinstatement, which was prevented by β3 integrin knockdown 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.
Bibliographical noteFunding Information:
This work was supported by National Institute on Drug Abuse Grant Nos. DA003906 , DA12513 , and DA015369 (to PWK) and Department of Defense UDAK (User Defined Accounting Key) Grant No. 8B705 (to PWK).
This work was supported by National Institute on Drug Abuse Grant Nos. DA003906, DA12513, and DA015369 (to PWK) and Department of Defense UDAK (User Defined Accounting Key) Grant No. 8B705 (to PWK). CG-K and PWK designed the research, CG-K, DN, A-CB, SS, VCC, and CM performed the research, CG-K and PWK analyzed the data, and CG-K and PWK wrote the article. We thank Madhura Athreya for advice and technical assistance and Heather A. Boger for allowing us to perform the rat locomotor measurement using her equipment. The authors report no biomedical financial interests or potential conflicts of interest.
© 2019 Society of Biological Psychiatry
- Drug abuse
- Focal adhesion kinase
- Nucleus accumbens
- Synaptic plasticity