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Updated: Jan 24, 2026
A Protocol for Measuring Cue Reactivity in a Rat Model of Cocaine Use Disorder
Published on: June 18, 2018
Extracellular Matrix Signaling Through β3 Integrin Mediates Cocaine Cue-Induced Transient Synaptic Plasticity and
Constanza Garcia-Keller1, Daniela Neuhofer1, Ana-Clara Bobadilla1
1Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina.
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.
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