Extracellular Matrix Signaling Through β3 Integrin Mediates Cocaine Cue-Induced Transient Synaptic Plasticity and Relapse
| Autor: | Peter W. Kalivas, Sade Spencer, Constanza Garcia-Keller, Cara Monforton, Daniela Neuhofer, Vivian C. Chioma, Ana-Clara Bobadilla |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Dendritic Spines Integrin Drug-Seeking Behavior Models Neurological Self Administration Nucleus accumbens Receptors N-Methyl-D-Aspartate Nucleus Accumbens Extinction Psychological Focal adhesion Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Cocaine Recurrence Extracellular Animals Receptors AMPA Biological Psychiatry Motivation Neuronal Plasticity biology Activator (genetics) Chemistry Glutamate receptor Integrin beta3 Long-term potentiation Cell biology Rats 030104 developmental biology Matrix Metalloproteinase 9 Synaptic plasticity biology.protein Matrix Metalloproteinase 2 Cues 030217 neurology & neurosurgery |
| Zdroj: | Biological psychiatry. 86(5) |
| ISSN: | 1873-2402 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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