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Extracellular Matrix Signaling Through ?3 Integrin Mediates Cocaine Cue-Induced Transient Synaptic Plasticity and Relapse.

ABSTRACT: 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 ?1 or ?3 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 ?3 integrin or FAK inhibitor, but not ?1 integrin or integrin-linked kinase inhibitor, prevented cue-induced cocaine seeking but not sucrose seeking. ?3 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 ?3 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 ?3 integrins and activates FAK to induce t-SP and promote cue-induced cocaine seeking.

SUBMITTER: Garcia-Keller C

PROVIDER: S-EPMC6697624 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Garcia-Keller Constanza C Neuhofer Daniela D Bobadilla Ana-Clara AC Spencer Sade S Chioma Vivian C VC Monforton Cara C Kalivas Peter W PW

Biological psychiatry 20190403 5

<h4>Background</h4>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.<h4>Methods</h4>Male Sprague Dawley rats (N ...[more]

PMID: 31126696

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Project description:Repeated exposure to cocaine causes sensitized behavioral responses and increased dendritic spines on medium spiny neurons of the nucleus accumbens (NAc). We find that cocaine regulates myocyte enhancer factor 2 (MEF2) transcription factors to control these two processes in vivo. Cocaine suppresses striatal MEF2 activity in part through a novel mechanism involving cAMP, the regulator of calmodulin signaling (RCS), and calcineurin. We show that reducing MEF2 activity in the NAc in vivo is required for the cocaine-induced increases in dendritic spine density. Surprisingly, we find that increasing MEF2 activity in the NAc, which blocks the cocaine-induced increase in dendritic spine density, enhances sensitized behavioral responses to cocaine. Together, our findings implicate MEF2 as a key regulator of structural synapse plasticity and sensitized responses to cocaine, and suggest that reducing MEF2 activity (and increasing spine density) in NAc may be a compensatory mechanism to limit long-lasting maladaptive behavioral responses to cocaine. Mice were treated for 7 days with daily injections of cocaine (20 mg/kg) and sacrificed 24 hrs later. Chromatin from bilateral punches of NAc was immunoprecipitated with an antibody against MEF2A as described previously with minor modifications (Renthal et al., 2007). Chromatin was sonicated to an average of ~500 bp and immunoprepitated with antibody against MEF2A (Santa Cruz, sc-313) or an IgG control (Upstate/Millipore). Antibody-bound chromatin was precipitated using Protein A beads from Upstate (06-157), which were washed with low salt, high salt, and LiCl buffers to remove non-specific DNA binding. Eluted chromatin was reverse-crosslinked at 65oC in the presence of proteinase K and EDTA. DNA was purified by chloroform extraction/ethanol precipitation and the enrichment of specific promoters was amplified by ligation-mediated PCR for genome-wide analysis (Sikder et al., 2006). Amplified DNA was then labeled with Cy3 (input-enriched) or Cy5 (MEF2-enriched) and hybridized to Nimblegen (Madison, WI) MM8 mouse promoter arrays. Bilateral nucleus accumbens from eight mice were pooled for microarray analysis.

Dataset Information

Extracellular Matrix Signaling Through ?3 Integrin Mediates Cocaine Cue-Induced Transient Synaptic Plasticity and Relapse.

Publications

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

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