Extracellular Matrix Signaling Through β3 Integrin Mediates Cocaine Cue-Induced Transient Synaptic Plasticity and Relapse.
Animals
Cocaine
/ administration & dosage
Cues
Dendritic Spines
/ drug effects
Drug-Seeking Behavior
/ drug effects
Extinction, Psychological
/ drug effects
Integrin beta3
/ metabolism
Male
Matrix Metalloproteinase 2
/ metabolism
Matrix Metalloproteinase 9
/ metabolism
Models, Neurological
Motivation
Neuronal Plasticity
/ drug effects
Nucleus Accumbens
/ drug effects
Rats
Rats, Sprague-Dawley
Receptors, AMPA
/ metabolism
Receptors, N-Methyl-D-Aspartate
/ metabolism
Recurrence
Self Administration
Cocaine
Drug abuse
Focal adhesion kinase
Integrin
Nucleus accumbens
Relapse
Synaptic plasticity
Journal
Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264
Informations de publication
Date de publication:
01 09 2019
01 09 2019
Historique:
received:
31
10
2018
revised:
05
03
2019
accepted:
25
03
2019
pubmed:
28
5
2019
medline:
14
8
2020
entrez:
26
5
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31126696
pii: S0006-3223(19)31153-9
doi: 10.1016/j.biopsych.2019.03.982
pmc: PMC6697624
mid: NIHMS1526209
pii:
doi:
Substances chimiques
Integrin beta3
0
Receptors, AMPA
0
Receptors, N-Methyl-D-Aspartate
0
Matrix Metalloproteinase 2
EC 3.4.24.24
Matrix Metalloproteinase 9
EC 3.4.24.35
Cocaine
I5Y540LHVR
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
377-387Subventions
Organisme : NIDA NIH HHS
ID : P50 DA015369
Pays : United States
Organisme : NIDA NIH HHS
ID : K99 DA041462
Pays : United States
Organisme : NIGMS NIH HHS
ID : R25 GM113278
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA003906
Pays : United States
Organisme : NIGMS NIH HHS
ID : R25 GM072643
Pays : United States
Organisme : NIDA NIH HHS
ID : R37 DA003906
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA012513
Pays : United States
Organisme : NIDA NIH HHS
ID : P50 DA046373
Pays : United States
Organisme : NIDA NIH HHS
ID : R00 DA041462
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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