Faculty Collaboration Database

Extracellular Matrix Signaling Through β3 Integrin Mediates Cocaine Cue-Induced Transient Synaptic Plasticity and Relapse. Biol Psychiatry 2019 Sep 01;86(5):377-387

Date

05/28/2019

Pubmed ID

31126696

Pubmed Central ID

PMC6697624

DOI

10.1016/j.biopsych.2019.03.982

Scopus ID

2-s2.0-85065825713 (requires institutional sign-in at Scopus site)   27 Citations

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 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.

Author List

Garcia-Keller C, Neuhofer D, Bobadilla AC, Spencer S, Chioma VC, Monforton C, Kalivas PW

Author

Constanza Garcia Keller PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cocaine
Cues
Dendritic Spines
Drug-Seeking Behavior
Extinction, Psychological
Integrin beta3
Male
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Models, Neurological
Motivation
Neuronal Plasticity
Nucleus Accumbens
Rats
Rats, Sprague-Dawley
Receptors, AMPA
Receptors, N-Methyl-D-Aspartate
Recurrence
Self Administration