Extracellular matrix plasticity and GABAergic inhibition of prefrontal cortex pyramidal cells facilitates relapse to heroin seeking.
Successful treatment of drug addiction is hampered by high relapse rates during periods of abstinence. Neuroadaptation in the medial prefrontal cortex (mPFC) is thought to have a crucial role in vulnerability to relapse to drug seeking, but the molecular and cellular mechanisms remain largely unknown. To identify protein changes that contribute to relapse susceptibility, we investigated synaptic membrane fractions from the mPFC of rats that underwent 21 days of forced abstinence following heroin self-administration. Quantitative proteomics revealed that long-term abstinence from heroin self-administration was associated with reduced levels of extracellular matrix (ECM) proteins. After extinction of heroin self-administration, downregulation of ECM proteins was also present in the mPFC, as well as nucleus accumbens (NAc), and these adaptations were partially restored following cue-induced reinstatement of heroin seeking. In the mPFC, these ECM proteins are condensed in the perineuronal nets that exclusively surround GABAergic interneurons, indicating that ECM adaptation might alter the activity of GABAergic interneurons. In support of this, we observed an increase in the inhibitory GABAergic synaptic inputs received by the mPFC pyramidal cells after the re-exposure to heroin-conditioned cues. Recovering levels of ECM constituents by metalloproteinase inhibitor treatment (FN-439; i.c.v.) prior to a reinstatement test attenuated subsequent heroin seeking, suggesting that the reduced synaptic ECM levels during heroin abstinence enhanced sensitivity to respond to heroin-conditioned cues. We provide evidence for a novel neuroadaptive mechanism, in which heroin self-administration-induced adaptation of the ECM increased relapse vulnerability, potentially by augmenting the responsivity of mPFC GABAergic interneurons to heroin-associated stimuli.
Van den Oever
Michel C
MC
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics & Cognitive Research, VU University Amsterdam, The Netherlands. michel.van.den.oever@cncr.vu.nl
Lubbers
Bart R
BR
Goriounova
Natalia A
NA
Li
Ka W
KW
Van der Schors
Roel C
RC
Loos
Maarten
M
Riga
Danai
D
Wiskerke
Joost
J
Binnekade
Rob
R
Stegeman
M
M
Schoffelmeer
Anton N M
AN
Mansvelder
Huibert D
HD
Smit
August B
AB
De Vries
Taco J
TJ
Spijker
Sabine
S
D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000145:classification / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D003932:Heroin / Q000009:adverse effects*; D006556:Heroin Dependence / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry; D009294:Narcotics / Q000009:adverse effects*; D009842:Oligopeptides / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000473:pathology*; D040901:Proteomics / Q000379:methods; D017966:Pyramidal Cells / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012055:Reinforcement Schedule; D012646:Self Administration / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D055366:Synaptic Potentials / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C095170:4-aminobenzoyl-glycyl-prolyl-leucyl-alanine hydroxamic acid; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D009294:Narcotics; D009842:Oligopeptides; D005680:gamma-Aminobutyric Acid; D003932:Heroin