Heroin Seeking and Extinction From Seeking Activate Matrix Metalloproteinases at Synapses on Distinct Subpopulations of Accumbens Cells

Published:December 08, 2020DOI:



      Seeking addictive drugs is regulated by synaptic plasticity in the nucleus accumbens core and involves distinct plasticity in D1 and D2 receptor–expressing medium spiny neurons (D1/2-MSNs). However, it is unknown how differential plasticity between the two cell types is coordinated. Synaptic plasticity and seeking behavior induced by drug-paired cues depends not only on plasticity in the canonical pre- and postsynapse, but also on cue-induced changes in astrocytes and the extracellular matrix adjacent to the synapse. Drug cue–induced signaling in the extracellular matrix is regulated by catalytic activity of matrix metalloproteinases MMP-2,9. We hypothesized that the cell type–specific synaptic plasticity is associated with parallel cell-specific activity of MMP-2 and MMP-9.


      Transgenic rats were trained on a heroin self-administration protocol in which a light/tone cue was paired with heroin delivery, followed by 2 weeks of drug withdrawal, and then reinstated to heroin-conditioned cues. Confocal microscopy was used to make morphological measurements in membrane reporter–transduced D1- and D2-MSNs and astrocytes, and MMP-2,9 gelatinase activity adjacent to cell surfaces was quantified using in vivo zymography.


      Presenting heroin-paired cues transiently increased MMP-9 activity around D1-MSN dendritic spines and synapse-proximal astroglial processes. Conversely, extinction training induced long-lasting increases in MMP-2 activity adjacent to D2-MSN synapses. Moreover, heroin-paired cues increased tissue inhibitor of metalloproteinases TIMP-1,2, which caused transient inhibition of MMP-2 activity around D2-MSNs during cue-induced heroin seeking.


      The differential regulation of heroin seeking and extinguished seeking by different MMP subtypes on distinct cell populations poses MMP-2,9 activity as an important mediator and contributor in heroin-induced cell-specific synaptic plasticity.


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      • A Third-Party Facilitator of Bipartisanship
        Biological PsychiatryVol. 89Issue 10
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          Biological processes are often reminiscent of a two-party system, wherein two differential or opposing forces must coordinate to achieve a balanced output, and drug addiction is no exception. In the nucleus accumbens (NAc), the two parties in play are D1 and D2 receptor–expressing medium spiny neurons (D1- and D2-MSNs). Differentially embedded in NAc circuits, D1- and D2-MSNs regulate different aspects of motivated behaviors related to drug addiction, often in opposing manners (1). To form coherent and reliable behavioral outputs, e.g., persistent cue-induced drug seeking, cooperative, as opposed to preferential, adaptations between these two neuronal types is required.
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