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

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.