Abstract
Treatments for substance use and stress disorders are based on ameliorating behavioral symptoms, not on reversing the synaptic pathology that has the potential to cure disorders. This failing arises in part from a research focus on how pre- and postsynaptic physiology is changed even though key neuropathology exists in the perisynaptic neuropil that homeostatically regulates synaptic transmission. We explore recent findings from the substance use and stress disorder literature pointing to a key role for perisynaptic astroglia and signaling in the extracellular matrix (ECM) in regulating synaptic pathology. We conclude that drugs and stress initiate long-lasting changes in brain synapses via enduring neuroadaptations in astroglia and the ECM, and that modulating extrasynaptic regulators may be therapeutically useful.