The Opioid-Addicted Tetrapartite Synapse

Abstract Opioid administration in preclinical models induces long-lasting adaptations in reward and habit circuitry. The latest research demonstrates that in the nucleus accumbens opioid-induced excitatory synaptic plasticity involves pre- and post-synaptic elements, as well as adjacent astroglial processes and the perisynaptic extracellular matrix. Here we outline opioid-induced modifications within each component of the tetrapartite synapse and provide a neurobiological perspective on how these adaptations converge to produce addiction-related behaviors in rodent models. By incorporating changes observed at each of the excitatory synaptic compartments into a unified framework of opioid-induced glutamate dysregulation, we highlight new avenues for restoring synaptic homeostasis that might limit opioid craving and relapse vulnerability.