Figure 2. Proposed role of known opioid adaptations in nucleus accumbens glutamate transmission in opioid addiction.

Repeated exposure to opioids promotes a number of pre- and postsynaptic modifications in excitatory currents, most of which appears to be mediated by the ionotropic AMPA-type receptors. (Top) Enduring adaptations at mPFC-to-NAc synapses aligning with plasticity associated with establishing learned drug associations, drug-seeking/taking behavior, and relapse. Modifications include increased glutamate release probability and insertion of AMPARs that are permeable (GluA1/GluA1; blue-blue) or impermeable (GluA1/GluA2; blue-green) at PrL-to-Core (light blue) and IL-to-Shell (dark blue) synapses on D1-MSNs (red) as well as reduced excitatory drive and increased synapse numbers in D2-MSNs (green). These cell-specific adaptations promote an overall shift in excitatory drive within D1- and D2-MSN circuits that favors strengthening of D1-MSN pathways. (Bottom) The cellular, temporal, and mechanistic nuances of NAc glutamate plasticity contributing to dependence and withdrawal are less clear. Morphine withdrawal is associated with increased extracellular glutamate, which may reflect increased release probability or impaired clearance, or both. It is possible that upregulation of excitatory signaling plays distinct roles depending on the MSN sub-type, with increased signaling at D1-MSNs reflecting changes related to reward/relapse whereas signaling at D2-MSNs is responsible for withdrawal-related symptoms, with specific pathways contributing to unique aspects of this withdrawal (i.e., negative affect vs. somatic).