Allostatic Changes in the cAMP System Drive Opioid-Induced Adaptation in Striatal Dopamine Signaling.

ABSTRACT: Opioids are powerful addictive agents that alter dopaminergic influence on reward signaling in medium spiny neurons (MSNs) of the nucleus accumbens. Repeated opioid exposure triggers adaptive changes, shifting reward valuation to the allostatic state underlying tolerance. However, the cellular substrates and molecular logic underlying such allostatic changes are not well understood. Here, we report that the plasticity of dopamine-induced cyclic AMP (cAMP) signaling in MSNs serves as a cellular substrate for drug-induced allostatic adjustments. By recording cAMP responses to optically evoked dopamine in brain slices from mice subjected to various opioid exposure paradigms, we define profound neuronal-type-specific adaptations. We find that opioid exposure pivots the initial hyper-responsiveness of D1-MSNs toward D2-MSN dominance as dependence escalates. Presynaptic dopamine transporters and postsynaptic phosphodiesterases critically enable cell-specific adjustments of cAMP that control the balance between opponent D1-MSN and D2-MSN channels. We propose a quantitative model of opioid-induced allostatic adjustments in cAMP signal strength that balances circuit activity.

SUBMITTER: Muntean BS 

PROVIDER: S-EPMC6871051 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature