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

Cell Rep. 2019 Oct 22;29(4):946-960.e2. doi: 10.1016/j.celrep.2019.09.034.


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.

Keywords: GPCR; addiction; cAMP; dopamine; nucleus accumbens; opioid; plasticity; striatum.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptation, Physiological*
  • Analgesics, Opioid / pharmacology
  • Animals
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Corpus Striatum / physiopathology
  • Cyclic AMP / metabolism*
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / metabolism
  • Neurons / physiology
  • Opioid-Related Disorders / metabolism*
  • Opioid-Related Disorders / physiopathology
  • Phosphoric Diester Hydrolases / metabolism
  • Synaptic Transmission*


  • Analgesics, Opioid
  • Dopamine Plasma Membrane Transport Proteins
  • Cyclic AMP
  • Phosphoric Diester Hydrolases
  • Dopamine