Allostatic plasticity of cAMP system drives opioid induced adaptations in striatal dopamine signaling

Abstract

Opioids generate euphoria by activating the reward system in the brain, however chronic exposure generates plastic changes in signal processing to program aversive reactions. A core element of the reward circuit involves the integration of dopamine in subpopulations of medium spiny striatal neurons, D1‐MSN and D2‐MSN, whereby these two parallel channels encode the opponent processes through cAMP‐dependent signaling. However, the precise mechanisms that bias circuit activity to encode a range of hedonic states during various stages of opioid exposure are not well understood. Uncovering the fundamental properties and molecular machinery for parsing GPCR signal integration in striatal neurons is a critical step in advancing our understanding of neurobiology necessary to comprehend the adaptations induced by opioids. By recording cAMP dynamics with nanomolar resolution from genetically defined striatal neurons in an intact neuronal circuit, we revealed elemental properties that promote D1‐MSN signaling during acute opioid exposure while favoring D2‐MSN signaling following chronic drug administration. Additionally, we identified two key molecular components that shape plasticity of cAMP signaling. We found that opioids enable phosphodiesterases to regulate D1‐MSN signaling capacity while reducing the role of presynaptic dopamine transporters to influence D2‐MSN response strength. Our results demonstrate the importance of balancing signal integration between concurrently activated subpopulations of striatal neurons while exploring pre‐ and postsynaptic mechanisms that impact accompanying computations performed by the circuit. We propose a quantitative model whereby differential exposure to opioids provides cell‐specific adjustments in cAMP signal strength that imbalances circuit activity to promote transitions between states of reward and aversion.Support or Funding InformationThis work was supported by NIH grants: DA041207 (to B.S.M.), DA036596 (to K.A.M.), and DA026405 (to K.A.M.)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.