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Kappa Opioid Receptors Negatively Regulate Real Time Spontaneous Dopamine Signals by Reducing Release and Increasing

Conner W Wallace1, Katherine M Holleran1, Clare Y Slinkard1

  • 1Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC.

Biorxiv : the Preprint Server for Biology
|February 19, 2024
PubMed

Insights

The kappa opioid receptor (KOR) system inhibits dopamine (DA) signaling by reducing DA release and enhancing DA reuptake. These effects, particularly on dopamine fluctuations, were more pronounced in male mice.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Neurochemistry

Background:

  • The dynorphin/kappa opioid receptor (KOR) system modulates dopamine (DA) neurotransmission.
  • KOR activation is known to decrease extracellular DA and enhance DA transporter (DAT) function.

Approach:

  • Utilized fiber photometry with the dLight1.2 photosensor in freely moving male and female mice.
  • Measured real-time DA fluctuations in the nucleus accumbens (NAc) core.
  • Administered the KOR agonist U50,488H (U50) with or without the KOR antagonist aticaprant (ATIC).

Key Points:

  • KOR activation reduced the amplitude and width of spontaneous DA signals in males, and reduced width in females.
  • Increased correlation slope between amplitude and width indicated enhanced DA uptake rates in both sexes.
  • KOR activation decreased the frequency of DA signals, with stronger effects observed in males.
  • KORs inhibit DA release, promote DAT-mediated uptake, and reduce signal frequency.

Conclusions:

  • KORs exert significant inhibitory control over spontaneous DA signaling in the NAc core.
  • KOR activation influences DA signaling through inhibition of DA release, promotion of DAT-mediated uptake, and reduction in signal frequency.
  • Sex-dependent differences exist in the magnitude of KOR system's inhibitory effects on DA signaling.

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