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κ-Opioid Receptor Activation in Dopamine Neurons Disrupts Behavioral Inhibition

Antony D Abraham1, Harrison M Fontaine1, Allisa J Song1

  • 1Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, USA.

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
|June 27, 2017
PubMed

Insights

Dynorphin/κ-opioid receptor (KOR) activation in the ventral tegmental area (VTA) dopamine neurons disrupts behavioral inhibition. KOR antagonists may reduce stress-induced compulsive behaviors.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Behavioral Science

Background:

  • The dynorphin/κ-opioid receptor (KOR) system's role in cognition is recognized, but the specific neural circuits and molecular pathways driving KOR-mediated cognitive impairment remain unclear.
  • Understanding these mechanisms is crucial for developing targeted interventions for cognitive dysfunction and compulsive behaviors.

Purpose of the Study:

  • To elucidate the neural circuitry and molecular mechanisms underlying KOR-mediated disruption of cognitive functions, specifically behavioral inhibition.
  • To investigate the role of VTA dopamine neurons and arrestin-dependent signaling in KOR-induced cognitive deficits.

Main Methods:

  • Utilized the differential reinforcement of low response rate (DRL) task in mice to assess cognitive performance and behavioral inhibition.
  • Administered systemic and local KOR agonists/antagonists (nor-BNI, nalfurafine) and employed genetic manipulations (Cre-dependent deletion of KOR, GRK3, p38α MAPK) in specific neuronal populations (VTA, PFC, DRN, dopaminergic, serotonergic neurons).
  • Measured marble burying behavior as an indicator of compulsive activity.

Main Results:

  • Systemic KOR activation impaired DRL task performance and increased compulsive behaviors (marble burying).
  • Local KOR antagonism in the VTA, but not PFC or DRN, prevented KOR-mediated DRL disruption.
  • Genetic deletion of KOR from dopaminergic neurons blocked these disruptive effects, implicating VTA dopamine neurons.
  • KOR-induced cognitive disruption occurred independently of GRK3/arrestin-dependent signaling pathways.

Conclusions:

  • KOR activation within VTA dopamine neurons is a key mediator of disrupted behavioral inhibition.
  • The cognitive effects of KOR are mediated through a GRK3/arrestin-independent pathway.
  • KOR antagonists show potential therapeutic value for mitigating stress-induced compulsive behaviors.

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