Mechanisms of Kappa Opioid Receptor Potentiation of Dopamine D2 Receptor Function in Quinpirole-Induced Locomotor Sensitization in Rats

Int J Neuropsychopharmacol. 2017 Aug 1;20(8):660-669. doi: 10.1093/ijnp/pyx042.


Background: Increased locomotor activity in response to the same stimulus is an index of behavioral sensitization observed in preclinical models of drug addiction and compulsive behaviors. Repeated administration of quinpirole, a D2/D3 dopamine agonist, induces locomotor sensitization. This effect is potentiated and accelerated by co-administration of U69593, a kappa opioid receptor agonist. The mechanism underlying kappa opioid receptor potentiation of quinpirole-induced locomotor sensitization remains to be elucidated.

Methods: Immunofluorescence anatomical studies were undertaken in mice brain slices and rat presynaptic synaptosomes to reveal kappa opioid receptor and D2R pre- and postsynaptic colocalization in the nucleus accumbens. Tonic and phasic dopamine release in the nucleus accumbens of rats repeatedly treated with U69593 and quinpirole was assessed by microdialysis and fast scan cyclic voltammetry.

Results: Anatomical data show that kappa opioid receptor and D2R colocalize postsynaptically in medium spiny neurons of the nucleus accumbens and the highest presynaptic colocalization occurs on the same dopamine terminals. Significantly reduced dopamine levels were observed in quinpirole, and U69593-quinpirole treated rats, explaining sensitization of D2R. Presynaptic inhibition induced by kappa opioid receptor and D2R of electrically evoked dopamine release was faster in U69593-quinpirole compared with quinpirole-repeatedly treated rats.

Conclusions: Pre- and postsynaptic colocalization of kappa opioid receptor and D2R supports a role for kappa opioid receptor potentiating both the D2R inhibitory autoreceptor function and the inhibitory action of D2R on efferent medium spiny neurons. Kappa opioid receptor co-activation accelerates D2R sensitization by contributing to decrease dopamine release in the nucleus accumbens.

Keywords: U69593; dopamine; kappa opioid receptor; locomotor sensitization; quinpirole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Animals
  • Benzeneacetamides / pharmacology
  • Dopamine / metabolism
  • Dopamine Agonists / pharmacology*
  • Extracellular Space / drug effects
  • Extracellular Space / metabolism
  • Male
  • Mice, Inbred C57BL
  • Motor Activity / drug effects*
  • Motor Activity / physiology
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism
  • Pyrrolidines / pharmacology
  • Quinpirole / pharmacology*
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / metabolism*
  • Synapses / drug effects
  • Synapses / metabolism
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Tissue Culture Techniques


  • Analgesics, Opioid
  • Benzeneacetamides
  • Dopamine Agonists
  • Pyrrolidines
  • Receptors, Dopamine D2
  • Receptors, Opioid, kappa
  • Quinpirole
  • U 69593
  • Dopamine