Acute and subchronic PCP attenuate D2 autoreceptor signaling in substantia nigra dopamine neurons

Eur Neuropsychopharmacol. 2019 Mar;29(3):444-449. doi: 10.1016/j.euroneuro.2019.01.108. Epub 2019 Jan 25.


Phencyclidine (PCP) administration is commonly used to model schizophrenia in laboratory animals. While PCP is well-characterized as an antagonist of glutamate-sensitive N-methyl-D-aspartate (NMDA) receptors, its effects on dopamine signaling are not well understood. Here we used whole-cell and cell-attached patch-clamp electrophysiology of substantia nigra dopamine neurons to determine the effects of acute and subchronic PCP exposure on both dopamine D2 autoreceptor-mediated currents and burst firing evoked by glutamate receptor activation. Acute PCP affected D2 autoreceptor-mediated currents through two apparently distinct mechanisms: a low-concentration dopamine transporter (DAT) inhibition and a high-concentration potassium (GIRK) channel inhibition. Subchronic administration of PCP (5 mg/kg, i.p., every 12 h for 7 days) decreased sensitivity to low dopamine concentrations, and also enhanced evoked burst firing of dopamine neurons. These findings suggest the effects of PCP on dopaminergic signaling in the midbrain could enhance burst firing and contribute to the development of schizophreniform behavior.

Keywords: Burst; DAT; Dopamine; GIRK; Mouse; Phencyclidine.

Publication types

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

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Dizocilpine Maleate / pharmacology
  • Dopamine / pharmacology
  • Dopaminergic Neurons / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Electric Stimulation
  • Excitatory Amino Acid Antagonists / pharmacology*
  • In Vitro Techniques
  • Iontophoresis
  • Kynurenic Acid / pharmacology
  • Male
  • Mice
  • Patch-Clamp Techniques
  • Phencyclidine / pharmacology*
  • Receptors, Dopamine D2 / metabolism*
  • Signal Transduction / drug effects*
  • Substantia Nigra / cytology*


  • Excitatory Amino Acid Antagonists
  • Receptors, Dopamine D2
  • Dizocilpine Maleate
  • Kynurenic Acid
  • Phencyclidine
  • Dopamine