The novel atypical antipsychotic cariprazine demonstrates dopamine D 2 receptor-dependent partial agonist actions on rat mesencephalic dopamine neuronal activity

CNS Neurosci Ther. 2018 Dec;24(12):1129-1139. doi: 10.1111/cns.12867. Epub 2018 May 4.


Aim: Cariprazine, a dopamine D3 -preferring D3 /D2 receptor partial agonist, is FDA approved for the treatment of schizophrenia and acute manic or mixed episodes of bipolar disorder. This study used in vivo electrophysiological techniques in anesthetized rats to determine cariprazine's effect on dopaminergic cell activity in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc).

Methods: Extracellular recordings of individual dopaminergic neurons were performed after oral or intravenous administration of cariprazine, the D3 receptor antagonist SB 277011A, the D2 receptor antagonist L741,626, and/or the D3 receptor agonist PD 128,907.

Results: Acute oral treatment with cariprazine significantly increased and chronic cariprazine significantly decreased the number of spontaneously firing dopaminergic neurons in the VTA, but not in the SNc. Intravenous administration of cariprazine partially but significantly inhibited dopaminergic neuronal firing in both regions, which was prevented by L741,626 but not SB 277011A. In both VTA and SNc, cariprazine, SB 277011A, and L741,626 significantly antagonized the suppression of dopamine cell firing elicited by PD 128,907.

Conclusions: Cariprazine significantly modulates the number of spontaneously active VTA dopamine neurons and moderately suppresses midbrain dopamine neuronal activity. The contribution of dopamine D2 receptors to cariprazine's in vivo effects is prevalent and that of D3 receptors is less apparent.

Keywords: cariprazine; dopamine receptors; electrophysiology; schizophrenia; substantia nigra pars compacta; ventral tegmental area.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Benzopyrans / pharmacology
  • Dopamine Agonists / pharmacology*
  • Dopaminergic Neurons / drug effects*
  • Dose-Response Relationship, Drug
  • Indoles / pharmacology
  • Male
  • Nitriles / pharmacology
  • Oxazines / pharmacology
  • Patch-Clamp Techniques
  • Piperazines / pharmacology*
  • Piperidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Substantia Nigra / cytology*
  • Tetrahydroisoquinolines / pharmacology
  • Time Factors
  • Ventral Tegmental Area / cytology*


  • Benzopyrans
  • Dopamine Agonists
  • Indoles
  • Nitriles
  • Oxazines
  • Piperazines
  • Piperidines
  • SB 277011
  • Tetrahydroisoquinolines
  • 3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol
  • 3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole
  • cariprazine