Skip to main content
    • Aa
    • Aa

Long-term effects of cariprazine exposure on dopamine receptor subtypes

  • Yong Kee Choi (a1), Nika Adham (a2), Béla Kiss (a3), István Gyertyán (a4) and Frank I. Tarazi (a1)...

All clinically effective antipsychotics are known to act on the dopaminergic system, and previous studies have demonstrated that repeated treatment with antipsychotics produced region-specific changes in dopamine receptor levels. Cariprazine is a dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors. We examined the effects of chronic cariprazine administration on dopamine receptor levels.


Rats were administered either vehicle or cariprazine (0.06, 0.2, or 0.6 mg/kg) for 28 days. Dopamine receptor levels were quantitated using autoradiographic assays on brain tissue sections from the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), caudate putamen (CPu), hippocampus (HIPP), olfactory tubercle (OT), and islands of Calleja (ICj).


Chronic treatment with cariprazine did not alter D1 receptor levels in any brain region tested. Cariprazine increased D2 receptor levels in mPFC (27%–43%), NAc (40%–45%), medial (41%–53%) and lateral (52%–63%) CPu, and HIPP (38%). Cariprazine dose-dependently upregulated D3 receptor levels in ICj (32%–57%), OT (27%–67%), and NAc shell (31%–48%). Repeated cariprazine treatment increased D4 receptor in NAc (53%–82%), medial (54%–98%) and lateral (58%–74%) CPu, and HIPP (38%–98%).


Similar to other antipsychotics, cariprazine upregulated D2 and D4 receptor levels in various brain regions. Cariprazine was unique among antipsychotics in increasing D3 receptor levels, which may support its unique psychopharmacologic properties.

Corresponding author
*Address for correspondence: Frank I. Tarazi, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. (Email:
Hide All

This study was funded by Forest Laboratories, Inc. and Gedeon Richter Plc. The authors would like to thank Vojislav Pejovic, PhD, and Adam Ruth, PhD, of Prescott Medical Communications Group for their technical writing, editing, and research support.

Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

2. JM Beaulieu , RR Gainetdinov . The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011; 63(1): 182217.

3. RJ Baldessarini , FI Tarazi . Brain dopamine receptors: a primer on their current status, basic and clinical. Harv Rev Psychiatry. 1996; 3(6): 301325.

4. S Caccia . Pharmacokinetics and metabolism update for some recent antipsychotics. Expert Opin Drug Metab Toxicol. 2011; 7(7): 829846.

5. RB Mailman , V Murthy . Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? Curr Pharm Des. 2010; 16(5): 488501.

6. J Arnt , T Skarsfeldt . Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology. 1998; 18(2): 63101.

7. F Biedermann , WW Fleischhacker . Emerging drugs for schizophrenia. Expert Opin Emerg Drugs. 2011; 16(2): 271282.

9. FI Tarazi , T Moran-Gates , EH Wong , B Henry , M Shahid . Differential regional and dose-related effects of asenapine on dopamine receptor subtypes. Psychopharmacology (Berl). 2008; 198(1): 103111.

11. FI Tarazi , RJ Baldessarini , NS Kula , K Zhang . Long-term effects of olanzapine, risperidone, and quetiapine on ionotropic glutamate receptor types: implications for antipsychotic drug treatment. J Pharmacol Exp Ther. 2003; 306(3): 11451151.

12. FI Tarazi , YK Choi , M Gardner , etal. Asenapine exerts distinctive regional effects on ionotropic glutamate receptor subtypes in rat brain. Synapse. 2009; 63(5): 413420.

13. FI Tarazi , WJ Florijn , I Creese . Regulation of ionotropic glutamate receptors following subchronic and chronic treatment with typical and atypical antipsychotics. Psychopharmacology (Berl). 1996; 128(4): 371379.

14. FI Tarazi , T Moran-Gates , EH Wong , B Henry , M Shahid . Asenapine induces differential regional effects on serotonin receptor subtypes. J Psychopharmacol. 2010; 24(3): 341348.

15. FI Tarazi , K Zhang , RJ Baldessarini . Long-term effects of olanzapine, risperidone, and quetiapine on serotonin 1A, 2A and 2C receptors in rat forebrain regions. Psychopharmacology (Berl). 2002; 161(3): 263270.

16. JA Lieberman , FP Bymaster , HY Meltzer , etal. Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection. Pharmacol Rev. 2008; 60(3): 358403.

17. B Kiss , A Horváth , Z Némethy , etal. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010; 333(1): 328340.

19. L Citrome . Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy. Adv Ther. Feb. 2013; 30(2): 114126.

20. L Citrome . Cariprazine in bipolar disorder: clinical efficacy, tolerability, and place in therapy. Adv Ther. 2013; 30(2): 102113.

24. I Gyertyán , B Kiss , K Sághy , etal. Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents. Neurochem Int. 2011; 59(6): 925935.

25. B Kiss , F Horti , A Bobok . Cariprazine, a D3/D2 dopamine receptor partial agonist antipsychotic, displays greater D3 receptor occupancy in vivo compared with other antipsychotics. Schizophr Res. 2012; 136(Suppl 1): S190.

27. G Gross , K Drescher . The role of dopamine D(3) receptors in antipsychotic activity and cognitive functions. Handb Exp Pharmacol. 2012 213): 167210.

28. DI Cho , M Zheng , KM Kim . Current perspectives on the selective regulation of dopamine D(2) and D(3) receptors. Arch Pharm Res. 2010; 33(10): 15211538.

29. J Laszy , I Laszlovszky , I Gyertyán . Dopamine D(3) receptor antagonists improve the learning performance in memory-impaired rats. Psychopharmacology (Berl). 2005; 179(3): 567575.

30. K Salimi , LF Jarskog , JA Lieberman . Antipsychotic drugs for first-episode schizophrenia: a comparative review. CNS Drugs. 2009; 23(10): 837855.

33. FI Tarazi , NS Kula , RJ Baldessarini . Regional distribution of dopamine D4 receptors in rat forebrain. Neuroreport. 1997; 8(16): 34233426.

36. FI Tarazi , WJ Florijn , I Creese . Differential regulation of dopamine receptors after chronic typical and atypical antipsychotic drug treatment. Neuroscience. 1997; 78(4): 985996.

37. FI Tarazi , SK Yeghiayan , RJ Baldessarini , NS Kula , JL Neumeyer . Long-term effects of S(+)N-n-propylnorapomorphine compared with typical and atypical antipsychotics: differential increases of cerebrocortical D2-like and striatolimbic D4-like dopamine receptors. Neuropsychopharmacology. 1997; 17(3): 186196.

38. R de Beaurepaire , A Labelle , D Naber , BD Jones , TR Barnes . An open trial of the D1 antagonist SCH 39166 in six cases of acute psychotic states. Psychopharmacology (Berl). 1995; 121(3): 323327.

39. DJ Lodge , AA Grace . Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. J Neurosci. 2007; 27(42): 1142411430.

40. EE Krieckhaus , JW Donahoe , MA Morgan . Paranoid schizophrenia may be caused by dopamine hyperactivity of CA1 hippocampus. Biol Psychiatry. 1992; 31(6): 560570.

41. RL Albin , AB Young , JB Penney . The functional anatomy of basal ganglia disorders. Trends Neurosci. 1989; 12(10): 366375.

42. MS Kleven , C Barret-Grevoz , L Bruins Slot , A Newman-Tancredi . Novel antipsychotic agents with 5-HT(1A) agonist properties: role of 5-HT(1A) receptor activation in attenuation of catalepsy induction in rats. Neuropharmacology. 2005; 49(2): 135143.

43. L Bardin , MS Kleven , C Barret-Grevoz , R Depoortere , A Newman-Tancredi . Antipsychotic-like vs cataleptogenic actions in mice of novel antipsychotics having D2 antagonist and 5-HT1A agonist properties. Neuropsychopharmacology. 2006; 31(9): 18691879.

44. K Zhang , NT Weiss , FI Tarazi , NS Kula , RJ Baldessarini . Effects of alkylating agents on dopamine D(3) receptors in rat brain: selective protection by dopamine. Brain Res. 1999; 847(1): 3237.

46. P Sokoloff , O Guillin , J Diaz , P Carroll , N Griffon . Brain-derived neurotrophic factor controls dopamine D3 receptor expression: implications for neurodevelopmental psychiatric disorders. Neurotox Res. 2002; 4(7–8): 671678.

47. VV Dias , V Balanza-Martinez , MG Soeiro-de-Souza , etal. Pharmacological approaches in bipolar disorders and the impact on cognition: a critical overview. Acta Psychiatr Scand. 2012; 126(5): 315331.

48. PD Harvey , AP Wingo , KE Burdick , RJ Baldessarini . Cognition and disability in bipolar disorder: lessons from schizophrenia research. Bipolar Disord. 2010; 12(4): 364375.

49. I Gyertyán , K Sághy , J Laszy , etal. Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: II. behavioural characterisation of RG-15. Naunyn Schmiedebergs Arch Pharmacol. 2008; 378(5): 529539.

51. V Micale , L Cristino , A Tamburella , etal. Enhanced cognitive performance of dopamine D3 receptor “knock-out” mice in the step-through passive-avoidance test: assessing the role of the endocannabinoid/endovanilloid systems. Pharmacol Res. 2010; 61(6): 531536.

52. MH Corrigan , CC Gallen , ML Bonura , KM Merchant . Effectiveness of the selective D4 antagonist sonepiprazole in schizophrenia: a placebo-controlled trial. Biol Psychiatry. 2004; 55(5): 445451.

53. MS Kramer , B Last , A Getson , SA Reines . The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 Dopamine Antagonist Group. Arch Gen Psychiatry. 1997; 54(6): 567572.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

CNS Spectrums
  • ISSN: 1092-8529
  • EISSN: 2165-6509
  • URL: /core/journals/cns-spectrums
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 3
Total number of PDF views: 18 *
Loading metrics...

Abstract views

Total abstract views: 238 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 23rd September 2017. This data will be updated every 24 hours.