title: Long-term effects of aripiprazole exposure on monoaminergic and glutamatergic receptor subtypes: comparison with cariprazine.
abstract: This study examined the chronic effects of aripiprazole and cariprazine on serotonin (5-HT1A and 5-HT2A) and glutamate (NMDA and AMPA) receptor subtypes. In addition, the effects of aripiprazole on D2 and D3 receptors were tested and compared with previously reported cariprazine data.
  
  
  
  Rats received vehicle, aripiprazole (2, 5, or 15 mg/kg), or cariprazine (0.06, 0.2, or 0.6 mg/kg) for 28 days. Receptor levels were quantified using autoradiographic assays on brain sections from the medial prefrontal cortex (MPC), dorsolateral frontal cortex (DFC), nucleus accumbens (NAc), caudate-putamen medial (CPu-M), caudate-putamen lateral (CPu-L), hippocampal CA1 (HIPP-CA1) and CA3 (HIPP-CA3) regions, and the entorhinal cortex (EC).
  
  
  
  Similar to previous findings with cariprazine, aripiprazole upregulated D2 receptor levels in various regions; D3 receptor changes were less than those reported with cariprazine. All aripiprazole doses and higher cariprazine doses increased 5-HT1A receptors in the MPC and DFC. Higher aripiprazole and all cariprazine doses increased 5-HT1A receptors in HIPP-CA1 and HIPP-CA3. Aripiprazole decreased 5-HT2A receptors in the MPC, DFC, HIPP-CA1, and HIPP-CA3 regions. Both compounds decreased NMDA receptors and increased AMPA receptors in select brain regions.
  
  
  
  Long-term administration of aripiprazole and cariprazine had similar effects on 5-HT1A, NMDA, and AMPA receptors. However, cariprazine more profoundly increased D3 receptors while aripiprazole selectively reduced 5-HT2A receptors. These results suggest that the unique actions of cariprazine on dopamine D3 receptors, combined with its effects on serotonin and glutamate receptor subtypes, may confer the clinical benefits, safety, and tolerability of this novel compound in schizophrenia and bipolar mania.
authors.affiliation: 1Department of Psychiatry & Neuroscience,Harvard Medical School, and McLean Hospital,Belmont,Massachusetts,USA.
authors.forename: Yong Kee
authors.initials: YK
authors.lastname: Choi
authors.affiliation: 2Department of Pharmacology,Allergan,Jersey City,New Jersey,USA.
authors.forename: Nika
authors.initials: N
authors.lastname: Adham
authors.affiliation: 3Department of Pharmacological and Safety Research,Gedeon Richter Plc,Budapest,Hungary.
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.affiliation: 4MTA-SE NAP B Cognitive Translational Behavioral Pharmacology Group,Department of Pharmacology and Pharmacotherapy,Semmelweis University,Budapest,Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Gyertyán
authors.affiliation: 1Department of Psychiatry & Neuroscience,Harvard Medical School, and McLean Hospital,Belmont,Massachusetts,USA.
authors.forename: Frank I
authors.initials: FI
authors.lastname: Tarazi
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects; D018091:Receptors, AMPA / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D050637:Receptors, Dopamine D3 / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013995:Time
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D018091:Receptors, AMPA; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D016194:Receptors, N-Methyl-D-Aspartate; D000068180:Aripiprazole; C533287:cariprazine
keywords: Aripiprazole; autoradiography; bipolar mania; cariprazine; dopamine; glutamate; schizophrenia; serotonin