Long-term effects of aripiprazole exposure on monoaminergic and glutamatergic receptor subtypes: comparison with cariprazine

Objective 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 D-2 and D-3 receptors were tested and compared with previously reported cariprazine data. Methods 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). Results Similar to previous findings with cariprazine, aripiprazole upregulated D-2 receptor levels in various regions; D-3 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. Conclusions Long-term administration of aripiprazole and cariprazine had similar effects on 5-HT1A, NMDA, and AMPA receptors. However, cariprazine more profoundly increased D-3 receptors while aripiprazole selectively reduced 5-HT2A receptors. These results suggest that the unique actions of cariprazine on dopamine D-3 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.