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.
Highlights
The atypical antipsychotics cariprazine and aripiprazole are both dopamine D2/D3 receptor partial agonists; the drugs differ in that cariprazine is D3 receptor-preferring and has moderate affinity for serotonin 5-HT1A receptors.[7]
We recently reported that long-term treatment with cariprazine increased D2 and D3 receptor levels in selected rat forebrain regions, whereas other typical and atypical antipsychotics upregulated D2 receptors with no effects on D3 receptors.[14]
We have previously reported that long-term administration of several atypical antipsychotics—including clozapine, olanzapine, risperidone, quetiapine, and asenapine—but not the typical antipsychotic haloperidol, resulted in decreased 5-HT2A receptor labeling in rat frontal cerebral cortex.15,22,42,43 5-HT2A receptor downregulation may minimize the higher incidence of extrapyramidal side effects associated with typical antipsychotic drug treatment.[1,44,45]
Summary
The atypical antipsychotics cariprazine and aripiprazole are both dopamine D2/D3 receptor partial agonists; the drugs differ in that cariprazine is D3 receptor-preferring and has moderate affinity for serotonin 5-HT1A receptors.[7] cariprazine, but not aripiprazole, demonstrated high and balanced occupancy of both D2 and D3 receptors at pharmacologically effective and antipsychotic doses in both animals[8] and schizophrenia patients.[9] In animal behavioral models, cariprazine showed procognitive[10] and antidepressant-like effects,[11] suggesting the potential benefits of cariprazine for both the cognitive deficits and depressive symptoms of schizophrenia. We quantified the long-term effects of aripiprazole on D2 and D3 receptors and compared them to findings previously obtained for cariprazine and other antipsychotics
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