<jats:sec id="S1092852916000894_abs1" sec-type="general"><jats:title>Objective</jats:title><jats:p>This study examined the chronic effects of aripiprazole and cariprazine on serotonin (5-HT<jats:sub>1A</jats:sub>and 5-HT<jats:sub>2A</jats:sub>) and glutamate (NMDA and AMPA) receptor subtypes. In addition, the effects of aripiprazole on D<jats:sub>2</jats:sub>and D<jats:sub>3</jats:sub>receptors were tested and compared with previously reported cariprazine data.</jats:p></jats:sec><jats:sec id="S1092852916000894_abs2" sec-type="methods"><jats:title>Methods</jats:title><jats:p>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).</jats:p></jats:sec><jats:sec id="S1092852916000894_abs3" sec-type="results"><jats:title>Results</jats:title><jats:p>Similar to previous findings with cariprazine, aripiprazole upregulated D<jats:sub>2</jats:sub>receptor levels in various regions; D<jats:sub>3</jats:sub>receptor changes were less than those reported with cariprazine. All aripiprazole doses and higher cariprazine doses increased 5-HT<jats:sub>1A</jats:sub>receptors in the MPC and DFC. Higher aripiprazole and all cariprazine doses increased 5-HT<jats:sub>1A</jats:sub>receptors in HIPP–CA1 and HIPP–CA3. Aripiprazole decreased 5-HT<jats:sub>2A</jats:sub>receptors in the MPC, DFC, HIPP–CA1, and HIPP–CA3 regions. Both compounds decreased NMDA receptors and increased AMPA receptors in select brain regions.</jats:p></jats:sec><jats:sec id="S1092852916000894_abs4" sec-type="conclusions"><jats:title>Conclusions</jats:title><jats:p>Long-term administration of aripiprazole and cariprazine had similar effects on 5-HT<jats:sub>1A</jats:sub>, NMDA, and AMPA receptors. However, cariprazine more profoundly increased D<jats:sub>3</jats:sub>receptors while aripiprazole selectively reduced 5-HT<jats:sub>2A</jats:sub>receptors. These results suggest that the unique actions of cariprazine on dopamine D<jats:sub>3</jats:sub>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.</jats:p></jats:sec>