Abstract
Cariprazine, approved to treat adults with schizophrenia (US and Europe) and manic or mixed episodes associated with bipolar I disorder (US), is a dopamine (DA) D3-preferring D3/D2 receptor partial agonist, serotonin 5-HT1A receptor partial agonist, and 5-HT2B and 5-HT2A receptor antagonist with a unique pharmacologic profile for an atypical antipsychotic drug. The purpose of this study was to clarify the importance of the D3 receptor mechanism to the effects of cariprazine and selective D3 receptor ligands on neurotransmitter efflux in the rat nucleus accumbens (NAC) and ventral hippocampus (HIP). In vivo microdialysis was performed in awake, freely moving rats after administration of cariprazine, (+)-PD-128907 (D3 receptor-preferring agonist), and/or SB-277011A (D3 receptor antagonist), and extracellular levels of acetylcholine (ACh), DA and 5-HT and their metabolites, norepinephrine (NE), serine, glycine, glutamate, and gamma-aminobutyric acid were measured in the NAC and HIP by UPLC-MS/MS. Cariprazine increased DA, NE, and 5-HT efflux in both regions, while it increased glycine and glutamate efflux only in the NAC, and 3,4-dihydroxyphenylacetic acid (DOPAC) as well as homovanillic acid (HVA) efflux only in the HIP. Similarly, SB-277011A increased DA, NE, DOPAC, and HVA, but not 5-HT, efflux in the NAC and HIP, and ACh efflux in the HIP. Most of the effects of cariprazine and SB-277011A were fully or partially blocked by (+)-PD-128907. These effects of cariprazine, are thought to be largely dependent on its D3 receptor partial agonism activity in various regions, may contribute to its efficacy in schizophrenia and bipolar disorder.
SIGNIFICANCE STATEMENT The novel atypical antipsychotic drug, cariprazine, increased nucleus accumbens and hippocampal neurotransmitter efflux, similar to the actions of the D3 receptor antagonist, SB-277011A. The D3 receptor-preferring agonist, (+)-PD-128907, diminished the effects of both compounds on neurotransmitter efflux in both regions. These results suggested D3 receptor partial agonist activity of cariprazine, producing functional antagonism, may contribute to its efficacy in schizophrenia and bipolar disorder.
- The American Society for Pharmacology and Experimental Therapeutics