The role of dopamine D₃ receptor partial agonism in cariprazine-induced neurotransmitter efflux in rat hippocampus and nucleus accumbens

Cariprazine is an approved antipsychotic and antidepressant which is a dopamine (DA) D₃-preferring D₃/D₂ receptor partial agonist, serotonin (5-HT) 5-HT_1A receptor partial agonist, and 5-HT_2B and 5-HT_2A receptor antagonist, a profile unique for atypical antipsychotic drugs. The purpose of this study was to clarify the effects of cariprazine and selective D₃ receptor ligands on neurotransmitter efflux in the rat nucleus accumbens (NAC) and ventral hippocampus (HIP), brain regions important for reality testing, rewarded behavior, and cognition. In vivo microdialysis was performed in awake, freely moving rats after administration of cariprazine; (1)-PD-128907 [(4aR,10bR)-3,4a,4,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride], a D₃ receptor–preferring agonist; and SB-277011A [trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide hydrochloride], a selective D₃ receptor antagonist, alone or combined, and extracellular levels of multiple neurotransmitters and metabolites were measured in the NAC and HIP by ultraperformance liquid chromatography with tandem mass spectrometry. Cariprazine increased DA, norepinephrine (NE), and 5-HT efflux in both regions, whereas it increased glycine (Gly) and glutamate efflux only in the NAC and efflux of DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) only in the HIP. Similarly, SB-277011A increased DA, NE, DOPAC, and HVA, but not 5-HT, efflux in the NAC and HIP, and acetylcholine efflux in the HIP. Most of these effects of cariprazine and SB-277011A were fully or partially attenuated by the D₃ receptor agonist (1)-PD-128907, suggesting these effects of cariprazine are related to its D₃ receptor partial agonism, and that this mechanism, leading to diminished stimulation of D₃ receptors, may contribute to its efficacy in both schizophrenia and bipolar disorder. The possible role of Gly in the action of cariprazine is discussed. 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 [trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide hydrochloride]. The D₃ receptor–preferring agonist (1)-PD-128907 [(4aR, 10bR)-3,4a,4,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride], 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.