The Role of Dopamine D₃ Receptor Partial Agonism in Cariprazine-Induced Neurotransmitter Efflux in Rat Hippocampus and Nucleus Accumbens

Abstract

Cariprazine is an approved antipsychotic and antidepressant which is a dopamine (DA) D 3 -preferring D 3 /D 2 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 D 3 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-4propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride], a D 3 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 D 3 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 D 3 receptor agonist (1)-PD-128907, suggesting these effects of cariprazine are related to its D 3 receptor partial agonism, and that this mechanism, leading to diminished stimulation of D 3 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 STATEMENTThe novel atypical antipsychotic drug cariprazine increased nucleus accumbens and hippocampal neurotransmitter efflux, similar to the actions of the D 3 receptor antagonist SB-277011A [trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide hydrochloride]. The D 3 receptor-preferring agonist (1)-PD-128907 [(4aR, 10bR)-3,4a,4,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4oxazin-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. This study was supported by grants from Allergan, Plc. and Gedeon Richter, Plc. H.Y.M. has been consulting for and receives research funding from Allergan. B.K. and B.F. are employees of Gedeon Richter Plc. N.A. is an employee of Allergan. M.H. and W.H. have no conflicts of interest to declare.This work w...

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

“…Some compounds can increase basal DA release in the prefrontal cortex and striatum such as the D3R preferring D2/D3 antagonist IRL-790 also known as mesodopetam [244]. The D3R preferring partial agonist cariprazine increases DA release in the nucleus accumbens and ventral hippocampus [245] as well as DA turnover in the striatum [204] in intact animals. Cariprazine also increases DA release in the prefrontal cortex in a PCP-exposure model of acute psychosis [246].…”

(3S)‐3‐(2,3‐difluorophenyl)‐3‐methoxypyrrolidine (IRL752) —a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent

“…Clozapine: Hertel et al, 1997;Westerink et al, 2001;Ichikawa et al, 2002;Shirazi-Southall et al, 2002;Devoto et al, 2003;Shilliam and Dawson, 2005;Abdul-Monim et al, 2006;Grayson et al, 2007;Robbins et al, 2008;IRL AB, unpublished data. Cariprazine: Neill et al, 2016;Kehr et al, 2018;Huang et al, 2019;Waters et al, 2020;IRL AB, unpublished data. Vortioxetine: Mørk et al, 2013;Pehrson et al, 2013Pehrson et al, , 2018du Jardin et al, 2014;Wallace et al, 2014;IRL AB, unpublished data.…”

Calbindin Deficits May Underlie Dissociable Effects of 5-HT6 and mGlu7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia

“…It may become necessary to explore alternative explanations including alterations in frontal cortical dopamine, which is also important for NOD [106] and modulated by 5-HT 6 antagonists [107] but as yet unexplored in PCP-Iso. Such alternatives may underlie the ability of cariprazine to reverse NOD deficits in PCP-Iso, since in vivo microdialysis shows this novel antipsychotic normalizes acute PCP-induced dopamine and glutamate efflux in the medial prefrontal cortex [108] and elevates dopamine efflux in the nucleus accumbens and hippocampus without having any effect on hippocampal glutamate [109]. On the basis of this latter observation, cariprazine would not be expected to influence the signal in our current microsensor studies and we therefore instead prioritized the inclusion of other putative procognitive drugs with established effects on glutamatergic neurotransmission within the hippocampus.…”