Hostname: page-component-745bb68f8f-mzp66 Total loading time: 0 Render date: 2025-02-06T01:47:43.711Z Has data issue: false hasContentIssue false
  • English
  • Français

The role of dopamine D3 receptors in the mechanism of action of cariprazine

Published online by Cambridge University Press:  23 April 2019

Francesca Calabrese ,
Frank I. Tarazi Open the ORCID record for Frank I. Tarazi [Opens in a new window] ,
Giorgio Racagni  and
Marco A. Riva Open the ORCID record for Marco A. Riva [Opens in a new window]
Francesca Calabrese
Affiliation:
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
Frank I. Tarazi
Affiliation:
Department of Psychiatry and Neuroscience Program, Harvard Medical School and McLean Hospital, Boston, MA, USA
Giorgio Racagni
Affiliation:
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy Associazione di Psicofarmacologia, Milan, Italy
Marco A. Riva*
Affiliation:
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
*
*Address correspondence to: Marco A. Riva, Professor, Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133Milan, Italy. (Email: M.Riva@unimi.it)
Rights & Permissions [Opens in a new window]

Abstract

Cariprazine is a new atypical antipsychotic drug (APD) with a unique pharmacodynamic profile, different from both typical and atypical APDs. Specifically, cariprazine acts as a partial agonist at the dopamine (DA) D2 and D3 receptors and serotonin 5-HT1A receptors, and as an antagonist at the 5-HT2B receptors. Moreover, it shows moderate affinities for adrenergic, histaminergic, and cholinergic receptors that are involved in mediating the side effects characteristic of typical APDs. In this review, we discuss the contribution of DA D3 receptors (D3Rs) in the etiology and pathophysiology of schizophrenia and the potential benefits that may be associated with a more selective targeting of D3R by APDs, as compared to other dopaminergic and non-dopaminergic receptor subtypes. Cariprazine, by acting on D3Rs, ameliorates anhedonia and cognitive deficits in animal models based on environmental or pharmacological manipulation. The reviewed results support the potential benefits of cariprazine in treating negative symptoms and cognitive deficits of schizophrenia, and therefore representing a promising approach in addressing the unmet clinical needs for the improved treatment of this serious neuropsychiatric disorder.

Keywords

Dopamine D3 receptorscariprazineantipsychotic drugsschizophrenianegative symptomscognitive deficits
Type
Review
Information
CNS Spectrums , Volume 25 , Issue 3 , June 2020 , pp. 343 - 351
Copyright
© Cambridge University Press 2019

Introduction

Dopamine (DA) is a key brain neurotransmitter that contributes to the control of different behaviors, including locomotion, cognition, reward, and motivation.Reference Biesdorf, Wang and Topic1–Reference Kegeles, Abi-Dargham and Frankle4 Its activity is mediated by two receptor families: the “D1-like” family includes D1 and D5 receptors that stimulate adenylyl cyclase activity, while the “D2-like” receptors (D2, D3, and D4) inhibit the production of cAMP and also regulate other systems, including K+ channels, AKT (AKT serine/threonine kinase)–GSK3 (glycogen synthase kinase 3 beta)–βarrestin as well as intracellular calcium levels.Reference Gingrich and Caron5–Reference Beaulieu, Gainetdinov and Caron7

Alterations of dopaminergic functions have been associated with the pathophysiology of different brain disorders, including Parkinson’s disease, attention-deficit hyperactivity disorder (ADHD), bipolar and mood disorders, schizophrenia, and drug addiction. The association between DA and schizophrenia is particularly complex since a dopaminergic hyperactivity in the mesolimbic regions appears to contribute to psychotic symptoms, such as hallucinations and delusions, as opposed to a dopaminergic hypoactivity in cortical regions, which underlies the negative symptoms and cognitive deficits of the disease. The management of these “opposite” dopaminergic dysfunctions may represent a major challenge for pharmacological intervention. With this respect, currently available antipsychotic drugs (APDs) are quite effective in managing the positive symptoms of schizophrenia, but they are less effective in addressing the negative symptoms and cognitive deficitsReference Leucht and Davis8 even if a partial agonist like aripiprazole has been shown to improve quality of life in schizophrenic patients compared to paliperidone.Reference Potkin, Loze and Forray9 On these bases, a better control of these core symptoms, which often persist during periods of clinical stability and can be severe enough to impair the daily functional activities of patients,Reference Nemeth, Laszlovszky and Czobor10, Reference Tsapakis, Dimopoulou and Tarazi11 represents a critical aspect for the improvement of the clinical outcome.

Considering that DA-related dysfunction represents a hallmark in schizophrenia, there is always a great deal of interest in developing novel strategies to modulate the “dopaminergic” function with the aim to address clinical “unmet needs.” Among different potential targets, there has been an increasing interest in DA D3 receptors (D3Rs), whose modulation may improve the outcome of schizophrenia treatment. In this review, we discuss the contribution of these receptors in the etiology and pathophysiology of schizophrenia and the potential benefits that may be associated with a more selective targeting of DA D3Rs by APDs, as compared to other dopaminergic and non-dopaminergic receptor subtypes.

From D2 to D3 Receptor

DA D3Rs, which were identified in 1990,Reference Sokoloff, Giros, Martres, Bouthenet and Schwartz12 show higher affinity for endogenous DA, as compared to D2, and their distribution is restricted to limbic regions, including the islands of Calleja, the shell of nucleus accumbens (NAc), and the olfactory tubercles, with much lower levels of expression in basal ganglia or other brain structures. Although restricted, the distribution of D3Rs appears to be critically involved in the regulation of important functions, such as motivation, emotion, and reward as well as cognition,Reference Sokoloff, Giros, Martres, Bouthenet and Schwartz12–Reference Sokoloff and Le Foll14 which represent key pathologic domains for several psychiatric disorders, including schizophrenia.Reference Sokoloff, Diaz and Le Foll15

DA D3Rs are scarcely found in the majority of DA symmetric synapses, while they are detected at the levels of asymmetric synapses at the head of dendritic spines, a localization that is in sharp contrast with DA D1Rs and DA D2Rs, which are either pre-synaptic or spread all over dendrites and dendritic spines in neurons of the caudate putamen and NAc.Reference Sokoloff and Le Foll14, Reference Stahl16 Since asymmetrical synapses are typically glutamatergic (Glu) and may be located at some distance from DA terminals, it is expected that DA D3Rs may play a peculiar role in the modulation of neurotransmitter circuitry. Indeed, on the basis of the higher affinity of endogenous DA for D3Rs, over other DA receptors, it has been hypothesized that DA D3Rs would be less sensitive to rapid (phasic release) than slower (tonic release) changes in DA concentration. Moreover, considering that phasic release in mesolimbic areas mediates the responses to salient stimuli (such as reward-relevant event or potential threat), while tonic release mediates the amplitude of the response,Reference Grace17 it is feasible that enhanced DA D3Rs sensitivity would result in the aberrant assignment of salience to elements one’s experiences as it may occur in schizophrenia.Reference Kapur18 Moreover, D3Rs may exert a tonic inhibition of DA neurons in the ventral tegmental area (VTA) projecting to the NAc by stimulating GABA release, whereas D3Rs expressed on dopaminergic neurons of the VTA inhibit DA synthesis and release. Taken together, these observations support a negative control of D3-mediated signaling on DA neurons, either by acting directly on its autoreceptors (located both at nerve terminals and in the cell bodies) or by modulating GABA release, which eventually leads to a downregulation of DA release in PFC.Reference Sokoloff, Diaz and Le Foll15, Reference Stahl16

Similar to the majority of GPCR, D3Rs may form homo- and heterodimersReference Maggio, Scarselli, Capannolo and Millan19 with D2RsReference Scarselli, Novi and Schallmach20 and D1Rs,Reference Fiorentini, Busi, Spano and Missale21, Reference Marcellino, Ferre and Casado22 as well as with the adenosine A2 receptors,Reference Torvinen, Marcellino and Canals23 and they may also interact with nicotinic acetylcholine receptors (nAChRs),Reference Collo, Bono and Cavalleri24 a property that could increase their functional heterogeneity. Moreover, it has been recently shown that D3Rs positively regulate several intracellular pathways such as Erk1/2 and Akt through G protein-dependent as well as independent mechanisms,Reference Cussac, Newman-Tancredi, Pasteau and Millan25, Reference Collo, Zanetti, Missale and Spano26 suggesting that their functional activity may be different depending on the interactions with other membrane receptors or transduction proteins, a concept known as bias agonism.

The high density of the D3Rs in the ventral striatum, as compared to the dorsal part, increased the expectation that selective D3 antagonists would exert antipsychotic activity with minimal or no side effects including extrapyramidal side effects (EPS)Reference Schwartz, Diaz, Pilon and Sokoloff27 and catalepsy.Reference Sokoloff and Le Foll14, Reference Gyertyan and Saghy28 Moreover, antagonists at D3Rs can increase cognitive performance and may reverse cognitive deficits in rodents and monkeys.Reference Nakajima, Gerretsen and Takeuchi29–Reference Watson, Loiseau, Ingallinesi, Millan, Marsden and Fone33 Additionally, D3Rs are implicated in executive functions that are often disrupted in schizophrenia.Reference Lumme, Aalto, Ilonen, Nagren and Hietala34 Interestingly, overexpression of D3Rs specifically in the ventral striatum is sufficient to decrease motivation, an important component of the negative symptoms in schizophrenia, and this may be due to secondary effects on DA D1Rs.Reference Simpson, Winiger, Biezonski, Haq, Kandel and Kellendonk35 While it can be inferred that D3R antagonism represents a relevant strategy to ameliorate the negative symptoms, a major unmet need in the treatment of schizophrenia,Reference Sokoloff, Diaz and Le Foll15, Reference Gross, Wicke and Drescher36, Reference Joyce and Millan37 it must be pointed out that DA D3R stimulation may also be neurotrophic and neuroprotective on DA neurons during development.Reference Collo, Zanetti, Missale and Spano26, Reference Van Kampen and Eckman38

On these bases, partial agonism at D2Rs and D3Rs may represent a promising approach, according to the concept of “dopamine stabilization,” since a single compound may increase or decrease dopaminergic activity according to the state of a given circuit.Reference Mailman and Murthy39, Reference Pich and Collo40 Specifically, in patients with schizophrenia, this strategy reduces the hyperactivity of the dopaminergic tone in the mesolimbic regions while increasing dopaminergic hypoactivity in the frontal cortex. The first partial D2/D3 agonist approved for the treatment of schizophrenia was aripiprazole, and there are now two drugs that share a similar mechanism of action: brexpiprazole and cariprazine.Reference Frankel and Schwartz41 We will specifically focus on cariprazine, based on its prominent affinity for DA D3Rs over other DA receptor subtypes.

Cariprazine

Cariprazine is a piperazine derivative developed by Gedeon-Richter in Hungary. In 2015, the drug was approved in the USA for the treatment of schizophrenia and for the treatment of acute manic or mixed episodes associated with bipolar I disorder. Cariprazine has a unique pharmacodynamic profile rendering it different from other typical and atypical APDs.Reference Miyamoto, Duncan, Marx and Lieberman42 Indeed, it is a partial agonist at DA D2Rs and D3Rs as well as 5-HT1A receptors while acting as antagonist at 5-HT2A and 5-HT2B receptors. Moreover, it shows low to moderate affinity for other neurotransmitter receptors that may be responsible for the occurrence of important side effects.Reference Kiss, Horvath and Nemethy43

Cariprazine shares unique pharmacological signatures with two other DA partial agonists: aripiprazole and brexpiprazole in terms of their partial agonist activity at DA D2Rs, D3Rs, and 5-HT1ARs, as well as antagonistic activity at 5-HT2ARs. However, cariprazine has the strongest affinity for DA D3Rs, as partial agonist, followed by aripiprazole and brexpiprazole, whereas brexpiprazole has the strongest affinity for DA D2Rs, as a partial agonist, followed by aripiprazole and cariprazine.Reference Frankel and Schwartz41, Reference Veselinovic, Paulzen and Grunder44–Reference Stahl46 Cariprazine’s selective actions as a potent DA D3R partial agonist [intrinsic activity of 0.70]Reference Kiss, Horvath and Nemethy43 may stabilize abnormalities in DA neurotransmission in different brain regions including the cerebral cortex and therefore may improve negative symptoms and cognitive deficits in schizophrenia patients. The activity of cariprazine on 5-HT1ARs and 5-HT2ARs may further improve psychotic or manic symptoms while maintaining a benign EPS profile.Reference Frankel and Schwartz41, Reference Veselinovic, Paulzen and Grunder44, Reference Goff45

Cariprazine is safe and effective at the dose range of 1.5–6 mg daily. It is mainly metabolized by CYP3A4 (and, to a lesser extent, CYP2D6), generating two active metabolites (desmethyl cariprazine and di-desmethyl cariprazine). The steady state is reached around weeks 1–2 for cariprazine and desmethyl cariprazine and around weeks 4–8 for di-desmethyl cariprazine.Reference Nakamura, Kubota, Iwakaji, Imada, Kapas and Morio47 The presence of these two active metabolites may prolong the efficacy of the parent compound, although more information is needed with respect to the efficacy of such metabolites. The pharmacokinetic of cariprazine and its metabolites are not affected in a clinically relevant degree by CYP2D6 poor metabolizer status, age, weight, sex, or race.Reference Garnock-Jones48 Cariprazine and its metabolites are weak inhibitors of CYP1A2, CYP2C9, CYP2D6, CYP3A4, CYP2C19, and CYP2E1. Moreover, pharmacokinetic interactions of cariprazine with substrates of these enzymes are not likely to occur, while the dose of cariprazine has to be reduced if co-administered with a strong CYP3A4 inhibitor such as ketoconazole. The association with CYP3A4 inducers, such as carbamazepine, is not recommended.

Since 2008, several studies and reviews have been published on the efficacy, safety, and tolerability of cariprazine in humans.Reference Garnock-Jones48, Reference De Berardis, Orsolini and Iasevoli49 As an example, cariprazine was effective in adult patients diagnosed with schizophrenia and generally well tolerated in three 6-week randomized double-blind, placebo-, and/or active-controlled phase-II and phase-III studies. The treatment was not associated with alterations in metabolic parameters, prolactin production, prolongation of QT interval, or substantial increases in body weight.Reference Calabrese, Keck and Starace50 Nevertheless, the incidence of akathisia and EPS was higher with cariprazine than with placebo. Accordingly, open-label extension studies (NCT00839852–NCT01104792) reported that both low and high doses of cariprazine were generally well tolerated and did not result in any new safety concerns.Reference Durgam, Cutler and Lu51–Reference Cutler, Durgam and Wang55 Moreover, cariprazine treatment was generally associated with a low rate of sedation and weight gain.Reference Ketter, Sachs and Durgam56–Reference Nasrallah, Earley and Cutler58

Notably, one of the main unmet needs in schizophrenia is the limited ability of APDs to improve negative symptoms. It is important to underline that negative symptoms may be distinguished between primary (an integral part of the disease) and secondary that develop as a consequence of the positive symptoms or as side effects of some APDs.Reference Buchanan, Breier, Kirkpatrick, Ball and Carpenter59 Therefore, it is important to perform clinical trials that enroll only patients with primary negative symptoms. In this context, a recent randomized, placebo-controlled clinical trial that compared the effects of cariprazine vs. risperidone on negative symptoms in schizophrenia patients found a significant superiority of one APD versus another given in monotherapy.Reference Nemeth, Laszlovszky and Czobor10 Cariprazine showed a significant effect on primary negative symptoms after 14 weeks of treatment and continued to improve until the endpoint, at week 26. The reduction of the Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) was paralleled by a greater improvement in functioning (self-care, interpersonal relationship, and social activities), with a consequent increase in the quality of lifeReference Nemeth, Molnar and Akehurst60 as previously shown for aripiprazole but not with paliperidoneReference Potkin, Loze and Forray9 emphasizing the added value of the partial agonism activity.

Molecular Effects of Cariprazine

A series of studies examined the long-term effects of cariprazine administration on regulation of different DA (D1, D2, and D3), 5-HT (5-HT1A and 5-HT2A), and glutamate (NMDA and AMPA) receptor subtypes in rat forebrain regions that represent limbic, cortical, and extrapyramidal brain systems, and then compared the effects to other typical and atypical antipsychotics on the same receptors from previous studies to determine if cariprazine would induce atypical-like effects on forebrain neurotransmitter receptors.

DA receptors

Long-term administration of cariprazine resulted in significant increases in DA D3R levels in olfactory tubercle, Islands of Calleja, and shell of NAc.Reference Choi, Adham, Kiss, Gyertyan and Tarazi61 Cariprazine-induced increases in forebrain DA D3Rs appear to be unique to this drug since the repeated administration of other typical and atypical APDs including haloperidol, fluphenazine, clozapine, olanzapine, risperidone, and asenapine failed to alter levels of DA D3Rs.Reference Tarazi, Florijn and Creese62–Reference Tarazi, Moran-Gates, Wong, Henry and Shahid65 It appears that cariprazine with its potent DA D3R affinity and occupancyReference Kiss, Horvath and Nemethy43, Reference Gyertyan, Kiss and Saghy66 is able to replace endogenous DA and occupy DA D3Rs to the level required to trigger receptor upregulation.Reference Zhang, Weiss, Tarazi, Kula and Baldessarini67 DA receptor upregulation is typically observed with repeated administration of DA receptor antagonists. However, despite its DA D3R partial agonist activity, cariprazine increased DA D3Rs, which may suggest it is acting as an antagonist at D3Rs in vivo. Cariprazine may normalize disturbances in DA D3R-mediated neurotransmission in patients with schizophrenia and bipolar mania, and improve their mood, cognitive, and executive functions.Reference Harvey, Wingo, Burdick and Baldessarini68, Reference Baldessarini, Tarazi, Brunton, Lazo and Parker69

Repeated administration of cariprazine also increased DA D2Rs in frontal cortex and hippocampus, an effect shared by other atypical APDs.Reference Tarazi, Zhang and Baldessarini64, Reference Tarazi, Moran-Gates, Wong, Henry and Shahid65 Such changes may contribute to the beneficial therapeutic effects of cariprazine in schizophrenia and bipolar mania. Higher doses of cariprazine increased DA D2Rs in basal ganglia, which may account for the higher incidence of akathisia (9% vs. 5%) and extrapyramidal disorder (12% vs. 5%), compared with placebo-treated patients, in clinical trials.Reference Citrome70, Reference Citrome71

Serotonin and glutamate receptors

The long-term effects of cariprazine were not limited to DA receptors. Repeated administration of cariprazine increased 5-HT1ARs in the cerebral cortex, an effect consistent with the effects of other atypical APDs such as olanzapine, risperidone, quetiapine, and asenapine on the same receptor in the same brain.Reference Tarazi, Moran-Gates, Wong, Henry and Shahid65, Reference Choi, Adham, Kiss, Gyertyan and Tarazi72, Reference Tarazi, Zhang and Baldessarini73 The effects of these APDs may result from direct blockade of 5-HT1A receptors or from secondary effects as a result of combined actions of these drugs on D2 and 5-HT2A receptors. These effects further validate cortical 5-HT1AR as common targets that mediate the beneficial actions of cariprazine and other atypical antipsychotics. Interestingly, long-term administration of cariprazine did not alter 5-HT2AR levels in the cerebral cortex. In contrast, several other atypical APDs significantly decreased these receptors in the same brain region, suggesting that 5-HT2ARs are less likely to contribute to the mechanism of action of cariprazine in vivo.Reference Tarazi, Moran-Gates, Wong, Henry and Shahid65, Reference Choi, Adham, Kiss, Gyertyan and Tarazi72, Reference Tarazi, Zhang and Baldessarini73 It is possible that long-term cariprazine treatment with the selected doses did not achieve the in vivo occupancy of 5-HT2A receptors needed to trigger changes in the concentrations of these receptors in different brain regions.

Long-term administration of cariprazine decreased NMDA receptors in caudate putamen and NAc, an effect shared by atypical and not typical APDs.Reference Choi, Adham, Kiss, Gyertyan and Tarazi72, Reference Tarazi, Baldessarini, Kula and Zhang74–Reference Tarazi, Florijn and Creese76 Downregulation of striatal NMDA receptors by cariprazine and several atypical APDs may contribute, at least in part, to the benign extrapyramidal profile of atypical antipsychotic agents.Reference Tarsy, Baldessarini and Tarazi77 Cariprazine also decreased NMDA and increased AMPA receptors in the hippocampus, which may improve psychotic symptoms by normalizing abnormalities in hippocampal Glu neurotransmission postulated to occur in schizophrenia patients.Reference Choi, Adham, Kiss, Gyertyan and Tarazi72, Reference Tsai and Coyle78

Behavioral Effects of Cariprazine

Acute administration of cariprazine was effective in behavioral tests with face validity for the positive symptoms of schizophrenia, including the blockade of amphetamine-induced hyperactivity, inhibition of apomorphine-induced climbing, as well as antagonism of the locomotor stimulating effect of non-competitive NMDA antagonists.Reference Gyertyan, Kiss and Saghy66

Cariprazine’s effects on cognitive functions were investigated using animal models based on the administration of the muscarinic antagonist scopolamine or the non-competitive NMDA receptors antagonist phencyclidine (PCP). Acute injection of cariprazine was able to normalize scopolamine-induced deficits in a water labyrinth task with a bell-shaped dose-response pattern, while risperidone, olanzapine, and aripiprazole were less effective.Reference Gyertyan, Kiss and Saghy66 Moreover, acute cariprazine pretreatment (0.08–0.15 mg/kg) significantly attenuated deficits on social recognition memory (hippocampal/perirhinal function), spatial working memory (SWM), and extradimensional attention set-shifting (prefrontal cortex-dependent), disrupted by acute PCP treatment.Reference Zimnisky, Chang, Gyertyan, Kiss, Adham and Schmauss79 Importantly, the positive effects of cariprazine were not observed when the drug was given to PCP-treated DA D3R KO mice, suggesting that, despite the complex mechanisms through which PCP elicits cognitive deficits, DA D3R modulation is critical in mediating the effects of cariprazine.Reference Zimnisky, Chang, Gyertyan, Kiss, Adham and Schmauss79

A recent study has shown that 5 days of PCP injection increased incorrect, premature, and timeout responses in the 5-choice serial reaction task.Reference Barnes, Young, Markou, Adham, Gyertyan and Kiss80 Interestingly, and different from aripiprazole, a 3-day treatment with cariprazine at a dose of 0.03 mg/kg attenuated PCP-induced deficits without producing non-specific response suppression.Reference Barnes, Young, Markou, Adham, Gyertyan and Kiss80 Neill and colleagues have also produced evidence on the ability of cariprazine to normalize the behavioral abnormalities observed after a sub-chronic treatment with PCP in female rats. PCP-induced alterations in cognition and social behavior, which were still present one week at the end of PCP administration, were normalized by a single dose of cariprazine (0.05 mg/kg) administered 1 h before the behavioral tests. Interestingly, risperidone (0.16 mg/kg) was only able to attenuate the PCP-induced avoidance, suggesting a larger effect of cariprazine.Reference Neill, Grayson, Kiss, Gyertyan, Ferguson and Adham81 The efficacy of cariprazine was also investigated in an experimental model that combines PCP treatment and social isolation. This model is of particular interest since the manipulations are conducted early in life and caused long-term neurodevelopmental, behavioral, structural, and neurochemical alterations with a translational relevance for a spectrum of symptoms seen in schizophrenia.Reference Reinwald, Becker and Mallien82 Interestingly, a single dose of cariprazine (0.1–0.3 mg/kg) or aripiprazole (3 mg/kg) reduced the hyperactivity and reversed the cognitive deficits in the novel object recognition (NOR) test that were observed in rats exposed to a combination of PCP and social isolation.Reference Watson, King, Gyertyan, Kiss, Adham and Fone83 Moreover, only cariprazine was able to correct pro-social behavioral and body-sniffing, which may reflect a potential effectiveness of cariprazine, but not aripiprazole, in treating negative symptoms.Reference Watson, King, Gyertyan, Kiss, Adham and Fone83

Recent studies have also shown that cariprazine is able to exert antidepressant- and anxiolytic-like behaviors in stress-based models, which mimic an important etiological mechanism for clinical depression and anxiety.Reference Duric, Banasr and Franklin84, Reference Papp, Gruca, Lason-Tyburkiewicz, Adham, Kiss and Gyertyan85 In particular, prolonged treatment with cariprazine was able to normalize the anhedonic-like behavior, measured as reduction of sucrose intake, induced by chronic stress exposure, an effect that appears to rely on the ability to modulate D3Rs.Reference Duric, Banasr and Franklin84, Reference Papp, Gruca, Lason-Tyburkiewicz, Adham, Kiss and Gyertyan85 Indeed, even if DA D3R knock-out (KO) mice do not exhibit anxiety and depressive-like behavior,Reference Chourbaji, Brandwein and Vogt86, Reference Leggio, Micale and Drago87 and the effect of prolonged stress exposure is similar between wild-type and DA D3R KO mice, cariprazine treatment was not able to normalize anhedonia in transgenic mice exposed to chronic stress.Reference Duric, Banasr and Franklin84 Cariprazine, similar to aripiprazole, was also able to attenuate the anxiolytic-like behavior in chronically stressed rats, as indicated by its ability to reduce drinking latency in the novelty-induced hypophagia test.Reference Duric, Banasr and Franklin84 Furthermore, it has been recently demonstrated that cariprazine, possibly through the modulation of D3Rs, increases DA, serotonin, and norepinephrine efflux in rat NAc and hippocampus, an effect that may also contribute to the procognitive, prosocial, and antipsychotic-like actions of cariprazine in animal models.Reference Meltzer, Huang, He, Kiss, Farkas and Adham88

Conclusions

In summary, cariprazine represents a novel APD with a peculiar receptor signature that is primarily characterized by a partial agonism at DA D3Rs and D2Rs, with higher affinity for the former receptor subtype when compared to partial agonists such as aripiprazole and brexpiprazole. Interestingly, preclinical studies, as summarized in Table 1, have clearly demonstrated the efficacy of cariprazine not only in regulating positive symptoms but also on negative symptoms and cognitive deterioration of schizophrenia. While the precise mechanism of action of cariprazine remains to be determined, its high affinity for the DA D3Rs is likely to play a key role, as supported by studies conducted in DA D3 KO mice.

Similar to other APDs, cariprazine improves positive symptoms primarily through its activity on D2R. Conversely, the partial agonism at the D3R may represent the main mechanism through which the drug ameliorates negative symptoms and cognitive deficits. Indeed, several evidences support the concept that D3Rs can participate in the complex and heterogeneous alterations of the dopaminergic system in schizophrenia. In particular, an overexpression of the D3Rs on the dopaminergic neuron projecting from the VTA to the PFC, therefore acting as autoreceptor, may reduce the dopaminergic activity leading to a hypofunction at cortical level. Such defects can be ameliorated by cariprazine that, by modulating these receptors, will ultimately improve the treatment of negative symptoms as well as cognitive deficits, which represent important elements for the functional disability found in schizophrenia patients (Figure 1).

FIGURE 1. Schematic representation of DA D3R dysfunction in schizophrenia and the potential impact of cariprazine treatment. In pathological condition (panel B), as compared to the healthy condition (panel A), the overexpression of the D3Rs located in the DA neuron projecting from the VTA to the cortex leads to an inhibition of DA release in the prefrontal cortex, which may eventually reduce the Glu output. Cariprazine (panel C), by acting as partial agonist on the DA D3Rs of the mesocortical pathways, may reduce the “pathologic” inhibition thus leading to a normalization of DA release within the prefrontal cortex.

TABLE 1. Summary of the D3 receptor preclinical studies

Disclosures

Marco A. Riva received compensation as speaker/consultant from Lundbeck, Otzuka, Sumitomo Dainippon Pharma, and Sunovion, and received research grants from Lundbeck, Sumitomo Dainippon Pharma, and Sunovion. Frank I. Tarazi received research grants from Lundbeck and Sunovion. Giorgio Racagni received consulting fees and/or honoraria from Indena, Servier, and Recordati. Francesca Calabrese has nothing to declare.

References

References:

Biesdorf, C, Wang, AL, Topic, B, et al.Dopamine in the nucleus accumbens core, but not shell, increases during signaled food reward and decreases during delayed extinction. Neurobiol Learn Mem. 2015; 123: 125–139.Google Scholar
Cools, R, D’Esposito, M.Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry. 2011; 69(12): e113–e125.Google Scholar
Hamid, AA, Pettibone, JR, Mabrouk, OS, et al.Mesolimbic dopamine signals the value of work. Nat Neurosci. 2016; 19(1): 117–126.Google Scholar
Kegeles, LS, Abi-Dargham, A, Frankle, WG, et al.Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry. 2010; 67(3): 231–239.Google Scholar
Gingrich, JA, Caron, MG.Recent advances in the molecular biology of dopamine receptors. Annu Rev Neurosci. 1993; 16: 299–321.Google Scholar
Sibley, DR, Monsma, FJ Jr.Molecular biology of dopamine receptors. Trends Pharmacol Sci. 1992; 13(2): 61–69.Google Scholar
Beaulieu, JM, Gainetdinov, RR, Caron, MG.The Akt-GSK-3 signaling cascade in the actions of dopamine. Trends Pharmacol Sci. 2007; 28(4): 166–172.Google Scholar
Leucht, S, Davis, JM.Schizophrenia, primary negative symptoms, and soft outcomes in psychiatry. Lancet. 2017; 389(10074): 1077–1078.Google Scholar
Potkin, SG, Loze, JY, Forray, C, et al.Multidimensional assessment of functional outcomes in schizophrenia: results from QUALIFY, a head-to-head trial of aripiprazole once-monthly and paliperidone palmitate. Int J Neuropsychopharmacol. 2017; 20(1): 40–49.Google Scholar
Nemeth, G, Laszlovszky, I, Czobor, P, et al.Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet. 2017; 389(10074): 1103–1113.Google Scholar
Tsapakis, EM, Dimopoulou, T, Tarazi, FI.Clinical management of negative symptoms of schizophrenia: an update. Pharmacol Ther. 2015; 153: 135–147.Google Scholar
Sokoloff, P, Giros, B, Martres, MP, Bouthenet, ML, Schwartz, JC.Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature. 1990; 347(6289): 146–151.Google Scholar
Gurevich, EV, Joyce, JN.Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor expressing neurons. Neuropsychopharmacology. 1999; 20(1): 60–80.Google Scholar
Sokoloff, P, Le Foll, B.The dopamine D3 receptor, a quarter century later. Eur J Neurosci. 2017; 45(1): 2–19.Google Scholar
Sokoloff, P, Diaz, J, Le Foll, B, et al.The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets. 2006; 5(1): 25–43.Google Scholar
Stahl, SM.Dazzled by the dominions of dopamine: clinical roles of D3, D2, and D1 receptors. CNS Spectr. 2017; 22(4): 305–311.Google Scholar
Grace, AA.Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci. 2016; 17(8): 524–532.Google Scholar
Kapur, S.Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry. 2003; 160(1): 13–23.Google Scholar
Maggio, R, Scarselli, M, Capannolo, M, Millan, MJ.Novel dimensions of D3 receptor function: focus on heterodimerisation, transactivation and allosteric modulation. Eur Neuropsychopharmacol. 2015; 25(9): 1470–1479.Google Scholar
Scarselli, M, Novi, F, Schallmach, E, et al.D2/D3 dopamine receptor heterodimers exhibit unique functional properties. J Biol Chem. 2001; 276(32): 30308–30314.Google Scholar
Fiorentini, C, Busi, C, Spano, P, Missale, C.Role of receptor heterodimers in the development of L-dopa-induced dyskinesias in the 6-hydroxydopamine rat model of Parkinson’s disease. Parkinsonism Relat Disord. 2008; 14(Suppl 2): S159–S164.Google Scholar
Marcellino, D, Ferre, S, Casado, V, et al.Identification of dopamine D1-D3 receptor heteromers. Indications for a role of synergistic D1-D3 receptor interactions in the striatum. J Biol Chem. 2008; 283(38): 26016–26025.Google Scholar
Torvinen, M, Marcellino, D, Canals, M, et al.Adenosine A2A receptor and dopamine D3 receptor interactions: evidence of functional A2A/D3 heteromeric complexes. Mol Pharmacol. 2005; 67(2): 400–407.Google Scholar
Collo, G, Bono, F, Cavalleri, L, et al.Nicotine-induced structural plasticity in mesencephalic dopaminergic neurons is mediated by dopamine D3 receptors and Akt-mTORC1 signaling. Mol Pharmacol. 2013; 83(6): 1176–1189.Google Scholar
Cussac, D, Newman-Tancredi, A, Pasteau, V, Millan, MJ.Human dopamine D(3) receptors mediate mitogen-activated protein kinase activation via a phosphatidylinositol 3-kinase and an atypical protein kinase C-dependent mechanism. Mol Pharmacol. 1999; 56(5): 1025–1030.Google Scholar
Collo, G, Zanetti, S, Missale, C, Spano, P.Dopamine D3 receptor-preferring agonists increase dendrite arborization of mesencephalic dopaminergic neurons via extracellular signal-regulated kinase phosphorylation. Eur J Neurosci. 2008; 28(7): 1231–1240.Google Scholar
Schwartz, JC, Diaz, J, Pilon, C, Sokoloff, P.Possible implications of the dopamine D(3) receptor in schizophrenia and in antipsychotic drug actions. Brain Res Brain Res Rev. 2000; 31(2-3): 277–287.Google Scholar
Gyertyan, I, Saghy, K.Effects of dopamine D3 receptor antagonists on spontaneous and agonist-reduced motor activity in NMRI mice and Wistar rats: comparative study with nafadotride, U 99194A and SB 277011. Behav Pharmacol. 2004; 15(4): 253–262.Google Scholar
Nakajima, S, Gerretsen, P, Takeuchi, H, et al.The potential role of dopamine D(3) receptor neurotransmission in cognition. Eur Neuropsychopharmacol. 2013; 23(8): 799–813.Google Scholar
Barth, V, Need, AB, Tzavara, ET, et al. In vivo occupancy of dopamine D3 receptors by antagonists produces neurochemical and behavioral effects of potential relevance to attention-deficit-hyperactivity disorder. J Pharmacol Exp Ther. 2013; 344(2): 501–510.Google Scholar
Laszy, J, Laszlovszky, I, Gyertyan, I.Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats. Psychopharmacology (Berl). 2005; 179(3): 567–575.Google Scholar
Millan, MJ, Di Cara, B, Dekeyne, A, et al.Selective blockade of dopamine D(3) versus D(2) receptors enhances frontocortical cholinergic transmission and social memory in rats: a parallel neurochemical and behavioural analysis. J Neurochem. 2007; 100(4): 1047–1061.Google Scholar
Watson, DJ, Loiseau, F, Ingallinesi, M, Millan, MJ, Marsden, CA, Fone, KC.Selective blockade of dopamine D3 receptors enhances while D2 receptor antagonism impairs social novelty discrimination and novel object recognition in rats: a key role for the prefrontal cortex. Neuropsychopharmacology. 2012; 37(3): 770–786.Google Scholar
Lumme, V, Aalto, S, Ilonen, T, Nagren, K, Hietala, J.Dopamine D2/D3 receptor binding in the anterior cingulate cortex and executive functioning. Psychiatry Res. 2007; 156(1): 69–74.Google Scholar
Simpson, EH, Winiger, V, Biezonski, DK, Haq, I, Kandel, ER, Kellendonk, C.Selective overexpression of dopamine D3 receptors in the striatum disrupts motivation but not cognition. Biol Psychiatry. 2014; 76(10): 823–831.Google Scholar
Gross, G, Wicke, K, Drescher, KU.Dopamine D(3) receptor antagonism--still a therapeutic option for the treatment of schizophrenia. Naunyn Schmiedebergs Arch Pharmacol. 2013; 386(2): 155–166.Google Scholar
Joyce, JN, Millan, MJ.Dopamine D3 receptor antagonists as therapeutic agents. Drug Discov Today. 2005; 10(13): 917–925.Google Scholar
Van Kampen, JM, Eckman, CB. Dopamine D3 receptor agonist delivery to a model of Parkinson’s disease restores the nigrostriatal pathway and improves locomotor behavior. J Neurosci. 2006; 26(27): 7272–7280.Google Scholar
Mailman, RB, Murthy, V.Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? Curr Pharm Des. 2010; 16(5): 488–501.Google Scholar
Pich, EM, Collo, G.Pharmacological targeting of dopamine D3 receptors: possible clinical applications of selective drugs. Eur Neuropsychopharmacol. 2015; 25(9): 1437–1447.Google Scholar
Frankel, JS, Schwartz, TL.Brexpiprazole and cariprazine: distinguishing two new atypical antipsychotics from the original dopamine stabilizer aripiprazole. Ther Adv Psychopharmacol. 2017; 7(1): 29–41.Google Scholar
Miyamoto, S, Duncan, GE, Marx, CE, Lieberman, JA.Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry. 2005; 10(1): 79–104.Google Scholar
Kiss, B, Horvath, A, Nemethy, Z, et al.Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010; 333(1): 328–340.Google Scholar
Veselinovic, T, Paulzen, M, Grunder, G.Cariprazine, a new, orally active dopamine D2/3 receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression. Expert Rev Neurother. 2013; 13(11): 1141–1159.Google Scholar
Goff, DC.Brexpiprazole: a new antipsychotic following in the footsteps of aripiprazole. Am J Psychiatry. 2015; 172(9): 820–821.Google Scholar
Stahl, SM.Drugs for psychosis and mood: unique actions at D3, D2, and D1 dopamine receptor subtypes. CNS Spectr. 2017; 22(5): 375–384.Google Scholar
Nakamura, T, Kubota, T, Iwakaji, A, Imada, M, Kapas, M, Morio, Y.Clinical pharmacology study of cariprazine (MP-214) in patients with schizophrenia (12-week treatment). Drug Des Devel Ther. 2016; 10: 327–338.Google Scholar
Garnock-Jones, KP.Cariprazine: a review in schizophrenia. CNS Drugs. 2017; 31(6): 513–525.Google Scholar
De Berardis, D, Orsolini, L, Iasevoli, F, et al.The novel antipsychotic cariprazine (RGH-188): State-of-the-art in the treatment of psychiatric disorders. Curr Pharm Des. 2016; 22(33): 5144–5162.Google Scholar
Calabrese, JR, Keck, PE Jr., Starace, A, et al.Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study. J Clin Psychiatry. 2015; 76(3): 284–292.Google Scholar
Durgam, S, Cutler, AJ, Lu, K, et al.Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, phase 3, randomized, double-blind, placebo- and active-controlled trial. J Clin Psychiatry. 2015; 76(12):e1574–e1582.Google Scholar
Durgam, S, Greenberg, WM, Li, D, et al.Safety and tolerability of cariprazine in the long-term treatment of schizophrenia: results from a 48-week, single-arm, open-label extension study. Psychopharmacology (Berl). 2017; 234(2): 199–209.Google Scholar
Durgam, S, Starace, A, Li, D, et al.An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res. 2014; 152(2-3): 450–457.Google Scholar
Kane, JM, Zukin, S, Wang, Y, et al.Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: Results from an international, phase III clinical trial. J Clin Psychopharmacol. 2015; 35(4): 367–373.Google Scholar
Cutler, AJ, Durgam, S, Wang, Y, et al.Evaluation of the long-term safety and tolerability of cariprazine in patients with schizophrenia: results from a 1-year open-label study. CNS Spectr. 2017: 1–12.Google Scholar
Ketter, TA, Sachs, GS, Durgam, S, et al.The safety and tolerability of cariprazine in patients with manic or mixed episodes associated with bipolar I disorder: A 16-week open-label study. J Affect Disord. 2018; 225: 350–356.Google Scholar
Earley, W, Durgam, S, Lu, K, Laszlovszky, I, Debelle, M, Kane, JM.Safety and tolerability of cariprazine in patients with acute exacerbation of schizophrenia: a pooled analysis of four phase II/III randomized, double-blind, placebo-controlled studies. Int Clin Psychopharmacol. 2017; 32(6): 319–328.Google Scholar
Nasrallah, HA, Earley, W, Cutler, AJ, et al.The safety and tolerability of cariprazine in long-term treatment of schizophrenia: a post hoc pooled analysis. BMC Psychiatry. 2017; 17(1): 305.Google Scholar
Buchanan, RW, Breier, A, Kirkpatrick, B, Ball, P, Carpenter, WT Jr.Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome. Am J Psychiatry. 1998; 155(6): 751–760.Google Scholar
Nemeth, B, Molnar, A, Akehurst, R, et al.Quality-adjusted life year difference in patients with predominant negative symptoms of schizophrenia treated with cariprazine and risperidone. J Comp Eff Res. 2017; 6(8): 639–648.Google Scholar
Choi, YK, Adham, N, Kiss, B, Gyertyan, I, Tarazi, FI.Long-term effects of cariprazine exposure on dopamine receptor subtypes. CNS Spectr. 2014; 19(3): 268–277.Google Scholar
Tarazi, FI, Florijn, WJ, Creese, I.Differential regulation of dopamine receptors after chronic typical and atypical antipsychotic drug treatment. Neuroscience. 1997; 78(4): 985–996.Google Scholar
Tarazi, FI, Yeghiayan, SK, Baldessarini, RJ, Kula, NS, Neumeyer, JL.Long-term effects of S(+)N-n-propylnorapomorphine compared with typical and atypical antipsychotics: differential increases of cerebrocortical D2-like and striatolimbic D4-like dopamine receptors. Neuropsychopharmacology. 1997; 17(3): 186–196.Google Scholar
Tarazi, FI, Zhang, K, Baldessarini, RJ.Long-term effects of olanzapine, risperidone, and quetiapine on dopamine receptor types in regions of rat brain: implications for antipsychotic drug treatment. J Pharmacol Exp Ther. 2001; 297(2): 711–717.Google Scholar
Tarazi, FI, Moran-Gates, T, Wong, EH, Henry, B, Shahid, M.Differential regional and dose-related effects of asenapine on dopamine receptor subtypes. Psychopharmacology (Berl). 2008; 198(1): 103–111.Google Scholar
Gyertyan, I, Kiss, B, Saghy, K, et al.Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents. Neurochem Int. 2011; 59(6): 925–935.Google Scholar
Zhang, K, Weiss, NT, Tarazi, FI, Kula, NS, Baldessarini, RJ.Effects of alkylating agents on dopamine D(3) receptors in rat brain: selective protection by dopamine. Brain Res. 1999; 847(1): 32–37.Google Scholar
Harvey, PD, Wingo, AP, Burdick, KE, Baldessarini, RJ.Cognition and disability in bipolar disorder: lessons from schizophrenia research. Bipolar Disord. 2010; 12(4): 364–375.Google Scholar
Baldessarini, RJ, Tarazi, FI.Pharmacotherapy of psychosis and mania. In: Brunton, LL, Lazo, JS, Parker, KL, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th ed.New York: McGraw-Hill; 2005:461–500.Google Scholar
Citrome, L.Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy. Adv Ther. 2013; 30(2): 114–126.Google Scholar
Citrome, L.Cariprazine in bipolar disorder: clinical efficacy, tolerability, and place in therapy. Adv Ther. 2013; 30(2): 102–113.Google Scholar
Choi, YK, Adham, N, Kiss, B, Gyertyan, I, Tarazi, FI.Long-term effects of aripiprazole exposure on monoaminergic and glutamatergic receptor subtypes: comparison with cariprazine. CNS Spectr. 2017: 1–11.Google Scholar
Tarazi, FI, Zhang, K, Baldessarini, RJ.Long-term effects of olanzapine, risperidone, and quetiapine on serotonin 1A, 2A and 2C receptors in rat forebrain regions. Psychopharmacology (Berl). 2002; 161(3): 263–270.Google Scholar
Tarazi, FI, Baldessarini, RJ, Kula, NS, Zhang, K.Long-term effects of olanzapine, risperidone, and quetiapine on ionotropic glutamate receptor types: implications for antipsychotic drug treatment. J Pharmacol Exp Ther. 2003; 306(3): 1145–1151.Google Scholar
Tarazi, FI, Choi, YK, Gardner, M, Wong, EH, Henry, B, Shahid, M.Asenapine exerts distinctive regional effects on ionotropic glutamate receptor subtypes in rat brain. Synapse. 2009; 63(5): 413–420.Google Scholar
Tarazi, FI, Florijn, WJ, Creese, I.Regulation of ionotropic glutamate receptors following subchronic and chronic treatment with typical and atypical antipsychotics. Psychopharmacology (Berl). 1996; 128(4): 371–379.Google Scholar
Tarsy, D, Baldessarini, RJ, Tarazi, FI.Effects of newer antipsychotics on extrapyramidal function. CNS Drugs. 2002; 16(1): 23–45.Google Scholar
Tsai, G, Coyle, JT.Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol. 2002; 42: 165–179.Google Scholar
Zimnisky, R, Chang, G, Gyertyan, I, Kiss, B, Adham, N, Schmauss, C.Cariprazine, a dopamine D(3)-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse. Psychopharmacology (Berl). 2013; 226(1): 91–100.Google Scholar
Barnes, SA, Young, JW, Markou, A, Adham, N, Gyertyan, I, Kiss, B.The effects of cariprazine and aripiprazole on PCP-induced deficits on attention assessed in the 5-choice serial reaction time task. Psychopharmacology (Berl). 2018; 235(5): 1403–1414.Google Scholar
Neill, JC, Grayson, B, Kiss, B, Gyertyan, I, Ferguson, P, Adham, N.Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology. Eur Neuropsychopharmacol. 2016; 26(1): 3–14.Google Scholar
Reinwald, JR, Becker, R, Mallien, AS, et al.Neural mechanisms of early-life social stress as a developmental risk factor for severe psychiatric disorders. Biol Psychiatry. 2017.Google Scholar
Watson, DJG, King, MV, Gyertyan, I, Kiss, B, Adham, N, Fone, KCF.The dopamine D(3)-preferring D(2)/D(3) dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia. Eur Neuropsychopharmacol. 2016; 26(2): 208–224.Google Scholar
Duric, V, Banasr, M, Franklin, T, et al.Cariprazine exhibits anxiolytic and dopamine D3 receptor-dependent antidepressant effects in the chronic stress model. Int J Neuropsychopharmacol. 2017; 20(10): 788–796.Google Scholar
Papp, M, Gruca, P, Lason-Tyburkiewicz, M, Adham, N, Kiss, B, Gyertyan, I.Attenuation of anhedonia by cariprazine in the chronic mild stress model of depression. Behav Pharmacol. 2014; 25(5-6): 567–574.Google Scholar
Chourbaji, S, Brandwein, C, Vogt, MA, et al.Dopamine receptor 3 (D3) knockout mice show regular emotional behaviour. Pharmacol Res. 2008; 58(5-6): 302–307.Google Scholar
Leggio, GM, Micale, V, Drago, F.Increased sensitivity to antidepressants of D3 dopamine receptor-deficient mice in the forced swim test (FST). Eur Neuropsychopharmacol. 2008; 18(4): 271–277.Google Scholar
Meltzer, HY, Huang, M, He, W, Kiss, B, Farkas, B, Adham, N.Cariprazine enhances monoaminergic activity in the hippocampus and ventral striatum of rats: A possible basis for its antipsychotic effect. Biol Psychiatry 2018; 83(9, supplement): S228.Google Scholar
Figure 0

FIGURE 1. Schematic representation of DA D3R dysfunction in schizophrenia and the potential impact of cariprazine treatment. In pathological condition (panel B), as compared to the healthy condition (panel A), the overexpression of the D3Rs located in the DA neuron projecting from the VTA to the cortex leads to an inhibition of DA release in the prefrontal cortex, which may eventually reduce the Glu output. Cariprazine (panel C), by acting as partial agonist on the DA D3Rs of the mesocortical pathways, may reduce the “pathologic” inhibition thus leading to a normalization of DA release within the prefrontal cortex.

Figure 1

TABLE 1. Summary of the D3 receptor preclinical studies