Antipsychotics and the Dopamine–Serotonin Connection

Ellenbroek, Bart A.; Cesura, Andrea M.

doi:10.1007/7355_2014_51

Cited by 12 publications

(20 citation statements)

References 187 publications

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“…As we have recently summarized, a number of 5-HT/DA multireceptor ligands have been developed, but few have shown any real benefit over the current generation of antipsychotics (Ellenbroek and Cesura, 2014). This is certainly to a large degree the result of the poor predictability of the current generation of animal models.…”

Section: Resultsmentioning

confidence: 99%

“…Together with Lex, we also investigated the influence of serotonergic drugs on the behavioural effects of antipsychotic drugs, focusing predominantly on 5-HT 1A and 5-HT 2A/C receptors Prinssen et al, 1994). The involvement of these 5-HT receptors in, especially the second generation of, antipsychotics has been discussed at length in many other papers (Meltzer, 2013;Ellenbroek and Cesura, 2014;Schreiber and Newman-Tancredi, 2014). In addition, several antipsychotics (such as asenapine, olanzapine, clozapine, quetiapine and ziprasidone) show appreciable binding to the 5-HT 6 receptor.…”

Section: Introductionmentioning

confidence: 99%

“…The involvement of these 5-HT receptors in, especially the second generation of, antipsychotics has been discussed at length in many other papers (Meltzer, 2013;Ellenbroek and Cesura, 2014;Schreiber and Newman-Tancredi, 2014). As 5-HT 6 receptor antagonists show procognitive effects in several animal models, several 5-HT 6 selective ligands are currently being investigated in dementia as well as for the treatment of cognitive deficits in schizophrenia (Ivachtchenko and Ivanenkov, 2013;Ellenbroek and Cesura, 2014). As 5-HT 6 receptor antagonists show procognitive effects in several animal models, several 5-HT 6 selective ligands are currently being investigated in dementia as well as for the treatment of cognitive deficits in schizophrenia (Ivachtchenko and Ivanenkov, 2013;Ellenbroek and Cesura, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Can 5-HT3 antagonists contribute toward the treatment of schizophrenia?

Ellenbroek

Prinssen

2015

Behavioural Pharmacology

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In one of his earlier papers, Lex Cools stated that the 'concept of an impaired balance between the in series connected […] dopamine system, […] 5-HT system and […] noradrenaline system offers a single coherent and integrated theory of schizophrenia' (Cools, 1975). Since then, considerable attention has focused on the interaction between dopamine and 5-HT and it is now well accepted that most antipsychotics (especially the second-generation drugs) modulate both dopaminergic and serotonergic receptors. However, the vast majority of research has focused on the 5-HT1A, 5-HT2A and 5-HT2C receptors. In the present paper, we review the literature pertaining to the 5-HT3 receptor, the only ionotropic 5-HT receptor. We discuss both the interactions between 5-HT3 receptors and dopamine, and the animal and human literature investigating the role of 5-HT3 receptors in schizophrenia. The results show that the interactions between 5-HT3 receptors and dopamine are complex, but that 5-HT3 receptors do not have a strong influence on the positive symptoms of schizophrenia. However, when added to standard antipsychotic medication, several recent studies have found that 5-HT3 receptor antagonists can induce a statistically significantly improvement in negative and cognitive symptoms. The implications of these findings in relation to animal modelling and drug development are discussed.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Can 5-HT3 antagonists contribute toward the treatment of schizophrenia?

Ellenbroek

Prinssen

2015

Behavioural Pharmacology

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“…Cariprazine, a novel, orally active antipsychotic agent that is a potent dopamine D 2 /D 3 receptor partial agonist with preferential binding to D 3 receptors, was recently approved by the U.S. Food and Drug Administration for the treatment of both schizophrenia and acute manic or mixed episodes associated with bipolar I disorder ( Ágai-Csongor et al, 2012 ; Veselinovic et al, 2013 ; Findlay et al, 2016 ). Among atypical antipsychotics, cariprazine displays the highest D 3 receptor binding affinity and D 3 vs. D 2 receptor selectivity (by approximately 6- to 8-fold) ( Kiss et al, 2010 ; McCormick et al, 2010 ; Ellenbroek and Cesura, 2015 ). These features could be responsible for cariprazine showing a more balanced dopamine D 2 and D 3 receptor brain occupancy in vivo in both rodents ( Gyertyán et al, 2011 ; Kiss et al, 2012 ) and patients ( Girgis et al, 2016 ) compared with other antipsychotics, which displayed preferential occupancy for D 2 vs. D 3 receptors ( Graff-Guerrero et al, 2009 ; McCormick et al, 2010 ; Mizrahi et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Cariprazine Exhibits Anxiolytic and Dopamine D3 Receptor-Dependent Antidepressant Effects in the Chronic Stress Model

Đurić

Banasr

Franklin

et al. 2017

International Journal of Neuropsychopharmacology

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BackgroundCariprazine, a D3-preferring dopamine D2/D3 receptor partial agonist, is a new antipsychotic drug recently approved in the United States for the treatment of schizophrenia and bipolar mania. We recently demonstrated that cariprazine also has significant antianhedonic-like effects in rats subjected to chronic stress; however, the exact mechanism of action for cariprazine’s antidepressant-like properties is not known. Thus, in this study we examined whether the effects of cariprazine are mediated by dopamine D3 receptors.MethodsWild-type and D3-knockout mice were exposed to chronic unpredictable stress for up to 26 days, treated daily with vehicle, imipramine (20 mg/kg), aripiprazole (1 and 5 mg/kg), or cariprazine (0.03, 0.1, 0.2, and 0.4 mg/kg), and tested in behavioral assays measuring anhedonia and anxiety-like behaviors.ResultsResults showed that cariprazine significantly attenuated chronic unpredictable stress-induced anhedonic-like behavior in wild-type mice, demonstrating potent antidepressant-like effects comparable with aripiprazole and the tricyclic antidepressant imipramine. This antianhedonic-like effect of cariprazine was not observed in D3-knockout mice, suggesting that the cariprazine antidepressant-like activity is mediated by dopamine D3 receptors. Moreover, cariprazine significantly reduced drinking latency in the novelty-induced hypophagia test in wild-type mice, further confirming its antianhedonic-like effect and showing that it also has anxiolytic-like activity.ConclusionsIn combination with previous studies, these results suggest that cariprazine has a unique pharmacological profile and distinct dopamine D3 receptor-dependent mechanism of action that may be beneficial in the treatment of schizophrenia, bipolar disorder, and major depressive disorder.

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“…[1][2][3][4] In addition to their effects at dopamine receptor subtypes, atypical antipsychotics modulate serotonergic and glutamatergic neurotransmission, which may contribute to their clinical efficacy, safety, and tolerability. 1,5,6 The atypical antipsychotics cariprazine and aripiprazole are both dopamine D 2 /D 3 receptor partial agonists; however, the drugs differ in that cariprazine is D 3 receptor-preferring and has moderate affinity for serotonin 5-HT 1A receptors. 7 Moreover, cariprazine, but not aripiprazole, demonstrated high and balanced occupancy of both D 2 and D 3 receptors at pharmacologically effective and antipsychotic doses in both animals 8 and schizophrenia patients.…”

Section: Introductionmentioning

confidence: 99%

Long-term effects of aripiprazole exposure on monoaminergic and glutamatergic receptor subtypes: comparison with cariprazine

et al. 2017

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Long-term administration of aripiprazole and cariprazine had similar effects on 5-HT1A, NMDA, and AMPA receptors. However, cariprazine more profoundly increased D3 receptors while aripiprazole selectively reduced 5-HT2A receptors. These results suggest that the unique actions of cariprazine on dopamine D3 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.

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Antipsychotics and the Dopamine–Serotonin Connection

Cited by 12 publications

References 187 publications

Can 5-HT3 antagonists contribute toward the treatment of schizophrenia?

Can 5-HT3 antagonists contribute toward the treatment of schizophrenia?

Cariprazine Exhibits Anxiolytic and Dopamine D3 Receptor-Dependent Antidepressant Effects in the Chronic Stress Model

Long-term effects of aripiprazole exposure on monoaminergic and glutamatergic receptor subtypes: comparison with cariprazine

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