The novel atypical antipsychotic cariprazine demonstrates dopamine D<sub>2</sub> receptor‐dependent partial agonist actions on rat mesencephalic dopamine neuronal activity

Delcourte, Sarah; Ashby, Charles R.; Rovera, Renaud; Kiss, Béla; Adham, Nika; Farkas, Bence; Haddjeri, Nasser

doi:10.1111/cns.12867

Cited by 11 publications

(12 citation statements)

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“…In vitro studies are necessary to identify potential therapeutic compounds, but it is also important to study the activity of a drug in vivo to have a thorough mechanistic understanding. Prior experiments of this nature have been conducted to characterize the effects of cariprazine on DA neurons (Delcourte et al, 2018) but not on 5-HT or NE systems. To this end, the objectives of the present study were to determine the in vivo effects of acute cariprazine administration at 5-HT 1A autoreceptors in the dorsal raphe nucleus (DRN), postsynaptic 5-HT 1A receptors in the hippocampus, 5-HT 2A receptors controlling NE neuron firing in the locus coeruleus (LC), and a 2 -adrenergic autoreceptors within the LC using electrophysiological techniques.…”

Section: Introductionmentioning

confidence: 99%

Involvement of 5-HT_1A and 5-HT_2A Receptors but Not α₂-Adrenoceptors in the Acute Electrophysiological Effects of Cariprazine in the Rat Brain In Vivo

et al. 2018

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Cariprazine, an orally active and potent dopamine D 3-preferring D 3 /D 2 receptor partial agonist, is approved to treat adults with schizophrenia (in the United States and Europe) and manic or mixed episodes associated with bipolar I disorder (in the United States). Cariprazine also displays partial agonism at serotonin [5-hydroxytryptamine (5-HT)] 5-HT 1A receptors and antagonism at 5-HT 2A and 5-HT 2B receptors in vitro. The study objective was to determine whether cariprazine leads to functional alterations of monoamine systems in vivo via electrophysiological recordings from anesthetized rats. Dorsal raphe nucleus (DRN), locus coeruleus (LC), and hippocampus pyramidal neurons were recorded, and cariprazine was administered systemically or locally through iontophoresis. In the DRN, cariprazine completely inhibited the firing activity of 5-HT neurons, which was fully reversed by the 5-HT 1A receptor antagonist, WAY100635. In the LC, cariprazine reversed the inhibitory effect of the preferential 5-HT 2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine, on norepinephrine (NE) neurons (ED 50 5 66 mg/kg) but did not block the inhibitory effect of the a 2-adrenergic receptor agonist, clonidine. Cariprazine, iontophorized into the hippocampus, diminished pyramidal neuronal firing through activation of 5-HT 1A receptors, while its concomitant administration did not dampen the suppressant effect of 5-HT. These results indicate that, in vivo, cariprazine acted as a 5-HT 1A autoreceptor agonist in the DRN, a 5-HT 2A receptor antagonist in modulating the firing activity of LC NE neurons, and a full agonist at 5-HT 1A receptors mediating the electrophysiological effect of 5-HT on pyramidal neurons. The modulatory actions of cariprazine on these monoaminergic systems may contribute to its therapeutic effectiveness in patients with depressive episodes.

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Section: Introductionmentioning

confidence: 99%

Involvement of 5-HT_1A and 5-HT_2A Receptors but Not α₂-Adrenoceptors in the Acute Electrophysiological Effects of Cariprazine in the Rat Brain In Vivo

et al. 2018

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“…Other sources of information included product labeling 10 and the author’s prior published reviews. 11 – 13 Searching for “cariprazine” using PubMed yielded 125 records, of which 15 were original reports of clinical trial data in persons with schizophrenia, 14 – 28 24 were medicinal chemistry or preclinical research reports, 29 – 52 9 were original reports of cariprazine clinical trial data for disorders other than schizophrenia, 53 – 61 and the remainder consisted of reviews, commentaries, or articles that did not appear directly relevant. Three meta-analyses were found that focused on cariprazine and included data for the treatment of schizophrenia.…”

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confidence: 99%

Cariprazine for acute and maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy

Citrome¹

2018

NDT

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Cariprazine is an oral antipsychotic approved in the US and EU for the treatment of schizophrenia. Cariprazine differs from other antipsychotics in that it is a dopamine D3- and D2-receptor partial agonist, with tenfold higher affinity for D3 receptors than for D2 receptors. Cariprazine is metabolized in two steps by CYP3A4 to didesmethyl-cariprazine (DDCAR). DDCAR has a long half-life of 1–3 weeks and is the predominant circulating active moiety. Efficacy and safety in persons with acute schizophrenia were assessed in four similarly designed, short-term, randomized, placebo-controlled clinical trials in nonelderly adults, with three studies considered positive and yielding a number needed to treat vs placebo for response (change from baseline ≥30% in Positive and Negative Syndrome Scale total score) of ten for the approved dose range of cariprazine 1.5–6 mg/day. The most common adverse reactions were extrapyramidal symptoms (15% and 19% for 1.5–3 and 4.5–6 mg/day, respectively, vs 8% for placebo) and akathisia (9% and 12.5% for 1.5–3 and 4.5–6 mg/day, respectively, vs 4% for placebo). For the approved dose range, rates of discontinuation because of an adverse event were lower overall for patients receiving cariprazine vs placebo (9% vs 12%). Weight and metabolic profile appear favorable. Cariprazine does not increase prolactin levels or prolong the electrocardiographic QT interval. Cariprazine has also been found to be effective for the maintenance treatment of schizophrenia by delaying time to relapse when compared with placebo (HR 0.45). A 26-week randomized clinical trial evidenced superiority of cariprazine over risperidone for the treatment of predominantly negative symptoms in patients with schizophrenia. Cariprazine is also approved in the US for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and is being studied for the treatment of bipolar I depression and major depressive disorder.

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“…administration of cariprazine or DDCAR in anesthetized rats. Drug effects on neuronal firing rates were determined as previously described 28. For further details, see Supplementary materials .…”

Section: Methodsmentioning

confidence: 99%

<p>Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine</p>

Kiss¹,

Némethy²,

Fazekas³

et al. 2019

DDDT

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Introduction: Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy.MethodsIn vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR. ResultsSimilar to cariprazine, both metabolites showed high affinity for human D3, D2L, 5-HT1A, 5-HT2A, and 5-HT2B receptors, albeit with higher selectivity than cariprazine for D3 versus D2 receptors. In [35S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D2 and D3 receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D2 and D3 receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT1A receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT2B receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D3 receptor occupancy in rat brain; however, cariprazine was more potent for D2 receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D2 receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine.ConclusionOverall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy.

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The novel atypical antipsychotic cariprazine demonstrates dopamine D₂ receptor‐dependent partial agonist actions on rat mesencephalic dopamine neuronal activity

Cited by 11 publications

References 58 publications

Involvement of 5-HT_1A and 5-HT_2A Receptors but Not α₂-Adrenoceptors in the Acute Electrophysiological Effects of Cariprazine in the Rat Brain In Vivo

Involvement of 5-HT_1A and 5-HT_2A Receptors but Not α₂-Adrenoceptors in the Acute Electrophysiological Effects of Cariprazine in the Rat Brain In Vivo

Cariprazine for acute and maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy

<p>Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine</p>

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The novel atypical antipsychotic cariprazine demonstrates dopamine D2 receptor‐dependent partial agonist actions on rat mesencephalic dopamine neuronal activity

Cited by 11 publications

References 58 publications

Involvement of 5-HT1A and 5-HT2A Receptors but Not α2-Adrenoceptors in the Acute Electrophysiological Effects of Cariprazine in the Rat Brain In Vivo

Involvement of 5-HT1A and 5-HT2A Receptors but Not α2-Adrenoceptors in the Acute Electrophysiological Effects of Cariprazine in the Rat Brain In Vivo

Cariprazine for acute and maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy

<p>Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine</p>

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The novel atypical antipsychotic cariprazine demonstrates dopamine D₂ receptor‐dependent partial agonist actions on rat mesencephalic dopamine neuronal activity

Involvement of 5-HT_1A and 5-HT_2A Receptors but Not α₂-Adrenoceptors in the Acute Electrophysiological Effects of Cariprazine in the Rat Brain In Vivo

Involvement of 5-HT_1A and 5-HT_2A Receptors but Not α₂-Adrenoceptors in the Acute Electrophysiological Effects of Cariprazine in the Rat Brain In Vivo