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

Abstract

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.

Long-term administration of cariprazine increases locus coeruleus noradrenergic neurons activity and serotonin1A receptor neurotransmission in the hippocampus

“…Increased 5-HT 1A receptor activation has been hypothesized to play an important role in the antidepressant properties of various strategies used in MDD (Blier and Ward, 2003), including the selective 5-HT 1A receptor agonist gepirone and the multi-targeted agents aripiprazole and brexpiprazole endowed with this property (Blier and de Montigny, 1990; Chernoloz et al, 2009; Ebrahimzadeh et al, 2018; Oosterhof et al, 2016). Furthermore, cariprazine, like brexpiprazole, has been shown to act as a full agonist in vivo at 5-HT 1A receptors of the pyramidal neurons in the CA3 region of the hippocampus (Herman et al, 2018; Oosterhof et al, 2014).…”

“…This reversal of inhibited NE neurons firing activity resulting from SSRIs might underlie, at least in part, their well-documented therapeutic efficacy in TRD. Similar to these drugs, cariprazine also acts in vivo as an antagonist on 5-HT 2A receptors controlling the firing activity of NE neurons (Herman et al, 2018).…”

Synthesis and Biological Evaluation of Five‐Atom‐Linker‐Based Arylpiperazine Derivatives with an Atypical Antipsychotic Profile

“…In clinical practice, atypical antipsychotics are often used together with antidepressants for schizophrenia to get maximum efficacy. [12][13][14] Furthermore, designing a molecule with serotonin (5-HT) transporter (SERT) inhibition function is beneficial to the treatment of schizophrenia and both the efficacy and safety of selective serotonin reuptake inhibitors (SSRIs) as augmentation therapy for schizophrenia have been proven clinically. This therapeutic regimen often leads to drug-drug interactions, particularly in patients with psychiatric comorbidity.…”

“…Besides dopamine D 2 receptors, various serotonin receptors are also important targets for schizophrenia. A wealth of preclinical and clinical evidence strongly supports the relevance of 5‐HT 1A receptor activation and 5‐HT 2A receptor inhibition for the treatment of schizophrenia . Furthermore, designing a molecule with serotonin (5‐HT) transporter (SERT) inhibition function is beneficial to the treatment of schizophrenia and both the efficacy and safety of selective serotonin reuptake inhibitors (SSRIs) as augmentation therapy for schizophrenia have been proven clinically .…”

“…) 13. C NMR (100 MHz, CHCl 3 ) δ 162.55, 154.11, 153.63, 148.28, 145.34, 140.48, 139.52, 130.16, 129.47, 128.28, 122.97, 121.38, 117.78, 114.90, 114.81, 113.14, 55.79, 51.46, 49.17, 35.45, 30.58, 26.11, 23.29.…”