Distinct functional profiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms

Zhang, Jean Y.; Kowal, Dianne; Nawoschik, Stanley; Lou, Zhuangwei; Dunlop, John

doi:10.1016/j.bcp.2005.11.007

Cited by 50 publications

(30 citation statements)

References 26 publications

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“…Furthermore, 5-HT 2C receptor agonists may show an improved safety profile in humans relative to existing antipsychotic drugs. This is observed in the clinic with aripiprazole (Abilify), which possesses 5-HT 2C receptor partial agonism and is associated with less weight gain compared with other antipsychotics drugs (Zhang et al, 2006;Leucht et al, 2013). Finally, because 5-HT 2C receptors are expressed predominantly in the central nervous system (Molineaux et al, 1989), compounds that specifically target and activate 5-HT 2C receptors should have limited impact on peripheral tissues, further decreasing the risk of side effects.…”

Section: Introductionmentioning

confidence: 99%

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

Canal

Morgan

Felsing

et al. 2014

J Pharmacol Exp Ther

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Development of 5-HT 2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT 2C selective agonists also activate 5-HT 2A and/or 5-HT 2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT 2C receptor agonist, (2) 2)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (2)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (2)-MBP, the enantiomer (1)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT 2C receptor-specific agonist, such as (2)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders.

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Section: Introductionmentioning

confidence: 99%

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

Canal

Morgan

Felsing

et al. 2014

J Pharmacol Exp Ther

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“…For example, haloperidol (a first-generation antipsychotic) and olanzapine (a second-generation antipsychotic) are potent dopamine D 2 receptor antagonists, while aripiprazole acts as a partial agonist (Correll, 2010) or a functionally selective ligand for the dopamine D 2 receptor (Mailman and Murthy, 2010). Additionally, olanzapine displays antagonism for serotonin 5-HT 2A,2C receptors, which interacts with dopamine D 2 receptor antagonism to achieve its clinical efficacy (Mathews and Muzina, 2007;Meltzer and Massey, 2011), while aripiprazole is a partial agonist of 5-HT 1A receptors and an antagonist of 5-HT 2A receptors (Jordan et al, 2002;Zhang et al, 2006). Therefore, the differential effects of various antipsychotic drugs on NRG1-ErbB4 expression might partly be related to their distinct pharmacological binding profiles .…”

Section: Discussionmentioning

confidence: 99%

Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

Deng

Pan

et al. 2015

Psychiatry Research

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Neuregulin-1 (NRG1) and ErbB4 genes have been identified as candidate genes for schizophrenia. Postmortem studies indicated that NRG1-ErbB4 signalling is impaired in schizophrenia subjects. This study investigated whether short-or long-term antipsychotic treatment has different effects on the expression of NRG1 and ErbB4 receptors. Female Sprague-Dawley rats were treated orally with either aripiprazole (0.75 mg/kg), haloperidol (0.1 mg/kg), olanzapine (0.5 mg/kg), or vehicle, 3 times/day for 1 or 12 weeks. Western blotting was performed to examine the expression of NRG1 isoforms (135 kDa, 70 kDa and 40 kDa) and ErbB4 receptors. Both 1-week haloperidol and olanzapine treatment increased NRG1-70 kDa expression in the hippocampus; haloperidol also up-regulated ErbB4 levels in the prefrontal cortex (PFC). In the 12-week group, aripiprazole decreased the expression of all three NRG1 isoforms and ErbB4 receptors in the PFC, NRG1-70 kDa and -40 kDa in the cingulate cortex (Cg), and NRG1-135 kDa, -70 kDa and ErbB4 receptors in the hippocampus; haloperidol reduced NRG1-135 kDa in the PFC, NRG1-40 kDa in all three brain regions, and ErbB4 receptor levels in the PFC and hippocampus; NRG1-40 kDa in the PFC and Cg was also downregulated by olanzapine. These results suggest that the time-dependent and region-specific effects of antipsychotics on NRG1-ErbB4 signalling may contribute to the efficacy of antipsychotics to treat schizophrenia. AbstractNeuregulin-1 (NRG1) and ErbB4 genes have been identified as candidate genes for schizophrenia. Post-mortem studies indicated that NRG1-ErbB4 signalling is impaired in schizophrenia subjects. This study investigated whether short-or long-term antipsychotic treatment has different effects on the expression of NRG1 and ErbB4 receptors. Female Sprague-Dawley rats were treated orally with either aripiprazole (0.75mg/kg), haloperidol (0.1mg/kg), olanzapine (0.5mg/kg), or vehicle, 3 times/day for 1 or 12 weeks. Western blotting was performed to examine the expression of NRG1 isoforms (135kDa, 70kDa and 40kDa) and ErbB4 receptors. Both 1-week haloperidol and olanzapine treatment increased NRG1-70kDa expression in the hippocampus; haloperidol also up-regulated ErbB4 levels in the prefrontal cortex (PFC). In the 12-week group, aripiprazole decreased the expression of all three NRG1 isoforms and ErbB4 receptors in the PFC, NRG1-70kDa and -40kDa in the cingulate cortex (Cg), and NRG1-135kDa, -70kDa and ErbB4 receptors in the hippocampus; haloperidol reduced NRG1-135kDa in the PFC, NRG1-40kDa in all three brain regions, and ErbB4 receptor levels in the PFC and hippocampus; NRG1-40kDa in the PFC and Cg was also down-regulated by olanzapine. These results suggest that the time-dependent and regionspecific effects of antipsychotics on NRG1-ErbB4 signalling may contribute to the efficacy of antipsychotics to treat schizophrenia.

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“…Cells stably expressing the nonedited, human 5-HT 2C-INI receptor (250 fmol/mg protein) or the edited, human 5-HT 2C-VNI receptor (50 fmol/mg protein) were derived from transfection of CHO-K1 cells as described previously (Berg et al, 1998;Zhang et al, 2006). Cells were maintained in ␣-minimal essential medium supplemented with 5% fetal bovine serum and seeded into 12-or 24-well tissue culture vessels for functional studies or 15-cm dishes for radioligand binding studies at a density of 4 ϫ 10 4 cells/ cm 2 .…”

Section: Materials the Myo-[mentioning

confidence: 99%

A Conservative, Single-Amino Acid Substitution in the Second Cytoplasmic Domain of the Human Serotonin_2CReceptor Alters Both Ligand-Dependent and -Independent Receptor Signaling

Berg¹,

Dunlop²,

Sanchez³

et al. 2007

J Pharmacol Exp Ther

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The post-transcriptional process of mRNA editing changes up to three amino acids in the second intracellular domain (i2) of the serotonin 2C (5-HT 2C ) receptor and alters some signaling characteristics of the receptor. Here, we report that the substitution of valine for isoleucine (I156V; 5-HT 2C-VNI ), which occurs naturally as a result of mRNA editing, alters both ligand-dependent and -independent signaling. Agonist functional selectivity at the 5-HT 2C-VNI receptor differed from the nonedited 5-HT 2C-INI receptor. Ligands with selectivity for phospholipase C (PLC) signaling in 5-HT 2C-INI cells retained this selectivity in 5-HT 2C-VNI -expressing cells. However, ligands with selectivity for phospholipase A2 (PLA2) signaling in 5-HT 2C-INI cells lost the capacity for preferential PLA2 activation in 5-HT 2C-VNI cells. Maximal PLC responses elicited by 5-HT (full agonist) and lysergic acid diethylamide and 2,5-dimethoxy-4-iodophenylisopropylamine (partial agonists) at edited receptors (5-HT 2C-VNI , 5-HT 2C-VSV , and 5-HT 2C-VGV ) were not different from 5-HT 2C-INI receptors, suggesting that the capacity of the agonist-occupied receptor to couple to G q/11 proteins was not different. Ligand-independent (i.e., constitutive) receptor activity toward PLC for the 5-HT 2C-VNI receptor was markedly reduced to a level similar to that for the fully edited 5-HT 2C-VSV isoform. However, there was no difference in the thermal stability of the edited receptors, suggesting that mRNA editing does not alter the capacity of receptors to adopt active conformations. These results indicate that a conservative change in one amino acid (I156V) located in i2 of the 5-HT 2C receptor produces profound changes in receptor function that differ depending upon whether the receptor is unoccupied or occupied by agonist.The serotonin 2C (5-HT 2C ) receptor is a member of the 5-HT2 seven transmembrane-spanning (7-TMS) receptor family, also known as G protein-coupled receptors. The 5-HT 2C receptor is widely expressed in numerous brain regions and plays significant roles in many physiological functions and behaviors, such as sleep, affective state, feeding behavior, and temperature regulation. In addition, the 5-HT 2C receptor is a focus for the development of drugs to treat schizophrenia, depression, Parkinson's disease, and obesity and is also a likely target for hallucinogenic drugs of abuse (Di Giovanni et al., 2006).It is noteworthy that the 5-HT 2C receptor is the only 7-TMS receptor whose mRNA undergoes adenosine-inosine editing events that change the coding for amino acids located within the putative second intracellular domain (i2) of the receptor. In human brain, the nonedited receptor contains the amino acids isoleucine, asparagine, and isoleucine (INI) at positions 156, 158, and 160, respectively, whereas the principle fully edited isoforms express valine, serine, and valine (VSV) or valine, glycine, and valine (VGV). Partially edited receptor isoforms also exist where alteration of one or two amino acids within i2 occurs....

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Distinct functional profiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms

Cited by 50 publications

References 26 publications

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

A Conservative, Single-Amino Acid Substitution in the Second Cytoplasmic Domain of the Human Serotonin_2CReceptor Alters Both Ligand-Dependent and -Independent Receptor Signaling

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Distinct functional profiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms

Cited by 50 publications

References 26 publications

A Novel Aminotetralin-Type Serotonin (5-HT)2CReceptor-Specific Agonist and 5-HT2ACompetitive Antagonist/5-HT2BInverse Agonist with Preclinical Efficacy for Psychoses

A Novel Aminotetralin-Type Serotonin (5-HT)2CReceptor-Specific Agonist and 5-HT2ACompetitive Antagonist/5-HT2BInverse Agonist with Preclinical Efficacy for Psychoses

Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

A Conservative, Single-Amino Acid Substitution in the Second Cytoplasmic Domain of the Human Serotonin2CReceptor Alters Both Ligand-Dependent and -Independent Receptor Signaling

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Product

Resources

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A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

A Conservative, Single-Amino Acid Substitution in the Second Cytoplasmic Domain of the Human Serotonin_2CReceptor Alters Both Ligand-Dependent and -Independent Receptor Signaling