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Burström V, Xu K, Garro-Martínez E, Mach RH, Sahlholm K, Betari N. A nanoluciferase complementation-based assay for monitoring β-arrestin2 recruitment to the dopamine D 3 receptor. Biochem Biophys Rep 2025; 42:102019. [PMID: 40290808 PMCID: PMC12032866 DOI: 10.1016/j.bbrep.2025.102019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 04/09/2025] [Accepted: 04/11/2025] [Indexed: 04/30/2025] Open
Abstract
Luciferase complementation assays have emerged as a simple means of monitoring receptor-effector interactions in living cells in a time-resolved manner. Here, we describe a nanoluciferase complementation assay capable of reporting on β-arrestin2 recruitment to the human dopamine D3 receptor (D3R) upon its activation in intact HEK293T cells. Using this assay in time-resolved experiments, we detect differences in arrestin response termination rates between the endogenous agonist dopamine and the synthetic D3R agonist FAUC-73. We also investigate the influence of exogenous GRK2 on β-arrestin2 recruitment to the D3R. We find that, in contrast to the D2R and D4R, the potency of dopamine to induce arrestin recruitment to D3R is not significantly influenced by GRK2 overexpression. In further agreement with a lack of GRK2 regulation of D3R signalling and again contrary to the D2R and D4R, we do not observe dopamine-induced recruitment of GRK2 to D3R. Conversely, dopamine concentration-dependently decreases the interaction between GRK2 and D3R. Additionally, we examine both the Ser-9 and Gly-9 variants of the human D3R, which, according to some earlier reports, differ in terms of dopamine affinity and functional potency. However, we find no difference in the concentration-response relationships between these two variants, neither when arrestin recruitment nor GRK2 interactions are studied. In summary, the present report demonstrates the utility of nanoluciferase complementation for studying D3R pharmacology in living cells.
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Affiliation(s)
- Viktor Burström
- Department of Medical and Translational Biology, Wallenberg Centre for Molecular Medicine, Umeå University, 901 87, Umeå, Sweden
| | - Kuiying Xu
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104-6323, United States
| | - Emilio Garro-Martínez
- Department of Medical and Translational Biology, Wallenberg Centre for Molecular Medicine, Umeå University, 901 87, Umeå, Sweden
| | - Robert H. Mach
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104-6323, United States
| | - Kristoffer Sahlholm
- Department of Medical and Translational Biology, Wallenberg Centre for Molecular Medicine, Umeå University, 901 87, Umeå, Sweden
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Solna, Sweden
| | - Nibal Betari
- Department of Medical and Translational Biology, Wallenberg Centre for Molecular Medicine, Umeå University, 901 87, Umeå, Sweden
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Herborg F. Substance- and Cell-Specific Roles of Mesolimbic Dopamine D 3 Receptors. Biol Psychiatry 2024; 96:691-693. [PMID: 39357968 DOI: 10.1016/j.biopsych.2024.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 08/09/2024] [Indexed: 10/04/2024]
Affiliation(s)
- Freja Herborg
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Rusheen AE, Rojas-Cabrera J, Goyal A, Shin H, Yuen J, Jang DP, Bennet KE, Blaha CD, Lee KH, Oh Y. Deep brain stimulation alleviates tics in Tourette syndrome via striatal dopamine transmission. Brain 2023; 146:4174-4190. [PMID: 37141283 PMCID: PMC10545518 DOI: 10.1093/brain/awad142] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 03/24/2023] [Accepted: 04/14/2023] [Indexed: 05/05/2023] Open
Abstract
Tourette syndrome is a childhood-onset neuropsychiatric disorder characterized by intrusive motor and vocal tics that can lead to self-injury and deleterious mental health complications. While dysfunction in striatal dopamine neurotransmission has been proposed to underlie tic behaviour, evidence is scarce and inconclusive. Deep brain stimulation (DBS) of the thalamic centromedian parafascicular complex (CMPf), an approved surgical interventive treatment for medical refractory Tourette syndrome, may reduce tics by affecting striatal dopamine release. Here, we use electrophysiology, electrochemistry, optogenetics, pharmacological treatments and behavioural measurements to mechanistically examine how thalamic DBS modulates synaptic and tonic dopamine activity in the dorsomedial striatum. Previous studies demonstrated focal disruption of GABAergic transmission in the dorsolateral striatum of rats led to repetitive motor tics recapitulating the major symptom of Tourette syndrome. We employed this model under light anaesthesia and found CMPf DBS evoked synaptic dopamine release and elevated tonic dopamine levels via striatal cholinergic interneurons while concomitantly reducing motor tic behaviour. The improvement in tic behaviour was found to be mediated by D2 receptor activation as blocking this receptor prevented the therapeutic response. Our results demonstrate that release of striatal dopamine mediates the therapeutic effects of CMPf DBS and points to striatal dopamine dysfunction as a driver for motor tics in the pathoneurophysiology of Tourette syndrome.
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Affiliation(s)
- Aaron E Rusheen
- Medical Scientist Training Program, Mayo Clinic, Rochester, MN 55902, USA
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55902, USA
| | - Juan Rojas-Cabrera
- Medical Scientist Training Program, Mayo Clinic, Rochester, MN 55902, USA
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55902, USA
| | - Abhinav Goyal
- Medical Scientist Training Program, Mayo Clinic, Rochester, MN 55902, USA
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55902, USA
| | - Hojin Shin
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55902, USA
- Department of Biomedical Engineering, Mayo Clinic, Rochester, MN 55902, USA
| | - Jason Yuen
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55902, USA
- IMPACT—the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Barwon Health, Geelong, VIC 3216, Australia
| | - Dong-Pyo Jang
- Department of Biomedical Engineering, Hanyang University, Seoul 04763, South Korea
| | - Keven E Bennet
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55902, USA
- Division of Engineering, Mayo Clinic, Rochester, MN 55902, USA
| | - Charles D Blaha
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55902, USA
| | - Kendall H Lee
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55902, USA
- Department of Biomedical Engineering, Mayo Clinic, Rochester, MN 55902, USA
| | - Yoonbae Oh
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55902, USA
- Department of Biomedical Engineering, Mayo Clinic, Rochester, MN 55902, USA
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Taylor D, Chithiramohan R, Grewal J, Gupta A, Hansen L, Reynolds GP, Pappa S. Dopamine partial agonists: a discrete class of antipsychotics. Int J Psychiatry Clin Pract 2023; 27:272-284. [PMID: 36495086 DOI: 10.1080/13651501.2022.2151473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 11/04/2022] [Accepted: 11/08/2022] [Indexed: 12/14/2022]
Abstract
Worldwide, there are now three marketed dopamine D2 partial agonists: aripiprazole, brexpiprazole and cariprazine. These three drugs share a number of properties other than their action at D2 receptors. Pharmacologically, they are 5HT2 antagonists and D3 and 5HT1A partial agonists but with little or no alpha-adrenergic, anticholinergic or antihistaminic activity. They also share a long duration of action. Clinically, D2 partial agonists are effective antipsychotics and generally have useful antimanic and antidepressant activity. They are usually well tolerated, causing akathisia and insomnia only at the start of treatment, and are non-sedating. These drugs also share a very low risk of increased prolactin and of weight gain and accompanying metabolic effects. They may also have a relatively low risk of tardive dyskinesia. There is some evidence that they are preferred by patients to dopamine antagonists. Individual dopamineD2 partial agonists have much in common and as a group they differ importantly from dopamine D2 antagonists. Dopamine D2 partial agonists should be considered a distinct class of antipsychotics.Key pointsD2 partial agonists share many pharmacological and clinical propertiesD2 partial agonists differ in several important respects from D2 antagonistsD2 partial agonists should be considered a discrete class of antipsychotics.
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Affiliation(s)
- David Taylor
- Institute of Pharmaceutical Science, King's College London, London, UK
- Pharmacy Department, South London and Maudsley NHS Foundation Trust, London, UK
| | | | | | - Avirup Gupta
- South London and Maudsley NHS Foundation Trust, London, UK
| | - Lars Hansen
- Southampton University, Hartley Library B12, Southampton, UK
- Southern Health NHS Foundation Trust, Southampton, UK
| | - Gavin P Reynolds
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, UK
| | - Sofia Pappa
- Department of Brain Sciences, Imperial College London, London, UK
- West London NHS Trust, London, UK
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Bo Q, Wang X, Liu X, Sang H, Xun Z, Zhang R, Yang X, Deng H, Li K, Chen J, Sun M, Zhao G, Liu X, Cai D, Zhan G, Li J, Li H, Wang G. Effectiveness and safety of blonanserin in young and middle-aged female patients with schizophrenia: data from a post-marketing surveillance. BMC Psychiatry 2023; 23:115. [PMID: 36810039 PMCID: PMC9945355 DOI: 10.1186/s12888-023-04598-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 02/07/2023] [Indexed: 02/23/2023] Open
Abstract
BACKGROUND A post-marketing surveillance of blonanserin has been ongoing since September 2018. The aim of this study was to assess the effectiveness and safety of oral blonanserin in Chinese young and middle-aged female patients with schizophrenia in real clinical settings, using the data from the post-marketing surveillance. METHODS A 12-week, prospective, multi-center, open-label, post-marketing surveillance was conducted. Female patients aged 18-40 years were included in this analysis. The Brief Psychiatric Rating Scale (BPRS) was used to evaluate the effectiveness of blonanserin in improving psychiatric symptoms. The incidence of adverse drug reactions (ADRs) such as of extrapyramidal symptoms (EPS), prolactin elevation and the weight gain were used to evaluate the safety profile of blonanserin. RESULTS A total of 392 patients were included both in the safety and full analysis sets, 311 patients completed the surveillance protocol. The BPRS total score was 48.8 ± 14.11 at the baseline, decreasing to 25.5 ± 7.56 at 12 weeks (P < 0.001, compared with baseline). EPS (20.2%) including akathisia, tremor, dystonia, and parkinsonism were found as the most frequent ADRs. The mean weight gain was 0.27 ± 2.5 kg at 12 weeks from the baseline. Four cases (1%) of prolactin elevation were observed during the period of surveillance. CONCLUSION Blonanserin significantly improved the symptoms of schizophrenia in female patients aged 18-40 years; the drug was well tolerated and had a low tendency to cause metabolic side effects, including prolactin elevation in these patients. Blonanserin might be a reasonable drug for the treatment of schizophrenia in young and middle-aged female patients.
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Affiliation(s)
- Qijing Bo
- grid.24696.3f0000 0004 0369 153XThe National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, 100088 China
| | - Xijin Wang
- Department of Psychiatry, The First Psychiatric Hospital of Harbin, Harbin, Heilongjiang 150010 China
| | - Xuejun Liu
- Department of Psychiatry, Brain Hospital of Hunan Province, Changsha, Hunan 410007 China
| | - Hong Sang
- Mental Health Center, Changchun Sixth Hospital, Changchun, Jilin 130052 China
| | - Zhiyuan Xun
- grid.440287.d0000 0004 1764 5550Department of Psychiatry, Tianjin Anding Hospital, Tianjin, Tianjin, 300222 China
| | - Ruiling Zhang
- Department of Psychiatry, Henan Mental Hospital, Xinxiang, Henan 453002 China
| | - Xiaodong Yang
- grid.452754.5Department of Psychiatry, Shandong Mental Health Center, Jinan, Shandong 250014 China
| | - Huaili Deng
- Department of Psychology, Psychiatric Hospital of Taiyuan City, Taiyuan, Shanxi, 030000 China
| | - Keqing Li
- Department of Psychiatry, Hebei Provincial Mental Health Center, Baoding, Hebei 071000 China
| | - Jindong Chen
- grid.452708.c0000 0004 1803 0208Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011 China
| | - Meijuan Sun
- Department of Pharmacy, Daqing Third Hospital, Daqing, Heilongjiang 163712 China
| | - Guijun Zhao
- Department of Psychiatry, Guangyuan Mental Health Center, Guangyuan, Sichuan 628001 China
| | - Xianglai Liu
- Institute of Mental Health, Hainan Provincial Anning Hospital, Haikou, Hainan, 570206 China
| | - Duanfang Cai
- Department of Psychiatry, The Fifth People’s Hospital of Zigong, Zigong, Sichuan 643020 China
| | - Guilai Zhan
- Department of Psychiatry, Xuhui Mental Health center, Shanghai, 200232 China
| | - Juhong Li
- grid.517561.1Department of Psychiatry, The Fourth People’s Hospital of Chengdu, Chengdu, Sichuan 610036 China
| | - Haiyun Li
- Medical Affairs, Sumitomo Pharma (Suzhou) Co., Ltd, Shanghai, 200025 China
| | - Gang Wang
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100088, China. .,The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China.
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Identification of Novel Dopamine D2 Receptor Ligands—A Combined In Silico/In Vitro Approach. Molecules 2022; 27:molecules27144435. [PMID: 35889317 PMCID: PMC9318694 DOI: 10.3390/molecules27144435] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 02/04/2023] Open
Abstract
Diseases of the central nervous system are an alarming global problem showing an increasing prevalence. Dopamine receptor D2 (D2R) has been shown to be involved in central nervous system diseases. While different D2R-targeting drugs have been approved by the FDA, they all suffer from major drawbacks due to promiscuous receptor activity leading to adverse effects. Increasing the number of potential D2R-targeting drug candidates bears the possibility of discovering molecules with less severe side-effect profiles. In dire need of novel D2R ligands for drug development, combined in silico/in vitro approaches have been shown to be efficient strategies. In this study, in silico pharmacophore models were generated utilizing both ligand- and structure-based approaches. Subsequently, different databases were screened for novel D2R ligands. Selected virtual hits were investigated in vitro, quantifying their binding affinity towards D2R. This workflow successfully identified six novel D2R ligands exerting micro- to nanomolar (most active compound KI = 4.1 nM) activities. Thus, the four pharmacophore models showed prospective true-positive hit rates in between 4.5% and 12%. The developed workflow and identified ligands could aid in developing novel drug candidates for D2R-associated pathologies.
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Liu X, Fan T, Guan J, Luo A, Yu Y, Chen D, Mao B, Jiang H, Liu W. Dopamine relieves inflammatory responses through the D2 receptor after electroacupuncture at ST36 in a mouse model of chronic obstructive pulmonary disease. Acupunct Med 2022:9645284221107684. [PMID: 35775581 DOI: 10.1177/09645284221107684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To detect the role of dopamine in the anti-inflammatory effect of electroacupuncture (EA) at ST36 in a mouse model of chronic obstructive pulmonary disease (COPD). METHODS Twenty-eight male BALB/c mice were randomly divided into the control group, model group, sham EA (sham) group or ST36 EA (ST36) group in a 1:1:1:1 ratio (n = 7 each). The COPD mouse model was established through cigarette smoke (CS) exposure for 12 weeks. During the last 2 weeks, EA was applied at a sham point location or ST36 before CS exposure. Lung function, histopathological changes, inflammatory cell counts in bronchoalveolar lavage fluid (BALF), inflammatory cytokines in BALF, plasma, lung tissue homogenate (LTH), and plasma dopamine levels were detected in the different groups. Furthermore, the role of different dopamine receptors was explored through intraperitoneal injections of non-specific dopamine receptor antagonist chlorpromazine, specific dopamine D1 receptor antagonist SCH 23390 and specific dopamine D2 receptor antagonist eticlopride hydrochloride prior to ST36 EA and CS exposure. RESULTS EA at ST36 improved lung function, alleviated lung and systemic inflammatory responses by reducing inflammatory cells and cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-8 and IL-1β in BALF, plasma and lung tissue in this COPD mouse model. Plasma dopamine was greatly increased after EA at ST36, negatively correlated with lung histological lesions and inflammatory cytokine levels, and positively correlated with mice body weight and lung function indicators. Chlorpromazine and eticlopride hydrochloride inhibited the anti-inflammatory effect of EA at ST36, while SCH 23390 showed no neutralizing effect. CONCLUSION EA at ST36 could alleviate inflammation in this mouse model of COPD through the dopamine D2 receptor pathway.
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Affiliation(s)
- Xuemei Liu
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China.,Department of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital of Sichuan University, Chengdu, China
| | - Tao Fan
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Jinshuai Guan
- Department of Medicine-Neurology, Meishan Cardiovascular and Cerebrovascular Disease Hospital, Meishan, China
| | - Ai Luo
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Yu
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Daohong Chen
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Bing Mao
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Hongli Jiang
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Liu
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
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Konishi N, Kumagai H, Sawatari H, Hoshino T, Murase Y, Yamaguchi M, Urabe A, Kiyohara Y, Arita A, Baku M, Sasanabe R, Shiomi T. Efficacy of a Combination Therapy for Difficulties Waking Up in Non-School-Attending Students. J Clin Med 2022; 11:jcm11123271. [PMID: 35743342 PMCID: PMC9225467 DOI: 10.3390/jcm11123271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/31/2022] [Accepted: 06/06/2022] [Indexed: 11/29/2022] Open
Abstract
School non-attendance due to difficulties waking up is increasing in Japan, and affected students are commonly diagnosed with orthostatic dysregulation (OD); however, OD-associated sleep problems are overlooked. To date, no sleep-medicine-based treatment for wake-up difficulties in non-school-attending students has been established. This study aimed to assess the efficacy of a novel combination therapy for these students. We assessed the combined effect of sleep hygiene guidance, low-dose aripiprazole administration (3 mg/day), and blue-light exposure on wake-up difficulty in 21 non-school-attending teenage patients. The patients were evaluated using sleep studies and questionnaires before and after treatment. The average subjective total sleep time calculated from sleep diaries before treatment in the patients was 10.3 h. The therapy improved wake-up difficulty by 85.7% and further improved school non-attendance by 66.7%. The subjective sleep time significantly decreased by 9.5 h after treatment (p = 0.0004). The self-rating Depression Scale and mental component summary of the 36-item Short-Form Health Survey significantly improved after treatment (p = 0.002 and p = 0.01, respectively). Wake-up difficulties were caused by the addition of a delayed sleep phase to the patients’ long sleep times. The novel combination therapy was effective in improving wake-up difficulty and mental quality of life in non-school-attending teenage students.
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Affiliation(s)
- Noriyuki Konishi
- Department of Sleep Medicine and Sleep Disorders Center, Aichi Medical University Hospital, Nagakute 4801195, Japan; (N.K.); (H.S.); (T.H.); (Y.M.); (M.Y.); (A.U.); (Y.K.); (A.A.); (M.B.); (R.S.); (T.S.)
- Department of Sleep Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348553, Japan
| | - Hajime Kumagai
- Department of Sleep Medicine and Sleep Disorders Center, Aichi Medical University Hospital, Nagakute 4801195, Japan; (N.K.); (H.S.); (T.H.); (Y.M.); (M.Y.); (A.U.); (Y.K.); (A.A.); (M.B.); (R.S.); (T.S.)
- Department of Sleep Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348553, Japan
- Correspondence: ; Tel.: +81-82-257-1922
| | - Hiroyuki Sawatari
- Department of Sleep Medicine and Sleep Disorders Center, Aichi Medical University Hospital, Nagakute 4801195, Japan; (N.K.); (H.S.); (T.H.); (Y.M.); (M.Y.); (A.U.); (Y.K.); (A.A.); (M.B.); (R.S.); (T.S.)
- Department of Perioperative and Critical Care Management, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348553, Japan
| | - Tetsuro Hoshino
- Department of Sleep Medicine and Sleep Disorders Center, Aichi Medical University Hospital, Nagakute 4801195, Japan; (N.K.); (H.S.); (T.H.); (Y.M.); (M.Y.); (A.U.); (Y.K.); (A.A.); (M.B.); (R.S.); (T.S.)
- Department of Sleep Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348553, Japan
| | - Yoko Murase
- Department of Sleep Medicine and Sleep Disorders Center, Aichi Medical University Hospital, Nagakute 4801195, Japan; (N.K.); (H.S.); (T.H.); (Y.M.); (M.Y.); (A.U.); (Y.K.); (A.A.); (M.B.); (R.S.); (T.S.)
- Department of Sleep Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348553, Japan
| | - Maiko Yamaguchi
- Department of Sleep Medicine and Sleep Disorders Center, Aichi Medical University Hospital, Nagakute 4801195, Japan; (N.K.); (H.S.); (T.H.); (Y.M.); (M.Y.); (A.U.); (Y.K.); (A.A.); (M.B.); (R.S.); (T.S.)
| | - Ayako Urabe
- Department of Sleep Medicine and Sleep Disorders Center, Aichi Medical University Hospital, Nagakute 4801195, Japan; (N.K.); (H.S.); (T.H.); (Y.M.); (M.Y.); (A.U.); (Y.K.); (A.A.); (M.B.); (R.S.); (T.S.)
| | - Yuka Kiyohara
- Department of Sleep Medicine and Sleep Disorders Center, Aichi Medical University Hospital, Nagakute 4801195, Japan; (N.K.); (H.S.); (T.H.); (Y.M.); (M.Y.); (A.U.); (Y.K.); (A.A.); (M.B.); (R.S.); (T.S.)
- Department of Sleep Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348553, Japan
| | - Aki Arita
- Department of Sleep Medicine and Sleep Disorders Center, Aichi Medical University Hospital, Nagakute 4801195, Japan; (N.K.); (H.S.); (T.H.); (Y.M.); (M.Y.); (A.U.); (Y.K.); (A.A.); (M.B.); (R.S.); (T.S.)
- Department of Sleep Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348553, Japan
| | - Masayo Baku
- Department of Sleep Medicine and Sleep Disorders Center, Aichi Medical University Hospital, Nagakute 4801195, Japan; (N.K.); (H.S.); (T.H.); (Y.M.); (M.Y.); (A.U.); (Y.K.); (A.A.); (M.B.); (R.S.); (T.S.)
| | - Ryujiro Sasanabe
- Department of Sleep Medicine and Sleep Disorders Center, Aichi Medical University Hospital, Nagakute 4801195, Japan; (N.K.); (H.S.); (T.H.); (Y.M.); (M.Y.); (A.U.); (Y.K.); (A.A.); (M.B.); (R.S.); (T.S.)
| | - Toshiaki Shiomi
- Department of Sleep Medicine and Sleep Disorders Center, Aichi Medical University Hospital, Nagakute 4801195, Japan; (N.K.); (H.S.); (T.H.); (Y.M.); (M.Y.); (A.U.); (Y.K.); (A.A.); (M.B.); (R.S.); (T.S.)
- Department of Sleep Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348553, Japan
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Chagraoui A, Di Giovanni G, De Deurwaerdère P. Neurobiological and Pharmacological Perspectives of D3 Receptors in Parkinson’s Disease. Biomolecules 2022; 12:biom12020243. [PMID: 35204744 PMCID: PMC8961531 DOI: 10.3390/biom12020243] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/19/2022] [Accepted: 01/26/2022] [Indexed: 12/02/2022] Open
Abstract
The discovery of the D3 receptor (D3R) subtypes of dopamine (DA) has generated an understandable increase in interest in the field of neurological diseases, especially Parkinson’s disease (PD). Indeed, although DA replacement therapy with l-DOPA has provided an effective treatment for patients with PD, it is responsible for invalidating abnormal involuntary movements, known as L-DOPA-induced dyskinesia, which constitutes a serious limitation of the use of this therapy. Of particular interest is the finding that chronic l-DOPA treatment can trigger the expression of D1R–D3R heteromeric interactions in the dorsal striatum. The D3R is expressed in various tissues of the central nervous system, including the striatum. Compelling research has focused on striatal D3Rs in the context of PD and motor side effects, including dyskinesia, occurring with DA replacement therapy. Therefore, this review will briefly describe the basal ganglia (BG) and the DA transmission within these brain regions, before going into more detail with regard to the role of D3Rs in PD and their participation in the current treatments. Numerous studies have also highlighted specific interactions between D1Rs and D3Rs that could promote dyskinesia. Finally, this review will also address the possibility that D3Rs located outside of the BG may mediate some of the effects of DA replacement therapy.
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Affiliation(s)
- Abdeslam Chagraoui
- Différenciation et Communication Neuroendocrine, Endocrine et Germinale Laboratory, Institute for Research and Innovation in Biomedicine of Normandy (IRIB), University of Rouen, INSERM 1239, 76000 Rouen, France
- Department of Medical Biochemistry, Rouen University Hospital, 76000 Rouen, France
- Correspondence: ; Tel.: +33-2-35-14-83-69
| | - Giuseppe Di Giovanni
- Laboratory of Neurophysiology, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, 2080 Msida, Malta;
- Neuroscience Division, School of Biosciences, Cardiff University, Cardiff CF10 3AT, UK
| | - Philippe De Deurwaerdère
- Unité Mixte de Recherche (UMR) 5287, Centre National de la Recherche Scientifique (CNRS), CEDEX, 33000 Bordeaux, France;
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Román V, Adham N, Foley AG, Hanratty L, Farkas B, Lendvai B, Kiss B. Cariprazine alleviates core behavioral deficits in the prenatal valproic acid exposure model of autism spectrum disorder. Psychopharmacology (Berl) 2021; 238:2381-2392. [PMID: 34264367 DOI: 10.1007/s00213-021-05851-6/figures/5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 04/12/2021] [Indexed: 05/20/2023]
Abstract
RATIONALE Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction and restricted, repetitive behaviors. The unmet medical need in ASD is considerable since there is no approved pharmacotherapy for the treatment of these deficits in social communication, interaction, and behavior. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, is already approved for the treatment of schizophrenia and bipolar I disorder in adults; investigation in patients with ASD is warranted. OBJECTIVES The aim of this study was to investigate the effects of cariprazine, compared with risperidone and aripiprazole, in the rat prenatal valporic acid (VPA) exposure model on behavioral endpoints representing the core and associated symptoms of ASD. METHODS To induce the ASD model, time-mated Wistar rat dams were treated with VPA during pregnancy. Male offspring were assigned to groups and studied in a behavioral test battery at different ages, employing social play, open field, social approach-avoidance, and social recognition memory tests. Animals were dosed orally, once a day for 8 days, with test compounds (cariprazine, risperidone, aripiprazole) or vehicle before behavioral assessment. RESULTS Cariprazine showed dose-dependent efficacy on all behavioral endpoints. In the social play paradigm, only cariprazine was effective. On the remaining behavioral endpoints, including the reversal of hyperactivity, risperidone and aripiprazole displayed similar efficacy to cariprazine. CONCLUSIONS In the present study, cariprazine effectively reversed core behavioral deficits and hyperactivity present in juvenile and young adult autistic-like rats. These findings indicate that cariprazine may be useful in the treatment of ASD symptoms.
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Affiliation(s)
| | | | - Andrew G Foley
- Berand Neuropharmacology Limited, NovaUCD, Belfield Innovation Park, University College Dublin, Dublin, Ireland
| | - Lynsey Hanratty
- Berand Neuropharmacology Limited, NovaUCD, Belfield Innovation Park, University College Dublin, Dublin, Ireland
| | | | | | - Béla Kiss
- Gedeon Richter Plc, Budapest, Hungary
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11
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Shiina A, Hasegawa T, Iyo M. Possible effect of blonanserin on gambling disorder: A clinical study protocol and a case report. World J Clin Cases 2021; 9:2469-2477. [PMID: 33889612 PMCID: PMC8040182 DOI: 10.12998/wjcc.v9.i11.2469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/08/2021] [Accepted: 02/01/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gambling disorder is characterized by excessive and recurrent gambling and can have serious negative social consequences. Although several psychotherapeutic and pharmacological approaches have been used to treat gambling disorder, new treatment strategies are needed. Growing evidence suggests that dopamine D3 receptor plays a specific role in the brain reward system. AIM To investigate if blonanserin, a dopamine D3 receptor antagonist, would be effective in reducing gambling impulses in patients with gambling disorder. METHODS We developed a study protocol to measure the efficacy and safety of blonanserin as a potential drug for gambling disorder, in which up to 12 mg/d of blonanserin was prescribed for 8 wk. RESULTS A 37-year-old female patient with gambling disorder, intellectual disability, and other physical diseases participated in the pilot study. The case showed improvement of gambling symptoms without any psychotherapy. However, blonanserin was discontinued owing to excessive saliva production. CONCLUSION This case suggests that blonanserin is potentially an effective treatment for patients with gambling disorder who resist standard therapies, but it also carries a risk of adverse effects. Further studies are needed to confirm the findings.
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Affiliation(s)
- Akihiro Shiina
- Division of Medical Treatment and Rehabilitation, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan
| | - Tadashi Hasegawa
- Department of Psychiatry, Chiba University Hospital, Chiba 260-8670, Japan
| | - Masaomi Iyo
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
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12
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Antidepressant Augmentation: A Review of the Literature and a Review of the Pharmacoeconomic Considerations. J Clin Psychopharmacol 2021; 40:396-400. [PMID: 32639292 DOI: 10.1097/jcp.0000000000001236] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE Antidepressant augmentation strategies for treatment-resistant depression (TRD) are discussed here with an analysis of patient out-of-pocket costs for various medications. The choice of agent ranges from newer atypical antipsychotics (aripiprazole, brexpiprazole, quetiapine) to older agents including buspirone, liothyronine (T3), and lithium. We sought to better understand the differences among these agents to aid in clinical decision making. METHODS We conducted a focused review of the support for each of the aforementioned agents in antidepressant augmentation. We then compared the approximate out-of-pocket cost for each medication during a typical augmentation trial using the typical prescription costs on ClinCalc.com derived from the Medical Expenditure Panel Survey. We calculated the cost to achieve response for one patient with TRD based on the number needed to treat (NNT). FINDINGS We observed significant variance in cost to achieve response based on the NNT derived from our review of each of the medications. For example, the overall out-of-pocket cost for one patient to achieve response with aripiprazole (the costliest generic agent) could cover lithium prescriptions for 4 to 5 patients with TRD to achieve response. Although brexpiprazole was estimated separately because of its brand name cost, we estimated that 324 patients receiving lithium could achieve response for same cost of single patient receiving brexpiprazole. IMPLICATIONS These findings suggest that among augmentation agents, there are differences in cost that may be highly important in clinical decision making. Other issues of medication monitoring may incur additional costs, and brand name medications offer significantly greater complexity and potential out-of-pocket costs to patients. The use of lithium as a first-line agent for TRD should be considered based on low cost, lowest NNT, and data in support of its efficacy.
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13
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Román V, Adham N, Foley AG, Hanratty L, Farkas B, Lendvai B, Kiss B. Cariprazine alleviates core behavioral deficits in the prenatal valproic acid exposure model of autism spectrum disorder. Psychopharmacology (Berl) 2021; 238:2381-2392. [PMID: 34264367 PMCID: PMC8373751 DOI: 10.1007/s00213-021-05851-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 04/12/2021] [Indexed: 12/14/2022]
Abstract
RATIONALE Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction and restricted, repetitive behaviors. The unmet medical need in ASD is considerable since there is no approved pharmacotherapy for the treatment of these deficits in social communication, interaction, and behavior. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, is already approved for the treatment of schizophrenia and bipolar I disorder in adults; investigation in patients with ASD is warranted. OBJECTIVES The aim of this study was to investigate the effects of cariprazine, compared with risperidone and aripiprazole, in the rat prenatal valporic acid (VPA) exposure model on behavioral endpoints representing the core and associated symptoms of ASD. METHODS To induce the ASD model, time-mated Wistar rat dams were treated with VPA during pregnancy. Male offspring were assigned to groups and studied in a behavioral test battery at different ages, employing social play, open field, social approach-avoidance, and social recognition memory tests. Animals were dosed orally, once a day for 8 days, with test compounds (cariprazine, risperidone, aripiprazole) or vehicle before behavioral assessment. RESULTS Cariprazine showed dose-dependent efficacy on all behavioral endpoints. In the social play paradigm, only cariprazine was effective. On the remaining behavioral endpoints, including the reversal of hyperactivity, risperidone and aripiprazole displayed similar efficacy to cariprazine. CONCLUSIONS In the present study, cariprazine effectively reversed core behavioral deficits and hyperactivity present in juvenile and young adult autistic-like rats. These findings indicate that cariprazine may be useful in the treatment of ASD symptoms.
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Affiliation(s)
| | - Nika Adham
- grid.431072.30000 0004 0572 4227AbbVie, Madison, NJ USA
| | - Andrew G. Foley
- grid.7886.10000 0001 0768 2743Berand Neuropharmacology Limited, NovaUCD, Belfield Innovation Park, University College Dublin, Dublin, Ireland
| | - Lynsey Hanratty
- grid.7886.10000 0001 0768 2743Berand Neuropharmacology Limited, NovaUCD, Belfield Innovation Park, University College Dublin, Dublin, Ireland
| | - Bence Farkas
- grid.418137.80000 0004 0621 5862Gedeon Richter Plc, Budapest, Hungary
| | - Balázs Lendvai
- grid.418137.80000 0004 0621 5862Gedeon Richter Plc, Budapest, Hungary
| | - Béla Kiss
- grid.418137.80000 0004 0621 5862Gedeon Richter Plc, Budapest, Hungary
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14
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Dopamine, Cognitive Impairments and Second-Generation Antipsychotics: From Mechanistic Advances to More Personalized Treatments. Pharmaceuticals (Basel) 2020; 13:ph13110365. [PMID: 33167370 PMCID: PMC7694365 DOI: 10.3390/ph13110365] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 10/31/2020] [Accepted: 11/03/2020] [Indexed: 12/17/2022] Open
Abstract
The pharmacological treatment of cognitive impairments associated with schizophrenia is still a major unmet clinical need. Indeed, treatments with available antipsychotics generate highly variable cognitive responses among patients with schizophrenia. This has led to the general assumption that antipsychotics are ineffective on cognitive impairment, although personalized medicine and drug repurposing approaches might scale down this clinical issue. In this scenario, evidence suggests that cognitive improvement exerted by old and new atypical antipsychotics depends on dopaminergic mechanisms. Moreover, the newer antipsychotics brexpiprazole and cariprazine, which might have superior clinical efficacy on cognitive deficits over older antipsychotics, mainly target dopamine receptors. It is thus reasonable to assume that despite more than 50 years of elusive efforts to develop novel non-dopaminergic antipsychotics, dopamine receptors remain the most attractive and promising pharmacological targets in this field. In the present review, we discuss preclinical and clinical findings showing dopaminergic mechanisms as key players in the cognitive improvement induced by both atypical antipsychotics and potential antipsychotics. We also emphasize the concept that these mechanistic advances, which help to understand the heterogeneity of cognitive responses to antipsychotics, may properly guide treatment decisions and address the unmet medical need for the management of cognitive impairment associated with schizophrenia.
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15
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Li K, Zhang Y, Tian E, Liu Z, Wang T, Fu F. The Effect of Rotigotine Extended-Release Microspheres Alone or With Celecoxib on the Inflammatory Pain. Front Pharmacol 2020; 11:594387. [PMID: 33192533 PMCID: PMC7663167 DOI: 10.3389/fphar.2020.594387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 09/24/2020] [Indexed: 12/14/2022] Open
Abstract
Clinical trials of rotigotine extended-release microspheres (RTGT-MS), which provides a sustained release of rotigotine for near 2 weeks in vivo, have been conducted in the treatment of Parkinson’s disease (PD). This study was to investigate the analgesic effect of RTGT-MS, and to know whether RTGT-MS have synergistic interaction with non-steroidal anti-inflammatory drug, celecoxib. The inflammatory pain model of rats was prepared by carrageenan-induced paw edema. The thermal and mechanical stimuli were applied and the hindpaw withdrawal latency (HWL) response was evaluated. Treatment with RTGT-MS increased the HWL in a dose-dependent manner. The ED50 of RTGT-MS was 24.68 ± 1.02 mg/kg. Isobolographic analysis shows that the combination of RTGT-MS and celecoxib resulted in a synergistic antinociceptive effect. Further results demonstrated that antinociceptive effect of RTGT-MS was accompanied with that PKA, cAMP, COX-2, and PGE2 levels were decreased. Chlorpromazine, a dopamine receptor blocker, not only weakened the analgesic effect of RTGT-MS, but also increased the levels of cAMP, PKA, COX-2, and PGE2. These findings provide a rationale for the combination of RTGT-MS and celecoxib in the treatment of PD, which may reduce the dose of celecoxib, thereby lowering the incidence of adverse effects and improving the pain management in PD patients.
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Affiliation(s)
- Keke Li
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China.,School of Pharmacy, Binzhou Medical University, Yantai, China
| | - Yijia Zhang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Enming Tian
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Zikai Liu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Tian Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Fenghua Fu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
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16
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Dopamine transporter is downregulated and its association with chaperone protein Hsc70 is enhanced by activation of dopamine D 3 receptor. Brain Res Bull 2020; 165:263-271. [PMID: 33049353 DOI: 10.1016/j.brainresbull.2020.10.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 10/01/2020] [Accepted: 10/05/2020] [Indexed: 01/11/2023]
Abstract
Synaptic dopamine (DA) concentrations are largely determined by the activities of presynaptic D2 and D3 autoreceptors (D2R and D3R) and DA transporter (DAT). Furthermore, the activity of DAT is regulated by phosphorylation events and protein interactions that affect its surface expression. Because DA autoreceptors and DAT coordinately maintain synaptic DA homeostasis, we hypothesized that D3R might crosstalk with DAT to fine-tune synaptic DA concentrations. To test this hypothesis, we established [3H]DA uptake and DAT surface expression assays in hD3/rDAT-double-transfected HEK-293 cells or limbic forebrain synaptosomal preparations. Ropinirole, a preferential D3R agonist, reduced [3H]DA uptake in HEK-hD3/rDAT cells in a dose-dependent manner, an effect which could be blocked by the D2R/D3R antagonist, raclopride. Furthermore, ropinirole also reduced DAT surface expression in limbic forebrain synaptosomes, and this effect could be blocked by raclopride or the internalization inhibitor, concanavalin A. To identify potential mediators of this apparent D3R-DAT crosstalk, DAT-associated proteins were co-immunoprecipitated from limbic forebrain synaptosomes after D3R activation and identified by MALDI-TOF. From this analysis, the Hsc70 chaperone was identified as a DAT-associated protein. Interestingly, ropinirole induced the association of Hsc70/Hsp70 with DAT, and the Hsc70/Hsp70 inhibitor, apoptozole, prevented the ropinirole-induced reduction of DAT surface expression. Together, these results suggest that D3R negatively regulates DAT activity by promoting the association of DAT and Hsc70/Hsp70.
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17
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Rendle DI, Doran G, Ireland J, Edwards S. Pharmacokinetics and pharmacodynamics of pergolide mesylate after oral administration in horses with pituitary pars intermedia dysfunction. Domest Anim Endocrinol 2019; 68:135-141. [PMID: 31082785 DOI: 10.1016/j.domaniend.2019.01.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 01/23/2019] [Accepted: 01/25/2019] [Indexed: 01/11/2023]
Abstract
Published information on the pharmacokinetic and pharmacodynamic properties of pergolide is limited. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of oral pergolide in horses with pituitary pars intermedia dysfunction (PPID). The study design was a nonrandomized clinical trial. Six horses with PPID diagnosed by thyrotropin-releasing hormone (TRH) stimulation tests received pergolide at 4 μg/kg for 18 d. Plasma samples for determination of pergolide and ACTH concentration were collected 0.5 h before and 2 and 12 h after each administration of pergolide. Maximum plasma concentrations after the first oral dose of pergolide (0.104-0.684 ng/mL; median 0.261 ng/mL; interquartile range [IQR] 0.184-0.416 ng/mL) were not significantly different to the maximum steady-state concentration at day 18 (0.197-0.628 ng/mL; median 0.274; IQR 0.232-0.458 ng/mL). Chronic administration was not associated with drug accumulation (R = 1.09) and pergolide concentration reached steady state within 3 d. Throughout, concentrations of pergolide fluctuated considerably, with median plasma peak concentrations more than four times higher than median trough concentrations. Plasma ACTH concentration reduced significantly within 12 h of administration with further reductions occurring up to 10 d after the initiation of treatment. Although there were parallel fluctuations in the concentrations of pergolide and ACTH, timing of ACTH measurement in relation to the administration of pergolide did not have a significant effect. Alterations in the response to TRH were identified at 8 d with no further change being identified at 18 d. A small number of horses were studied. Oral pergolide results in significant suppression of pars intermedia activity within hours. Pergolide and ACTH concentrations fluctuated in tandem although correlation was poor. Fluctuations in pergolide concentration were consistent with a terminal elimination half-life of less than 12 h. To reduce the level of fluctuation of ACTH, twice-daily dosing of pergolide may be more appropriate.
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Affiliation(s)
- D I Rendle
- School of Animal and Veterinary Sciences, EH Graham Centre for Agricultural Innovation, Charles Sturt University, Wagga Wagga, New South Wales 2650, Australia.
| | - G Doran
- School of Agricultural and Wine Sciences, EH Graham Centre for Agricultural Innovation, Charles Sturt University, Wagga Wagga, New South Wales 2650, Australia
| | - J Ireland
- Institute of Veterinary Science, University of Liverpool, Chester High Road, Neston CH64 7TE, UK
| | - S Edwards
- School of Animal and Veterinary Sciences, EH Graham Centre for Agricultural Innovation, Charles Sturt University, Wagga Wagga, New South Wales 2650, Australia
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18
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Lv H, Yu F, Sha C, Huang Y, Lu Y, Zhang L, Zhai R, Wang T, Fu F. Effects of rotigotine and rotigotine extended-release microsphere therapy on myocardial ischemic injury in mice. Eur J Pharm Sci 2019; 134:1-6. [DOI: 10.1016/j.ejps.2019.04.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 03/25/2019] [Accepted: 04/04/2019] [Indexed: 01/09/2023]
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19
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Horikoshi S, Miura I, Ichinose M, Yamamoto S, Ito M, Watanabe K, Kanno-Nozaki K, Kaneko H, Yabe H. Low- and high-dose aripiprazole augmentation and plasma levels of homovanillic acid in major depressive disorder: A randomized, open-label study. Hum Psychopharmacol 2019; 34:e2696. [PMID: 31044463 DOI: 10.1002/hup.2696] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 03/20/2019] [Accepted: 03/22/2019] [Indexed: 12/28/2022]
Abstract
OBJECTIVE This randomized controlled study evaluated the efficacy of low-dose (LD) and high-dose (HD) aripiprazole augmentation in major depressive disorder. Additionally, we examined the relationship between clinical response and changes in plasma homovanillic acid (pHVA) levels during aripiprazole augmentation. METHODS Thirty-one patients with inadequate response to antidepressants were randomized to receive adjunctive treatment with LD (3 mg/day, n = 17) or HD (up to 12 mg/day, n = 14) aripiprazole for 6 weeks. We evaluated the Montgomery-Åsberg Depression Rating Scale (MADRS) and measured pHVA at baseline, Week 2, and end point. RESULTS Both LD and HD aripiprazole significantly decreased MADRS score after 6 weeks, and the response rate was higher in HD aripiprazole group at end point. HD aripiprazole significantly decreased MADRS score at Week 2 compared with LD aripiprazole (p = .015). There was a significant difference in changes in pHVA between responders and nonresponders, showing pHVA decreased significantly in responders at Week 2 (p = .044). CONCLUSIONS Increasing aripiprazole from the early period appeared useful for immediate response, although caution is needed when increasing the dose >6 mg/day. pHVA may be a possible indicator of the response to aripiprazole augmentation. Caution is needed in interpreting these findings because of the small sample size.
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Affiliation(s)
- Sho Horikoshi
- Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Itaru Miura
- Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Mizue Ichinose
- Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Shinnosuke Yamamoto
- Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Masashi Ito
- Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kenya Watanabe
- Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan.,Department of Pharmacy, Fukushima Medical University School, Fukushima, Japan
| | - Keiko Kanno-Nozaki
- Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Haruka Kaneko
- Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan.,Department of Neuropsychiatry, Hoshigaoka Hospital, Fukushima, Japan
| | - Hirooki Yabe
- Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan
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20
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Takeuchi S, Hida H, Uchida M, Naruse R, Yoshimi A, Kitagaki S, Ozaki N, Noda Y. Blonanserin ameliorates social deficit through dopamine-D 3 receptor antagonism in mice administered phencyclidine as an animal model of schizophrenia. Neurochem Int 2019; 128:127-134. [PMID: 30998952 DOI: 10.1016/j.neuint.2019.04.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 04/02/2019] [Accepted: 04/15/2019] [Indexed: 01/02/2023]
Abstract
Blonanserin differs from other antipsychotic drugs, such as risperidone and olanzapine, and exhibits a higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effect of blonanserin on the social deficit observed in an animal model of schizophrenia and sought to elucidate the molecular mechanism underlying its action. Mice received phencyclidine (PCP: 10 mg/kg/day, s.c.), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, once a day for 14 consecutive days. We then evaluated the sociability, using a social interaction test, and the expression of GluN1 subunit, an essential subunit of the NMDA receptors, in these mice. Blonanserin significantly ameliorated the PCP-induced social deficit, whereas olanzapine and haloperidol did not. This effect of blonanserin was antagonized by 7-OH-DPAT, a dopamine-D3 receptor agonist, and SCH23390, a dopamine-D1 receptor antagonist. However, the ameliorating effect of blonanserin was not inhibited by DOI, a serotonin 5-HT2A receptor agonist. The PCP-induced social deficit was also ameliorated by U99194, a dopamine-D3 receptor antagonist and SKF38393, a dopamine-D1 receptor agonist, being effects antagonized by 7-OH-DPAT or SCH23390. Blonanserin significantly inhibited the decrease in the phosphorylation levels of GluN1 at Ser897 by protein kinase A (PKA) in the prefrontal cortex (PFC) in PCPadministered mice. These results suggest that activation of NMDA receptors due to Ser897-phosphorylation of GluN1 subunit, which is a step linked to dopamine-D1 receptor-PKA signaling through dopamine-D3 receptor antagonism in the PFC, is required for the ameliorating effect of blonanserin on the PCP-induced social deficit. These findings also provide in vivo evidence that blonanserin antagonism of the dopamine-D3 receptors may be useful as a novel treatment strategy and that the dopamine-D3 receptors can be a novel therapeutic target molecule for the social deficit observed in schizophrenia.
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Affiliation(s)
- Saori Takeuchi
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty of Pharmacy, Meijo University, Nagoya, 468-8503, Japan
| | - Hirotake Hida
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty of Pharmacy, Meijo University, Nagoya, 468-8503, Japan
| | - Mizuki Uchida
- Division of Clinical Sciences and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, 468-8503, Japan
| | - Ryo Naruse
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty of Pharmacy, Meijo University, Nagoya, 468-8503, Japan
| | - Akira Yoshimi
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty of Pharmacy, Meijo University, Nagoya, 468-8503, Japan
| | - Shinji Kitagaki
- Department of Medical Chemistry, Graduate School of Pharmacy, Meijo University, Nagoya, 468-8503, Japan
| | - Norio Ozaki
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, 466-8560, Japan
| | - Yukihiro Noda
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty of Pharmacy, Meijo University, Nagoya, 468-8503, Japan; Division of Clinical Sciences and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, 468-8503, Japan; Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, 466-8560, Japan.
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21
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Simon N, Azorin JM. [Aripiprazole as dopamine partial agonist model: Basic concepts and clinical impact]. Encephale 2018; 44:558-564. [PMID: 30466778 DOI: 10.1016/j.encep.2018.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Accepted: 10/16/2018] [Indexed: 01/11/2023]
Abstract
Aripiprazole may be viewed as the prototype of third-generation antipsychotics. This concept is based on the notion of D2 partial agonism, whereas all molecules of first-and second generation were D2 antagonists. After reviewing the basic pharmacological notions linked to such concepts, the mechanisms of action of these molecules are addressed, with a particular focus on functional selectivity and biased ligand. One of the essential pharmacological properties of D2 agonists, and particularity aripiprazole, is their ability to not induce D2 supersensitivity as well as to reverse this supersensitivity when it has been induced by D2 antagonists. In clinical practice, this impacts the choice of treatment in first episode psychosis as well as in refractory schizophrenia. Animal research shows that D2 supersensitivity could contribute to worsen addictive trends. The pharmacokinetic incidence of D2 supersensitivity tends to favour the long-acting forms of partial agonists. The notion of partial agonism could finally lead to design fourth-generation antipsychotics, on the basis on research focusing on functional selectivity.
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Affiliation(s)
- N Simon
- Service de pharmacologie clinique, PTSIII Order Aix Marseille université, AP-HM, Inserm, IRD, SESSTIM, Hop Sainte-Marguerite, CAP-TV, 270, boulevard Sainte-Marguerite, 13000 Marseille, France.
| | - J-M Azorin
- SHU psychiatrie adultes, hôpital Sainte-Marguerite, 13009 Marseille, France
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Maia TV, Conceição VA. Dopaminergic Disturbances in Tourette Syndrome: An Integrative Account. Biol Psychiatry 2018; 84:332-344. [PMID: 29656800 DOI: 10.1016/j.biopsych.2018.02.1172] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 02/04/2018] [Accepted: 02/25/2018] [Indexed: 12/28/2022]
Abstract
Tourette syndrome (TS) is thought to involve dopaminergic disturbances, but the nature of those disturbances remains controversial. Existing hypotheses suggest that TS involves 1) supersensitive dopamine receptors, 2) overactive dopamine transporters that cause low tonic but high phasic dopamine, 3) presynaptic dysfunction in dopamine neurons, or 4) dopaminergic hyperinnervation. We review evidence that contradicts the first two hypotheses; we also note that the last two hypotheses have traditionally been considered too narrowly, explaining only small subsets of findings. We review all studies that have used positron emission tomography and single-photon emission computerized tomography to investigate the dopaminergic system in TS. The seemingly diverse findings from those studies have typically been interpreted as pointing to distinct mechanisms, as evidenced by the various hypotheses concerning the nature of dopaminergic disturbances in TS. We show, however, that the hyperinnervation hypothesis provides a simple, parsimonious explanation for all such seemingly diverse findings. Dopaminergic hyperinnervation likely causes increased tonic and phasic dopamine. We have previously shown, using a computational model of the role of dopamine in basal ganglia, that increased tonic dopamine and increased phasic dopamine likely increase the propensities to express and learn tics, respectively. There is therefore a plausible mechanistic link between dopaminergic hyperinnervation and TS via increased tonic and phasic dopamine. To further bolster this argument, we review evidence showing that all medications that are effective for TS reduce signaling by tonic dopamine, phasic dopamine, or both.
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Affiliation(s)
- Tiago V Maia
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
| | - Vasco A Conceição
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
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Matsumoto H, Ishigooka J, Ono H, Tadori Y. Safety and efficacy from a 6-week double-blind study and a 52-week open-label extension of aripiprazole in adolescents with schizophrenia in Japan. Psychiatry Clin Neurosci 2018; 72:701-712. [PMID: 29774635 DOI: 10.1111/pcn.12681] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 05/11/2018] [Accepted: 05/14/2018] [Indexed: 01/07/2023]
Abstract
AIM The purpose of this study was to evaluate the safety and efficacy of aripiprazole in adolescents with schizophrenia (SCZ) in Japan. METHODS In a 6-week, randomized, double-blind, dose-comparison study, adolescents (aged 13-17 years) with SCZ were randomized to receive aripiprazole 2, 6-12, or 24-30 mg/day. Patients who completed the 6-week study participated in a 52-week, flexible-dose, open-label extension (OLE) study of aripiprazole (initial dose: 2 mg/day, maintenance dose: 6-24 mg/day, maximum dose: 30 mg/day). RESULTS In the 6-week study, the percentage of patients completing treatment was: 77.1% (27/35) for 2 mg/day; 80.0% (24/30) for 6-12 mg/day; and 85.4% (35/41) for 24-30 mg/day. The least squares mean change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to endpoint (primary efficacy endpoint, last observation carried forward) was -19.6 for 2 mg/day, -16.5 for 6-12 mg/day, and - 21.6 for 24-30 mg/day. The most common (≥20% patients in any group) treatment-emergent adverse events (TEAE) were nausea, akathisia, insomnia, and somnolence. Most TEAE were mild or moderate in severity. There were no deaths. In the OLE, 60.3% (41/68) of patients completed treatment, and the PANSS total score decreased by -7.9 from OLE baseline to week 52. The most common (≥20% patients) TEAE were nasopharyngitis and somnolence. Most TEAE were mild or moderate in severity. There were no deaths. CONCLUSION These study results suggest that aripiprazole would be safe and well tolerated in both short- and long-term treatment for adolescents with SCZ in Japan.
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Affiliation(s)
- Hideo Matsumoto
- Department of Psychiatry, Tokai University School of Medicine, Kanagawa, Japan
| | | | - Hiroaki Ono
- Headquarters of Clinical Development, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Yoshihiro Tadori
- Department of Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan
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Kamijima K, Kimura M, Kuwahara K, Kitayama Y, Tadori Y. Randomized, double-blind comparison of aripiprazole/sertraline combination and placebo/sertraline combination in patients with major depressive disorder. Psychiatry Clin Neurosci 2018; 72:591-601. [PMID: 29660207 DOI: 10.1111/pcn.12663] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 03/27/2018] [Accepted: 04/09/2018] [Indexed: 12/28/2022]
Abstract
AIM This study compared the efficacy and safety of aripiprazole/sertraline combination (ASC) and placebo/sertraline combination (PSC) in patients with major depressive disorder (MDD) who showed an inadequate response to sertraline 100 mg/day. METHODS The study comprised a screening period, an 8-week prospective treatment (single-blind sertraline 25-100 mg/day) period, and a 6-week double-blind treatment period. Patients with DSM-5-defined MDD were enrolled. Following the prospective treatment, non-responders were randomly assigned to the ASC group (aripiprazole 3-12 mg/day/sertraline 100 mg/day) or the PSC group (sertraline 100 mg/day). The primary efficacy end-point was the mean change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to 6 weeks. RESULTS A total of 412 patients were randomly assigned to either the ASC group (n = 209) or the PSC group (n = 203). Mean change in MADRS total score was significantly greater in patients with ASC than PSC (-9.2 vs -7.2; P = 0.0070). Treatment-emergent adverse events (TEAE) that occurred in ≥10% of patients with ASC versus PSC were nasopharyngitis (13.4% vs 11.3%) and akathisia (12.9% vs 3.4%). All TEAE reported in the ASC group were mild or moderate in severity. Rates of discontinuations due to TEAE were low in both the ASC (1.9%) and PSC (1.5%) groups. There were no notable issues in safety assessments in the ASC group compared with the PSC group. CONCLUSION In patients with MDD who showed an inadequate response to treatment with sertraline 100 mg/day, ASC was efficacious and well tolerated.
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Affiliation(s)
| | - Mahito Kimura
- Department of Mental Health, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Kazuo Kuwahara
- Headquarters of Clinical Development, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Yuri Kitayama
- Headquarters of Clinical Development, Otsuka Pharmaceutical Co., Ltd., Osaka, Japan
| | - Yoshihiro Tadori
- Department of Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan
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Omran A, Eslamimehr S, Crider AM, Neumann WL. Synthesis of 3-(3-hydroxyphenyl)pyrrolidine dopamine D 3 receptor ligands with extended functionality for probing the secondary binding pocket. Bioorg Med Chem Lett 2018; 28:1897-1902. [PMID: 29631959 DOI: 10.1016/j.bmcl.2018.03.084] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 03/14/2018] [Accepted: 03/29/2018] [Indexed: 01/10/2023]
Abstract
A series of 3-(3-hydroxyphenyl)pyrrolidine analogues which incorporate N-alkyl groups and N-butylamide-linked benzamide functionality have been synthesized and their in vitro binding affinities at human dopamine receptors have been evaluated. Our ligand design strategy was to take the 3-(3-hydroxyphenyl)pyrrolidine scaffold and extend functionality from the orthosteric binding site to the secondary binding pocket for enhancing affinity and selectivity for the D3 receptor. The N-alkyl analogues constitute a homologous series from N-pentyl to N-decyl to probe the length/bulk tolerance of the secondary binding pocket of the D3 receptor. Enantiomeric 3-(3-hydroxyphenyl)pyrrolidine analogues were also prepared in order to test the chirality preference of the orthosteric binding site for this scaffold. Benzamide analogues were prepared to enhance affinity and/or selectivity based upon the results of the homologous series.
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Affiliation(s)
- Anahid Omran
- Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, 220 University Park Drive, Edwardsville, IL 62026, USA
| | - Shakiba Eslamimehr
- Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, 220 University Park Drive, Edwardsville, IL 62026, USA
| | - A Michael Crider
- Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, 220 University Park Drive, Edwardsville, IL 62026, USA
| | - William L Neumann
- Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, 220 University Park Drive, Edwardsville, IL 62026, USA.
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Azmanova M, Pitto-Barry A, Barry NPE. Schizophrenia: synthetic strategies and recent advances in drug design. MEDCHEMCOMM 2018; 9:759-782. [PMID: 30108966 PMCID: PMC6072500 DOI: 10.1039/c7md00448f] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 03/09/2018] [Indexed: 12/19/2022]
Abstract
Schizophrenia is a complex and unpredictable mental disorder which affects several domains of cognition and behaviour. It is a heterogeneous illness characterised by positive, negative, and cognitive symptoms, often accompanied by signs of depression. In this tutorial review, we discuss recent progress in understanding the target sites and mechanisms of action of second-generation antipsychotic drugs. Progress in identifying and defining target sites has been accelerated recently by advances in neuroscience, and newly developed agents that regulate signalling by the main excitatory neurotransmitters in the brain are surveyed. Examples of novel molecules for the treatment of schizophrenia in preclinical and clinical development and their industrial sponsors are highlighted.
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Affiliation(s)
- Maria Azmanova
- School of Chemistry and Biosciences , University of Bradford , Bradford BD7 1DP , UK . ;
| | - Anaïs Pitto-Barry
- School of Chemistry and Biosciences , University of Bradford , Bradford BD7 1DP , UK . ;
| | - Nicolas P E Barry
- School of Chemistry and Biosciences , University of Bradford , Bradford BD7 1DP , UK . ;
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Tateno A, Sakayori T, Kim WC, Honjo K, Nakayama H, Arakawa R, Okubo Y. Comparison of Dopamine D3 and D2 Receptor Occupancies by a Single Dose of Blonanserin in Healthy Subjects: A Positron Emission Tomography Study With [11C]-(+)-PHNO. Int J Neuropsychopharmacol 2018; 21:522-527. [PMID: 29346639 PMCID: PMC6007421 DOI: 10.1093/ijnp/pyy004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 01/10/2018] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Blockade of D3 receptor, a member of the dopamine D2-like receptor family, has been suggested as a possible medication for schizophrenia. Blonanserin has high affinity in vitro for D3 as well as D2 receptors. We investigated whether a single dose of 12 mg blonanserin, which was within the daily clinical dose range (i.e., 8-24 mg) for the treatment of schizophrenia, occupies D3 as well as D2 receptors in healthy subjects. METHODS Six healthy males (mean 35.7±7.6 years) received 2 positron emission tomography scans, the first prior to taking blonanserin, and the second 2 hours after the administration of a single dose of 12 mg blonanserin. Dopamine receptor occupancies by blonanserin were evaluated by [11C]-(+)-PHNO. RESULTS Occupancy of each region by 12 mg blonanserin was: caudate (range 64.3%-81.5%; mean±SD, 74.3±5.6%), putamen (range 60.4%-84.3%; mean±SD, 73.3%±8.2%), ventral striatum (range 40.1%-88.2%; mean±SD, 60.8%±17.1%), globus pallidus (range 65.8%-87.6%; mean±SD, 75.7%±8.6%), and substantia nigra (range 56.0%-88.7%; mean±SD, 72.4%±11.0%). Correlation analysis between plasma concentration of blonanserin and receptor occupancy in D2-rich (caudate and putamen) and D3-rich (globus pallidus and substantia nigra) regions showed that EC50 for D2-rich region was 0.39 ng/mL (r=0.43) and EC50 for D3-rich region was 0.40 ng/mL (r=0.79). CONCLUSIONS A single dose of 12 mg blonanserin occupied D3 receptor to the same degree as D2 receptor in vivo. Our results were consistent with previous studies that reported that some of the pharmacological effect of blonanserin is mediated via D3 receptor antagonism.
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Affiliation(s)
- Amane Tateno
- Department of Neuropsychiatry, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Takeshi Sakayori
- Department of Neuropsychiatry, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Woo-chan Kim
- Department of Neuropsychiatry, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Kazuyoshi Honjo
- Clinical Imaging Center for Healthcare, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Haruo Nakayama
- Healthcare Solutions Division, Advanced Medical Services Department, Healthcare Business Unit, Hitachi, Ltd., Taito-ku, Tokyo, Japan
| | - Ryosuke Arakawa
- Department of Neuropsychiatry, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Yoshiro Okubo
- Department of Neuropsychiatry, Nippon Medical School, Bunkyo-ku, Tokyo, Japan,Correspondence: Yoshiro Okubo, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113–8602, Japan ()
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Omori Y, Kanbayashi T, Sagawa Y, Imanishi A, Tsutsui K, Takahashi Y, Takeshima M, Takaki M, Nishino S, Shimizu T. Low dose of aripiprazole advanced sleep rhythm and reduced nocturnal sleep time in the patients with delayed sleep phase syndrome: an open-labeled clinical observation. Neuropsychiatr Dis Treat 2018; 14:1281-1286. [PMID: 29849459 PMCID: PMC5965391 DOI: 10.2147/ndt.s158865] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVES Delayed sleep phase syndrome (DSPS) is a chronic dysfunction of circadian rhythm of the subject that impairs functioning in social, occupational, or other spheres. High rate of depression is found among DSPS patients. Aripiprazole (APZ), a second-generation antipsychotic, is effective in treatment of depression as well as schizophrenia. Recently, few case reports show the effectiveness of APZ in treating DSPS and non-24-hour sleep-wake rhythm disorder. Therefore, we tried to treat DSPS with depression using APZ. METHODS Twelve subjects (including four women) aged 19-64 years were included. The subjects were prescribed initially 0.5-3 mg of APZ once a day with subsequent dose adjustments. RESULTS Sleep onset, midpoint of sleep, and sleep offset were significantly advanced by 1.1, 1.8, and 2.5 hours, respectively. Unexpectedly, sleep duration became significantly shorter by 1.3 hours after treatment. Their depressive moods showed an unremarkable change. CONCLUSION Low dose of APZ advanced the sleep rhythm and reduced nocturnal sleep time in the subjects with DSPS. Since it is not easy for physicians to treat prolonged sleep duration often associated with DSPS, this medication would become a new therapeutic option for these patients.
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Affiliation(s)
- Yuki Omori
- Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan
| | - Takashi Kanbayashi
- Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan.,International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan
| | - Yohei Sagawa
- Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan
| | - Aya Imanishi
- Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan
| | - Ko Tsutsui
- Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan
| | - Yuya Takahashi
- Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan
| | - Masahiro Takeshima
- Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan
| | - Manabu Takaki
- Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Okayama, Japan
| | - Seiji Nishino
- Department of Psychiatry and Behavioral Sciences, Sleep and Circadian Neurobiology Laboratory & Center for Narcolepsy, Stanford University School of Medicine, Stanford, CA, USA
| | - Tetsuo Shimizu
- Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan.,International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan
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Agass RF, Brennan M, Rendle DI. Extrapyramidal side effects following subcutaneous metoclopramide injection for the treatment of post operative ileus. EQUINE VET EDUC 2017. [DOI: 10.1111/eve.12586] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- R. F. Agass
- Rainbow Equine Hospital; Old Malton Malton North Yorkshire UK
| | - M. Brennan
- Rainbow Equine Hospital; Old Malton Malton North Yorkshire UK
| | - D. I. Rendle
- Rainbow Equine Hospital; Old Malton Malton North Yorkshire UK
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Kanamitsu K, Arakawa R, Sugiyama Y, Suhara T, Kusuhara H. Prediction of CNS occupancy of dopamine D2 receptor based on systemic exposure and in vitro experiments. Drug Metab Pharmacokinet 2016; 31:395-404. [DOI: 10.1016/j.dmpk.2016.07.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 07/14/2016] [Accepted: 07/23/2016] [Indexed: 01/27/2023]
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Leggio GM, Bucolo C, Platania CBM, Salomone S, Drago F. Current drug treatments targeting dopamine D3 receptor. Pharmacol Ther 2016; 165:164-77. [DOI: 10.1016/j.pharmthera.2016.06.007] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 06/08/2016] [Indexed: 12/29/2022]
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Duration of drug action of dopamine D2 agonists in mice with 6-hydroxydopamine-induced lesions. Neuroreport 2016; 26:1126-32. [PMID: 26559726 DOI: 10.1097/wnr.0000000000000484] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Although 6-hydroxydopamine-induced (6-OHDA-induced) rats are a well-known Parkinson's disease model, the effects of dopamine D2 agonists in mice with 6-OHDA-induced lesions are not completely understood. We produced mice with 6-OHDA-induced lesions and measured their total locomotion counts following administration of several dopamine D2 agonists (pramipexole, ropinirole, cabergoline, rotigotine, apomorphine, talipexole, and quinelorane). Cabergoline showed the longest duration of drug action, which was in agreement with its long-lived anti-Parkinson effects in rats and humans. In contrast, pramipexole and ropinirole had notably short durations of drug action. We demonstrated that mice with 6-OHDA-induced lesions accompanied with significant lesions in the striatum may be reasonable models to predict the action duration of anti-Parkinson drug candidates in humans.
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Cortés A, Moreno E, Rodríguez-Ruiz M, Canela EI, Casadó V. Targeting the dopamine D3 receptor: an overview of drug design strategies. Expert Opin Drug Discov 2016; 11:641-64. [PMID: 27135354 DOI: 10.1080/17460441.2016.1185413] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Dopamine is a neurotransmitter widely distributed in both the periphery and the central nervous system (CNS). Its physiological effects are mediated by five closely related G protein-coupled receptors (GPCRs) that are divided into two major subclasses: the D1-like (D1, D5) and the D2-like (D2, D3, D4) receptors. D3 receptors (D3Rs) have the highest density in the limbic areas of the brain, which are associated with cognitive and emotional functions. These receptors are therefore attractive targets for therapeutic management. AREAS COVERED This review summarizes the functional and pharmacological characteristics of D3Rs, including the design and clinical relevance of full agonists, partial agonists and antagonists, as well as the capacity of these receptors to form active homodimers, heterodimers or higher order receptor complexes as pharmacological targets in several neurological and neurodegenerative disorders. EXPERT OPINION The high sequence homology between D3R and the D2-type challenges the development of D3R-selective compounds. The design of new D3R-preferential ligands with improved physicochemical properties should provide a better pharmacokinetic/bioavailability profile and lesser toxicity than is found with existing D3R ligands. It is also essential to optimize D3R affinity and, especially, D3R vs. D2-type binding and functional selectivity ratios. Developing allosteric and bitopic ligands should help to improve the D3R selectivity of these drugs. As most evidence points to the ability of GPCRs to form homomers and heteromers, the most promising therapeutic strategy in the future is likely to involve the application of heteromer-selective drugs. These selective ligands would display different affinities for a given receptor depending on the receptor partners within the heteromer. Therefore, designing novel compounds that specifically target and modulate D1R-D3R heteromers would be an interesting approach for the treatment of levodopa (L-DOPA)-induced dyskinesias.
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Affiliation(s)
- Antoni Cortés
- a Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Spain.,b Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB) , University of Barcelona , Barcelona , Spain
| | - Estefanía Moreno
- a Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Spain.,b Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB) , University of Barcelona , Barcelona , Spain
| | - Mar Rodríguez-Ruiz
- a Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Spain.,b Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB) , University of Barcelona , Barcelona , Spain
| | - Enric I Canela
- a Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Spain.,b Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB) , University of Barcelona , Barcelona , Spain
| | - Vicent Casadó
- a Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Spain.,b Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB) , University of Barcelona , Barcelona , Spain
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Schepisi C, Pignataro A, Doronzio SS, Piccinin S, Ferraina C, Di Prisco S, Feligioni M, Pittaluga A, Mercuri NB, Ammassari-Teule M, Nisticò R, Nencini P. Inhibition of hippocampal plasticity in rats performing contrafreeloading for water under repeated administrations of pramipexole. Psychopharmacology (Berl) 2016; 233:727-37. [PMID: 26572895 DOI: 10.1007/s00213-015-4150-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 11/06/2015] [Indexed: 12/23/2022]
Abstract
RATIONALE Compulsive symptoms develop in patients exposed to pramipexole (PPX), a dopaminergic agonist with high selectivity for the D3 receptor. Consistently, we demonstrated that PPX produces an exaggerated increase in contrafreeloading (CFL) for water, a repetitive and highly inflexible behavior that models core aspects of compulsive disorders. OBJECTIVES Given the role of the hippocampus in behavioral flexibility, motivational control, and visuospatial working memory, we investigated the role of hippocampus in the expression of PPX-induced CFL. To this aim, rats were subjected to CFL under chronic PPX, and then examined for the electrophysiological, structural, and molecular properties of their hippocampus. METHODS We measured long-term potentiation (LTP) at CA1 Schaffer collaterals, dendritic spine density in CA1 pyramidal neurons, and then glutamate release and expression of pre and postsynaptic proteins in hippocampal synaptosomes. The effects of PPX on hippocampal-dependent working memory were assessed through the novel object recognition (NOR) test. RESULTS We found that PPX-treated rats showing CFL exhibited a significant decrease in hippocampal LTP and failed to exhibit the expected increase in hippocampal spine density. Glutamate release and PSD-95 expression were decreased, while pSYN expression was increased in hippocampal synaptosomes of PPX-treated rats showing CFL. Despite a general impairment of hippocampal synaptic function, working memory was unaffected by PPX treatment. CONCLUSIONS Our findings demonstrate that chronic PPX affects synaptic function in the hippocampus, an area that is critically involved in the expression of flexible, goal-centered behaviors. We suggest that the hippocampus is a promising target in the pharmacotherapy of compulsive disorders.
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Affiliation(s)
- Chiara Schepisi
- Department of Physiology and Pharmacology, Sapienza University, Piazzale Aldo Moro 5, 00185, Rome, Italy.
| | | | - Salvatore Simone Doronzio
- Department of Physiology and Pharmacology, Sapienza University, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | | | | | - Silvia Di Prisco
- Department of Pharmacy, Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | | | - Anna Pittaluga
- Department of Pharmacy, Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | | | - Martine Ammassari-Teule
- IRCCS Santa Lucia, Rome, Italy
- Institute of Cell Biology and Neurobiology, National Research Council, Rome, Italy
| | - Robert Nisticò
- Department of Physiology and Pharmacology, Sapienza University, Piazzale Aldo Moro 5, 00185, Rome, Italy
- European Brain Research Institute, Rome, Italy
| | - Paolo Nencini
- Department of Physiology and Pharmacology, Sapienza University, Piazzale Aldo Moro 5, 00185, Rome, Italy
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Lemercier CE, Schulz SB, Heidmann KE, Kovács R, Gerevich Z. Dopamine D3 Receptors Inhibit Hippocampal Gamma Oscillations by Disturbing CA3 Pyramidal Cell Firing Synchrony. Front Pharmacol 2016; 6:297. [PMID: 26779018 PMCID: PMC4702013 DOI: 10.3389/fphar.2015.00297] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 12/03/2015] [Indexed: 11/13/2022] Open
Abstract
Cortical gamma oscillations are associated with cognitive processes and are altered in several neuropsychiatric conditions such as schizophrenia and Alzheimer’s disease. Since dopamine D3 receptors are possible targets in treatment of these conditions, it is of great importance to understand their role in modulation of gamma oscillations. The effect of D3 receptors on gamma oscillations and the underlying cellular mechanisms were investigated by extracellular local field potential and simultaneous intracellular sharp micro-electrode recordings in the CA3 region of the hippocampus in vitro. D3 receptors decreased the power and broadened the bandwidth of gamma oscillations induced by acetylcholine or kainate. Blockade of the D3 receptors resulted in faster synchronization of the oscillations, suggesting that endogenous dopamine in the hippocampus slows down the dynamics of gamma oscillations by activation of D3 receptors. Investigating the underlying cellular mechanisms for these effects showed that D3 receptor activation decreased the rate of action potentials (APs) during gamma oscillations and reduced the precision of the AP phase coupling to the gamma cycle in CA3 pyramidal cells. The results may offer an explanation how selective activation of D3 receptors may impair cognition and how, in converse, D3 antagonists may exert pro-cognitive and antipsychotic effects.
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Affiliation(s)
- Clément E Lemercier
- Institute of Neurophysiology, Charité - Universitätsmedizin Berlin Berlin, Germany
| | - Steffen B Schulz
- Institute of Neurophysiology, Charité - Universitätsmedizin Berlin Berlin, Germany
| | - Karin E Heidmann
- Institute of Neurophysiology, Charité - Universitätsmedizin Berlin Berlin, Germany
| | - Richard Kovács
- Institute of Neurophysiology, Charité - Universitätsmedizin Berlin Berlin, Germany
| | - Zoltan Gerevich
- Institute of Neurophysiology, Charité - Universitätsmedizin Berlin Berlin, Germany
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36
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Huang M, Kwon S, Oyamada Y, Rajagopal L, Miyauchi M, Meltzer HY. Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement. Pharmacol Biochem Behav 2015; 138:49-57. [DOI: 10.1016/j.pbb.2015.09.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 09/09/2015] [Accepted: 09/11/2015] [Indexed: 12/01/2022]
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Kassel S, Schwed JS, Stark H. Dopamine D3 receptor agonists as pharmacological tools. Eur Neuropsychopharmacol 2015; 25:1480-99. [PMID: 25498414 DOI: 10.1016/j.euroneuro.2014.11.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 09/23/2014] [Accepted: 11/04/2014] [Indexed: 01/10/2023]
Abstract
Dysregulation of the dopaminergic innervation in the central nervous system plays a key role in different neurological disorders like Parkinson´s disease, restless legs syndrome, schizophrenia etc. Although dopamine D3 receptors have been recognized as an important target in these diseases, their full pharmacological properties need further investigations. With focus on dopamine D3 receptor full agonists, this review has divided the ergoline and non-ergoline ligands in dissimilar chemical subclasses describing their pharmacodynamic properties on different related receptors, on species differences and their functional properties on different signaling mechanism. This is combined with a short description of structure-activity relationships for each class. Therefore, this overview should support the rational choice for the optimal compound selection based on affinity, selectivity and efficacy data in biochemical and pharmacological studies.
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Affiliation(s)
- S Kassel
- Heinrich-Heine-University, Universitaetsstr. 1, 40225 Duesseldorf, Germany
| | - J S Schwed
- Heinrich-Heine-University, Universitaetsstr. 1, 40225 Duesseldorf, Germany
| | - H Stark
- Heinrich-Heine-University, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
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38
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Tabata Y, Murai N, Sasaki T, Taniguchi S, Suzuki S, Yamazaki K, Ito M. Multiparametric Phenotypic Screening System for Profiling Bioactive Compounds Using Human Fetal Hippocampal Neural Stem/Progenitor Cells. ACTA ACUST UNITED AC 2015; 20:1074-83. [DOI: 10.1177/1087057115598119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 07/07/2015] [Indexed: 01/25/2023]
Abstract
Stem cell research has been progressing rapidly, contributing to regenerative biology and regenerative medicine. In this field, small-molecule compounds affecting stem cell proliferation/differentiation have been explored to understand stem cell biology and support regenerative medicine. In this study, we established a multiparametric screening system to detect bioactive compounds affecting the cell fate of human neural stem/progenitor cells (NSCs/NPCs), using human fetal hippocampal NSCs/NPCs, HIP-009 cells. We examined effects of 410 compounds, which were collected based on mechanisms of action (MOAs) and chemotypes, on HIP-009’s cell fate (self-renewal, neuronal and astrocytic differentiation) and morphology by automated multiparametric assays and profiled induced cellular phenotypes. We found that this screening classified compounds with the same MOAs into subgroups according to additional pharmacological effects (e.g., mammalian target of rapamycin complex 1 [mTORC1] inhibitors and mTORC1/mTORC2 dual inhibitors among mTOR inhibitors). Moreover, it identified compounds that have off-target effects under matrix analyses of MOAs and structure similarities (e.g., neurotropic effects of amitriptyline among tri- and tetracyclic compounds). Therefore, this automated, medium-throughput and multiparametric screening system is useful for finding compounds that affect the cell fate of human NSCs/NPCs for supporting regenerative medicine and to fingerprint compounds based on human stem cells’ multipotency, leading to understanding of stem cell biology.
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Affiliation(s)
- Yoshikuni Tabata
- Next Generation Systems CFU, Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai, Tsukuba, Ibaraki, Japan
| | - Norio Murai
- Next Generation Systems CFU, Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai, Tsukuba, Ibaraki, Japan
| | - Takeo Sasaki
- Global Discovery Research, Neuroscience and General Medicine PCU, Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai, Tsukuba, Ibaraki, Japan
| | - Sachie Taniguchi
- Next Generation Systems CFU, Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai, Tsukuba, Ibaraki, Japan
| | - Shuichi Suzuki
- Next Generation Systems CFU, Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai, Tsukuba, Ibaraki, Japan
| | - Kazuto Yamazaki
- Next Generation Systems CFU, Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai, Tsukuba, Ibaraki, Japan
| | - Masashi Ito
- Next Generation Systems CFU, Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai, Tsukuba, Ibaraki, Japan
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Kucka M, Tomić M, Bjelobaba I, Stojilkovic SS, Budimirovic DB. Paliperidone and aripiprazole differentially affect the strength of calcium-secretion coupling in female pituitary lactotrophs. Sci Rep 2015; 5:8902. [PMID: 25754735 PMCID: PMC4894395 DOI: 10.1038/srep08902] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Accepted: 02/02/2015] [Indexed: 12/27/2022] Open
Abstract
Hyperprolactinemia is a common adverse in vivo effect of antipsychotic medications that are used in the treatment of patients with schizophrenia. Here, we compared the effects of two atypical antipsychotics, paliperidone and aripiprazole, on cAMP/calcium signaling and prolactin release in female rat pituitary lactotrophs in vitro. Dopamine inhibited spontaneous cAMP/calcium signaling and prolactin release. In the presence of dopamine, paliperidone rescued cAMP/calcium signaling and prolactin release in a concentration-dependent manner, whereas aripiprazole was only partially effective. In the absence of dopamine, paliperidone stimulated cAMP/calcium signaling and prolactin release, whereas aripiprazole inhibited signaling and secretion more potently but less effectively than dopamine. Forskolin-stimulated cAMP production was facilitated by paliperidone and inhibited by aripiprazole, although the latter was not as effective as dopamine. None of the compounds affected prolactin transcript activity, intracellular prolactin accumulation, or growth hormone secretion. These data indicate that paliperidone has dual hyperprolactinemic actions in lactotrophs i) by preserving the coupling of spontaneous electrical activity and prolactin secretion in the presence of dopamine and ii) by inhibiting intrinsic dopamine receptor activity in the absence of dopamine, leading to enhanced calcium signaling and secretion. In contrast, aripiprazole acts on prolactin secretion by attenuating, but not abolishing, calcium-secretion coupling.
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Affiliation(s)
- Marek Kucka
- Section on Cellular Signaling, National Institutes of Child Health and Human Development, NIH, Bethesda, MD 20892
| | - Melanija Tomić
- Section on Cellular Signaling, National Institutes of Child Health and Human Development, NIH, Bethesda, MD 20892
| | - Ivana Bjelobaba
- Section on Cellular Signaling, National Institutes of Child Health and Human Development, NIH, Bethesda, MD 20892
| | - Stanko S Stojilkovic
- Section on Cellular Signaling, National Institutes of Child Health and Human Development, NIH, Bethesda, MD 20892
| | - Dejan B Budimirovic
- Clinical Trials Unit, Kennedy Krieger Institute/Johns Hopkins School of Medicine, Baltimore, MD 21205
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Ma GF, Raivio N, Sabrià J, Ortiz J. Agonist and antagonist effects of aripiprazole on D₂-like receptors controlling rat brain dopamine synthesis depend on the dopaminergic tone. Int J Neuropsychopharmacol 2015; 18:pyu046. [PMID: 25522390 PMCID: PMC4360222 DOI: 10.1093/ijnp/pyu046] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The atypical antipsychotic drug aripiprazole binds with high affinity to a number of G protein coupled receptors, including dopamine D₂ receptors, where its degree of efficacy as a partial agonist remains controversial. METHODS We examined the properties of aripiprazole at D₂-like autoreceptors by monitoring the changes of dopamine synthesis in adult rat brain striatal minces incubated ex vivo. The effects of the dopaminergic tone on the properties of aripiprazole were assayed by comparing a basal condition (2 mM K(+), low dopaminergic tone) and a stimulated condition (15 mM K(+), where dopamine release mimics a relatively higher dopaminergic tone). We also used 2 reference compounds: quinpirole showed a clear agonistic activity and preclamol (S-(-)-PPP) showed partial agonism under both basal and stimulated conditions. RESULTS Aripiprazole under the basal condition acted as an agonist at D₂-like autoreceptors and fully activated them at about 10 nM, inhibiting dopamine synthesis similarly to quinpirole. Higher concentrations of aripiprazole had effects not restricted to D₂-like autoreceptor activation. Under the stimulated (15 mM K(+)) condition, nanomolar concentrations of aripiprazole failed to decrease dopamine synthesis but could totally block the effect of quinpirole. CONCLUSIONS Under high dopaminergic tone, aripiprazole acts as a D₂-like autoreceptor antagonist rather than as an agonist. These data show that, ex vivo, alteration of dopaminergic tone by depolarization affects the actions of aripiprazole on D₂-like autoreceptors. Such unusual effects were not seen with the typical partial agonist preclamol and are consistent with the hypothesis that aripiprazole is a functionally selective D₂R ligand.
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Affiliation(s)
| | | | | | - Jordi Ortiz
- Neuroscience Institute and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Barcelona, Spain.
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Gorbunov EA, Ertuzun IA, Kachaeva EV, Tarasov SA, Epstein OI. In vitro screening of major neurotransmitter systems possibly involved in the mechanism of action of antibodies to S100 protein in released-active form. Neuropsychiatr Dis Treat 2015; 11:2837-46. [PMID: 26604768 PMCID: PMC4639559 DOI: 10.2147/ndt.s92456] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Experimentally and clinically, it was shown that released-active form of antibodies to S100 protein (RAF of Abs to S100) exerts a wide range of pharmacological activities: anxiolytic, antiasthenic, antiaggressive, stress-protective, antihypoxic, antiischemic, neuroprotective, and nootropic. The purpose of this study was to determine the influence of RAF of Abs to S100 on major neurotransmitter systems (serotoninergic, GABAergic, dopaminergic, and on sigma receptors as well) which are possibly involved in its mechanism of pharmacological activity. Radioligand binding assays were used for assessment of the drug influence on ligand-receptor interaction. [(35)S]GTPγS binding assay, cyclic adenosine monophosphate HTRF™, cellular dielectric spectroscopy assays, and assays based on measurement of intracellular concentration of Ca(2+) ions were used for assessment of agonist or antagonist properties of the drug toward receptors. RAF of Abs to S100 increased radioligand binding to 5-HT1F, 5-HT2B, 5-HT2Cedited, 5-HT3, and to D3 receptors by 142.0%, 131.9%, 149.3%, 120.7%, and 126.3%, respectively. Also, the drug significantly inhibited specific binding of radioligands to GABAB1A/B2 receptors by 25.8%, and to both native and recombinant human sigma1 receptors by 75.3% and 40.32%, respectively. In the functional assays, it was shown that the drug exerted antagonism at 5-HT1B, D3, and GABAB1A/B2 receptors inhibiting agonist-induced responses by 23.24%, 32.76%, and 30.2%, respectively. On the contrary, the drug exerted an agonist effect at 5-HT1A receptors enhancing receptor functional activity by 28.0%. The pharmacological profiling of RAF of Abs to S100 among 27 receptor provides evidence for drug-related modification of major neurotransmitter systems.
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Affiliation(s)
| | - Irina A Ertuzun
- OOO "NPF "MATERIA MEDICA HOLDING", Moscow, Russian Federation
| | | | | | - Oleg I Epstein
- OOO "NPF "MATERIA MEDICA HOLDING", Moscow, Russian Federation
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de Bartolomeis A, Tomasetti C, Iasevoli F. Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies Beyond Dopamine Receptor Antagonism. CNS Drugs 2015; 29:773-99. [PMID: 26346901 PMCID: PMC4602118 DOI: 10.1007/s40263-015-0278-3] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Dopamine partial agonism and functional selectivity have been innovative strategies in the pharmacological treatment of schizophrenia and mood disorders and have shifted the concept of dopamine modulation beyond the established approach of dopamine D2 receptor (D2R) antagonism. Despite the fact that aripiprazole was introduced in therapy more than 12 years ago, many questions are still unresolved regarding the complexity of the effects of this agent on signal transduction and intracellular pathways, in part linked to its pleiotropic receptor profile. The complexity of the mechanism of action has progressively shifted the conceptualization of this agent from partial agonism to functional selectivity. From the induction of early genes to modulation of scaffolding proteins and activation of transcription factors, aripiprazole has been shown to affect multiple cellular pathways and several cortical and subcortical neurotransmitter circuitries. Growing evidence shows that, beyond the consequences of D2R occupancy, aripiprazole has a unique neurobiology among available antipsychotics. The effect of chronic administration of aripiprazole on D2R affinity state and number has been especially highlighted, with relevant translational implications for long-term treatment of psychosis. The hypothesized effects of aripiprazole on cell-protective mechanisms and neurite growth, as well as the differential effects on intracellular pathways [i.e. extracellular signal-regulated kinase (ERK)] compared with full D2R antagonists, suggest further exploration of these targets by novel and future biased ligand compounds. This review aims to recapitulate the main neurobiological effects of aripiprazole and discuss the potential implications for upcoming improvements in schizophrenia therapy based on dopamine modulation beyond D2R antagonism.
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Affiliation(s)
- Andrea de Bartolomeis
- Unit of Treatment Resistant Psychosis, Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine of Napoli "Federico II", Via Pansini, 5, Edificio n.18, 3rd floor, 80131, Naples, Italy.
| | - Carmine Tomasetti
- Unit of Treatment Resistant Psychosis, Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine of Napoli "Federico II", Via Pansini, 5, Edificio n.18, 3rd floor, 80131, Naples, Italy
| | - Felice Iasevoli
- Unit of Treatment Resistant Psychosis, Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine of Napoli "Federico II", Via Pansini, 5, Edificio n.18, 3rd floor, 80131, Naples, Italy
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Tadori Y, Kobayashi H. [In vitro pharmacology of antipsychotics at human dopamine D2 and D3 receptors]. Nihon Yakurigaku Zasshi 2014; 144:265-271. [PMID: 25492361 DOI: 10.1254/fpj.144.265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
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Vrignaud L, Aouille J, Mallaret M, Durrieu G, Jonville-Béra AP. Hypersexualité induite par l’aripiprazole : à propos d’un cas et revue de la littérature. Therapie 2014; 69:525-7. [DOI: 10.2515/therapie/2014064] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 07/25/2014] [Indexed: 11/20/2022]
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Winters SJ, Ghooray DT, Yang RQ, Holmes JB, O'Brien AR, Morgan J, Moore JP. Dopamine-2 receptor activation suppresses PACAP expression in gonadotrophs. Endocrinology 2014; 155:2647-57. [PMID: 24823390 PMCID: PMC4060190 DOI: 10.1210/en.2013-2147] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is expressed at a high level in the fetal pituitary and decreases profoundly between embryonic day 19 and postnatal day 1 (PN1), with a further decrease from PN1 to PN4. In this series of experiments, we investigated the hypothesis that dopamine 2 receptor (Drd2) activation interrupts a cAMP-dependent feed-forward loop that maintains PACAP expression at a high level in the fetal pituitary. Using single-cell RT-PCR of pituitary cell cultures from newborn rats, Drd2 mRNA was identified in gonadotrophs that were also positive for PACAP mRNA. PACAP expression in pituitary cultures from embryonic day 19 rats was suppressed by the PACAP6-38 antagonist and by the Drd2 agonist bromocriptine. Increasing concentrations of bromocriptine inhibited cAMP production as well as cAMP signaling based on cAMP response element-luciferase activity, decreased PACAP promoter activity, and decreased PACAP mRNA levels in αT3-1 gonadotroph cells. Furthermore, blockade of dopamine receptors by injecting haloperidol into newborn rat pups partially reversed the developmental decline in pituitary PACAP mRNA that occurs between PN1 and PN4. These results provide evidence that dopamine receptor signaling regulates PACAP expression under physiological conditions and lend support to the hypothesis that a rise in hypothalamic dopamine at birth abrogates cAMP signaling in fetal gonadotrophs to interrupt a feed-forward mechanism that maintains PACAP expression at a high level in the fetal pituitary. We propose that this perinatal decline in pituitary PACAP reduces pituitary follistatin which permits GnRH receptors and FSH-β to increase to facilitate activation of the neonatal gonad.
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Affiliation(s)
- Stephen J Winters
- Division of Endocrinology, Metabolism & Diabetes (S.J.W., D.T.G., J.B.H., A.R.W.O., J.M., J.P.M.), and Department of Anatomy and Neurobiology (R.Q.Y., J.P.M.), University of Louisville, Louisville, Kentucky 40202
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Linder JR, Sodhi SK, Haynes WG, Fiedorowicz JG. Effects of antipsychotic drugs on cardiovascular variability in participants with bipolar disorder. Hum Psychopharmacol 2014; 29:145-51. [PMID: 24590543 PMCID: PMC4080916 DOI: 10.1002/hup.2380] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Accepted: 11/18/2013] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The risk for cardiovascular diseases is elevated in persons with bipolar disorder. However, it remains unknown how much of this excess risk is secondary to pharmacologic treatment. We tested the hypothesis that current and cumulative antipsychotic drug exposure is associated with increased cardiovascular risk as indicated by lower heart rate variability (HRV) and increased blood pressure variability (BPV). METHODS Fifty-five individuals with bipolar disorder (33 ± 7 years; 67% female) underwent noninvasive electrocardiogram assessment of time-domain and frequency-domain HRV, as well as BPV analysis. Medication histories were obtained through systematic review of pharmacy records for the past 5 years. RESULTS Current antipsychotic exposure was associated with lower standard deviation of NN intervals. Second-generation antipsychotics were associated with lower standard deviation of NN intervals and root mean square of successive differences. There was no significant relationship between 5-year antipsychotic exposure and HRV in subjects with bipolar disorder. Exploratory analysis revealed a possible link between selective serotonin reuptake inhibitor exposure and increased low-frequency spectral HRV. CONCLUSIONS Current antipsychotic use (particularly second-generation antipsychotics with high affinities for the D2S receptor) is associated with reduced autonomic-mediated variability of the HR. The absence of an association with cumulative exposure suggests that the effects are acute in onset and may therefore relate more to altered autonomic function than structural cardiovascular abnormalities. Future studies should prospectively examine effects of these antipsychotics on autonomic function.
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Affiliation(s)
- Jonathan R. Linder
- Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, 52242
| | - Simrit K. Sodhi
- Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, 52242
| | - William G. Haynes
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, 52242,Institute for Clinical and Translational Science, The University of Iowa, Iowa City, Iowa, 52242
| | - Jess G. Fiedorowicz
- Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, 52242,Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, 52242,Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa, 52242,Corresponding author. Address: 200 Hawkins Drive W278GH, Iowa City, IA 52242-1057, Phone: (319) 384-9267, Fax (319) 353-8656,
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Abdel-Fattah MAO, Lehmann J, Abadi AH. An Interactive SAR Approach to Discover Novel Hybrid Thieno Probes as Ligands for D2-Like Receptors with Affinities in the Subnanomolar Range. Chem Biodivers 2013; 10:2247-66. [DOI: 10.1002/cbdv.201300204] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Indexed: 11/06/2022]
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Kast RE, Ellingson BM, Marosi C, Halatsch ME. Glioblastoma treatment using perphenazine to block the subventricular zone’s tumor trophic functions. J Neurooncol 2013; 116:207-12. [DOI: 10.1007/s11060-013-1308-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 11/10/2013] [Indexed: 02/02/2023]
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49
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Savio LEB, Vuaden FC, Kist LW, Pereira TC, Rosemberg DB, Bogo MR, Bonan CD, Wyse ATS. Proline-induced changes in acetylcholinesterase activity and gene expression in zebrafish brain: reversal by antipsychotic drugs. Neuroscience 2013; 250:121-8. [PMID: 23867765 DOI: 10.1016/j.neuroscience.2013.07.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Revised: 06/10/2013] [Accepted: 07/06/2013] [Indexed: 11/28/2022]
Abstract
Hyperprolinemia is an inherited disorder of proline metabolism and hyperprolinemic patients can present neurological manifestations, such as seizures, cognitive dysfunctions, and schizoaffective disorders. However, the mechanisms related to these symptoms are still unclear. In the present study, we evaluated the in vivo and in vitro effects of proline on acetylcholinesterase (AChE) activity and gene expression in the zebrafish brain. For the in vivo studies, animals were exposed at two proline concentrations (1.5 and 3.0mM) during 1h or 7 days (short- or long-term treatments, respectively). For the in vitro assays, different proline concentrations (ranging from 3.0 to 1000 μM) were tested. Long-term proline exposures significantly increased AChE activity for both treated groups when compared to the control (34% and 39%). Moreover, the proline-induced increase on AChE activity was completely reverted by acute administration of antipsychotic drugs (haloperidol and sulpiride), as well as the changes induced in ache expression. When assessed in vitro, proline did not promote significant changes in AChE activity. Altogether, these data indicate that the enzyme responsible for the control of acetylcholine levels might be altered after proline exposure in the adult zebrafish. These findings contribute for better understanding of the pathophysiology of hyperprolinemia and might reinforce the use of the zebrafish as a complementary vertebrate model for studying inborn errors of amino acid metabolism.
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Affiliation(s)
- L E B Savio
- Laboratório de Neuroproteção e Doenças Metabólicas, Programa de Pós-Graduação em Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600-Anexo, 90035-003 Porto Alegre, RS, Brazil
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Gross G, Drescher K. The role of dopamine D(3) receptors in antipsychotic activity and cognitive functions. Handb Exp Pharmacol 2013:167-210. [PMID: 23027416 DOI: 10.1007/978-3-642-25758-2_7] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Dopamine D(3) receptors have a pre- and postsynaptic localization in brain stem nuclei, limbic parts of the striatum, and cortex. Their widespread influence on dopamine release, on dopaminergic function, and on several other neurotransmitters makes them attractive targets for therapeutic intervention. The signaling pathways of D(3) receptors are distinct from those of other members of the D(2)-like receptor family. There is increasing evidence that D(3) receptors can form heteromers with dopamine D(1), D(2), and probably other G-protein-coupled receptors. The functional consequences remain to be characterized in more detail but might open new interesting pharmacological insight and opportunities. In terms of behavioral function, D(3) receptors are involved in cognitive, social, and motor functions, as well as in filtering and sensitization processes. Although the role of D(3) receptor blockade for alleviating positive symptoms is still unsettled, selective D(3) receptor antagonism has therapeutic features for schizophrenia and beyond as demonstrated by several animal models: improved cognitive function, emotional processing, executive function, flexibility, and social behavior. D(3) receptor antagonism seems to contribute to atypicality of clinically used antipsychotics by reducing extrapyramidal motor symptoms; has no direct influence on prolactin release; and does not cause anhedonia, weight gain, or metabolic dysfunctions. Unfortunately, clinical data with new, selective D(3) antagonists are still incomplete; their cognitive effects have only been communicated in part. In vitro, virtually all clinically used antipsychotics are not D(2)-selective but also have affinity for D(3) receptors. The exact D(3) receptor occupancies achieved in patients, particularly in cortical areas, are largely unknown, mainly because only nonselective or agonist PET tracers are currently available. It is unlikely that a degree of D(3) receptor antagonism optimal for antipsychotic and cognitive function can be achieved with existing antipsychotics. Therefore, selective D(3) antagonism represents a promising mechanism still to be fully exploited for the treatment of schizophrenia, cognitive deficits in schizophrenia, and comorbid conditions such as substance abuse.
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Affiliation(s)
- Gerhard Gross
- Abbott, Neuroscience Research, Ludwigshafen, Germany.
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