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Blicharz-Futera K, Kamiński M, Grychowska K, Canale V, Zajdel P. Current development in sulfonamide derivatives to enable CNS-drug discovery. Bioorg Chem 2025; 156:108076. [PMID: 39889550 DOI: 10.1016/j.bioorg.2024.108076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 12/08/2024] [Accepted: 12/15/2024] [Indexed: 02/03/2025]
Abstract
The encouraging therapeutic potential of sulfonamide-based derivatives has been unraveled by breakthrough discovery of Paul Ehrlich, who pointed out the possibility of fighting microbes with chemicals. Over the decades, the utility of sulfonamides has expanded beyond antimicrobial agents, revealing their usefulness in many areas of pharmacotherapy, including the treatment of central nervous system (CNS) diseases. Through a detailed analysis of preclinical and clinical data, we identify key sulfonamide-based compounds that have demonstrated significant CNS activity. We also discuss the challenges in the development of sulfonamide derivatives as enzyme/ion channel inhibitors or receptor ligands for CNS applications, describing their mode of action and therapeutic significance. This is followed by the characteristics of pharmacological targets, structure-activity relationships, ADMET properties, efficacy in experimental animal models, and outcomes from clinical trials. Overall, the versatile nature of arylsulfonamides makes them a valuable motif in drug discovery, offering diverse opportunities for the development of novel agents for treating CNS disorders.
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Affiliation(s)
- Klaudia Blicharz-Futera
- Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, 16 Łazarza Street, 31-530 Krakow, Poland
| | - Michał Kamiński
- Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, 16 Łazarza Street, 31-530 Krakow, Poland
| | - Katarzyna Grychowska
- Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Vittorio Canale
- Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Paweł Zajdel
- Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
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Stamenović J, Živadinović B, Đurić V. Clinical characteristics and treatment of psychosis in Parkinson's disease: A narrative review. J Chin Med Assoc 2024; 87:972-979. [PMID: 39118220 DOI: 10.1097/jcma.0000000000001146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/10/2024] Open
Abstract
Parkinson's disease (PD) is a chronic, progressive, neurodegenerative disorder whose clinical presentation consists of motor and non-motor signs and symptoms. Among the non-motor symptoms, psychosis can occur in the later stages of the disease. Psychosis in PD (PDP) is a common, complex, and significantly disabling disorder associated with poorer quality of life, accelerated cognitive decline, need for hospitalization or institutionalization, and mortality. Hallucinations are a significant symptom of PDP, sporadic at first but more frequent in the later course of the disease, and significantly disrupt daily activities. Appropriate and timely screening of psychotic manifestations is necessary for adequate therapeutic procedures. After the exclusion of comorbid conditions as a possible cause of psychosis, correction of antiparkinsonian therapy may be required, and if necessary, the introduction of antipsychotics. The latest therapeutic recommendations include the use of pimavanserin, if available, otherwise second-generation or atypical antipsychotics. Although PDP has long been recognized as a possible complication in the course of the disease, further clinical studies are needed to fully understand its etiopathogenesis and pathophysiological mechanisms.
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Affiliation(s)
- Jelena Stamenović
- Medical Faculty, Department of Neurology, University of Niš, Niš, Serbia
- Clinic of Neurology, University Clinical Center of Niš, Niš, Serbia
| | - Biljana Živadinović
- Medical Faculty, Department of Neurology, University of Niš, Niš, Serbia
- Clinic of Neurology, University Clinical Center of Niš, Niš, Serbia
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Feng Z, Hu Z, Li L, Yu M, Zhang Y, Jing P, Xu X, Wu J, Hu Y, Xu X. Assessing NH300094, a novel dopamine and serotonin receptor modulator with cognitive enhancement property for treating schizophrenia. Front Pharmacol 2024; 15:1298061. [PMID: 38327987 PMCID: PMC10848157 DOI: 10.3389/fphar.2024.1298061] [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: 09/21/2023] [Accepted: 01/03/2024] [Indexed: 02/09/2024] Open
Abstract
Background: Schizophrenia is a serious psychiatric disorder that significantly affects the quality of life of patients. The objective of this study is to discover a novel antipsychotic candidate with highly antagonistic activity against both serotonin and dopamine receptors, demonstrating robust efficacy in animal models of positive, negative, and cognitive symptoms of schizophrenia. Methods: In the present study, we examined the activity of antipsychotic drug (NH300094) on 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B, 5-HT7, H1, M1, Alpha1A, D2L, D2S, Alpha2A, D3 receptor functional assay in vitro. In addition, multiple animal models, including dizocilpine (MK-801) induced hyper-locomotion; APO induced climbing; Conditioned Avoidance Response (CAR); DOI-Induced Head Twitch; Forced swimming test; Scopolamine induced cognitive impairment model, were used to verify the antipsychotic activity of NH300094 in preclinical. Results: In vitro functional assays have indicated that NH300094 is a potent antagonist of 5-HT receptors and dopamine receptors, with higher relative antagonistic activity against 5-HT2A receptor (5-HT2A IC50 = 0.47 nM) than dopamine receptors (D2L IC50 = 1.04 nM; D2S IC50 = 11.71 nM; D3 IC50 = 31.55 nM). Preclinical in vivo pharmacological study results showed that NH300094 was effective in multiple models, which is more extensive than the clinic drug Risperidone. Furthermore, the safety window for extrapyramidal side effects of NH300094 is significantly wider than that of Risperidone (For NH300094, mice catalepsy model ED50/ Mice MK-801 model ED50 = 104.6-fold; for Risperidone, mice catalepsy model ED50/ Mice MK-801 model ED50 = 12.9-fold), which suggests a potentially better clinical safety profile for NH300094. Conclusion: NH300094 is a novel potent serotonin and dopamine receptors modulator, which has good safety profile and therapeutic potential for the treatment of schizophrenia with cognition disorders.
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Affiliation(s)
- Zijin Feng
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
| | - Zhijing Hu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
| | - Lei Li
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
| | - Minquan Yu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
| | - Yiting Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
| | - Peng Jing
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
| | - Xiangqing Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
| | - Jinhui Wu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
| | - Yiqiao Hu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
| | - Xiangyang Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
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Simon IA, Bjørn-Yoshimoto WE, Harpsøe K, Iliadis S, Svensson B, Jensen AA, Gloriam DE. Ligand selectivity hotspots in serotonin GPCRs. Trends Pharmacol Sci 2023; 44:978-990. [PMID: 37914598 DOI: 10.1016/j.tips.2023.09.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 09/20/2023] [Accepted: 09/28/2023] [Indexed: 11/03/2023]
Abstract
Serotonin is a neurotransmitter regulating numerous physiological processes also modulated by drugs, for example, schizophrenia, depression, migraine, and obesity. However, these drugs typically have adverse effects caused by promiscuous binding across 12 serotonin and more than 20 homologous receptors. Recently, structures of the entire serotonin receptor family uncovered molecular ligand recognition. Here, we present a map of 19 'selectivity hotspots', that is, nonconserved binding site residues governing selectivity via favorable target interactions or repulsive 'off-target' contacts. Furthermore, we review functional rationale from observed ligand-binding affinities and mutagenesis effects. Unifying knowledge underlying specific probes and drugs is critical toward the functional characterization of different receptors and alleviation of adverse effects.
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Affiliation(s)
- Icaro A Simon
- Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Walden E Bjørn-Yoshimoto
- Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Kasper Harpsøe
- Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Stylianos Iliadis
- Centre for Endocrinology, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, University of London, London EC1M 6BQ, UK
| | - Bo Svensson
- SARomics Biostructures AB, Scheelevägen 2, 223 63 Lund, Sweden
| | - Anders A Jensen
- Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - David E Gloriam
- Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
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Yamada R, Wada A, Stickley A, Yokoi Y, Sumiyoshi T. Augmentation therapy with serotonin 1A receptor partial agonists on neurocognitive function in schizophrenia: A systematic review and meta-analysis. Schizophr Res Cogn 2023; 34:100290. [PMID: 37732133 PMCID: PMC10507645 DOI: 10.1016/j.scog.2023.100290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 09/05/2023] [Accepted: 09/06/2023] [Indexed: 09/22/2023]
Abstract
Background In a previous meta-analysis, the use of serotonin1A(5-HT1A) receptor partial agonists of the azapirone class as an add-on therapy was associated with beneficial effects on positive symptoms and attention/processing speed in schizophrenia patients. This meta-analysis builds on that study by examining the effects of adjunctive treatment with 5-HT1A partial agonists in improving other domains of neurocognitive function in schizophrenia patients. Methods A literature search was performed from 1987 to May 2023 to identify randomized controlled trials. The standardized mean difference (SMD) with 95 % confidence intervals (CI) was calculated when there were two or more studies. Four studies, involving 313 patients, met the inclusion criteria and were used in the analysis. Results 5-HT1A partial agonists (buspirone or tandospirone) did not have a significant effect on verbal learning (SMD = 0.08, 95 % CI = -0.31 to 0.47) or working memory (SMD = 0.15, 95 % CI = -0.09 to 0.39). Regarding executive functions (Wisconsin Card Sorting Test), positive but non-significant results were seen with the category number (SMD = 0.26, 95 % CI = -0.81 to 1.32), while non-significant effects were noted for percent preservation errors (SMD = -0.10, 95 % CI = -0.53 to 0.33). Conclusions The absence of any significant benefits in the cognitive domains studied here may have been due to the variance in the concomitant medication (typical vs atypical antipsychotic drugs), the level of cognition at baseline, or other factors. Further studies with various types of 5-HT1A agonists are warranted to examine the potential cognitive efficacy of stimulating these receptors.
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Affiliation(s)
- Risa Yamada
- Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8553, Japan
- Department of Psychiatry, National Center Hospital of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8551, Japan
- Department of Psychiatry, The Jikei University School of Medicine, 3-25-8, Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Ayumu Wada
- Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8553, Japan
- Department of Psychiatry, National Center Hospital of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8551, Japan
- Department of Brain Bioregulatory Science, The Jikei University School of Medicine, 3-25-8, Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Andrew Stickley
- Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8553, Japan
| | - Yuma Yokoi
- Department of Educational Promotion, Clinical Research and Education Promotion Division, National Center of Neurology and Psychiatry, National Center Hospital, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8551, Japan
| | - Tomiki Sumiyoshi
- Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8553, Japan
- Department of Psychiatry, National Center Hospital of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8551, Japan
- Department of Brain Bioregulatory Science, The Jikei University School of Medicine, 3-25-8, Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan
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Matsuzaki H, Hatano M, Iwata M, Saito T, Yamada S. Effectiveness of Clozapine on Employment Outcomes in Treatment-Resistant Schizophrenia: A Retrospective Bidirectional Mirror-Image Study. Neuropsychiatr Dis Treat 2023; 19:615-622. [PMID: 36945253 PMCID: PMC10024870 DOI: 10.2147/ndt.s402945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 03/09/2023] [Indexed: 03/23/2023] Open
Abstract
Purpose Clozapine is more effective than other antipsychotics and is the only antipsychotic approved for treatment-resistant schizophrenia. The objective of this study is to reveal the effect of clozapine on employment using a bidirectional mirror-image model. Patients and Methods This design was a retrospective observational study that investigated the employment status of patients with treatment-resistant schizophrenia based on medical records. The bidirectional mirror-image model consisted of 1) switching from other antipsychotics to clozapine and 2) switching from clozapine to other antipsychotics. The observation period was 1 year for each pre- and post-clozapine initiation and discontinuation. Results We included 36 patients in the bidirectional mirror-image model. The regular employment plus employment support rate was significantly higher in the clozapine phase than in the other antipsychotic phase in the bidirectional mirror-image model (30.6% vs 11.1%, P = 0.039). The days of regular employment plus employment support were also significantly longer in the clozapine phase (61.3 ± 106.2 vs 24.7 ± 82.7 days, P = 0.032). As per the unidirectional mirror-image model, switching to clozapine resulted in significantly higher regular employment plus employment support rates in the clozapine phase than those in the other antipsychotic phase (33.3% vs 10.0%, P = 0.039). Switching from clozapine to other antipsychotics did not exhibit significant differences in any outcomes. Conclusion The results suggest that clozapine is superior to other antipsychotics with respect to achieving employment in patients with treatment-resistant schizophrenia. However, biases specific to the mirror-image model need to be considered.
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Affiliation(s)
- Haruna Matsuzaki
- Department of Clinical Pharmacy, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan
| | - Masakazu Hatano
- Department of Clinical Pharmacy, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan
- Correspondence: Masakazu Hatano, Department of Clinical Pharmacy, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake, Toyoake, Aichi, Japan, Tel +81 562932157, Fax +81 562934537, Email
| | - Miko Iwata
- Department of Clinical Pharmacy, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan
| | - Takeo Saito
- Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan
| | - Shigeki Yamada
- Department of Clinical Pharmacy, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan
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de Bartolomeis A, Ciccarelli M, Vellucci L, Fornaro M, Iasevoli F, Barone A. Update on novel antipsychotics and pharmacological strategies for treatment resistant schizophrenia. Expert Opin Pharmacother 2022; 23:2035-2052. [DOI: 10.1080/14656566.2022.2145884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Andrea de Bartolomeis
- Laboratory of Molecular and Translational Psychiatry and Unit of Treatment Resistant Psychosis, Section of Psychiatry, Department of Neuroscience, Reproductive Science and Dentistry, University of Naples “Federico II”, Naples, Italy
| | - Mariateresa Ciccarelli
- Laboratory of Molecular and Translational Psychiatry and Unit of Treatment Resistant Psychosis, Section of Psychiatry, Department of Neuroscience, Reproductive Science and Dentistry, University of Naples “Federico II”, Naples, Italy
| | - Licia Vellucci
- Laboratory of Molecular and Translational Psychiatry and Unit of Treatment Resistant Psychosis, Section of Psychiatry, Department of Neuroscience, Reproductive Science and Dentistry, University of Naples “Federico II”, Naples, Italy
| | - Michele Fornaro
- Laboratory of Molecular and Translational Psychiatry and Unit of Treatment Resistant Psychosis, Section of Psychiatry, Department of Neuroscience, Reproductive Science and Dentistry, University of Naples “Federico II”, Naples, Italy
| | - Felice Iasevoli
- Laboratory of Molecular and Translational Psychiatry and Unit of Treatment Resistant Psychosis, Section of Psychiatry, Department of Neuroscience, Reproductive Science and Dentistry, University of Naples “Federico II”, Naples, Italy
| | - Annarita Barone
- Laboratory of Molecular and Translational Psychiatry and Unit of Treatment Resistant Psychosis, Section of Psychiatry, Department of Neuroscience, Reproductive Science and Dentistry, University of Naples “Federico II”, Naples, Italy
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Zhang S, Ma Y. Emerging role of psychosis in Parkinson's disease: From clinical relevance to molecular mechanisms. World J Psychiatry 2022; 12:1127-1140. [PMID: 36186499 PMCID: PMC9521528 DOI: 10.5498/wjp.v12.i9.1127] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 06/12/2022] [Accepted: 08/16/2022] [Indexed: 02/05/2023] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease. Psychosis is one of the common psychiatric presentations in the natural course of PD. PD psychosis is an important non-motor symptom, which is strongly correlated with a poor prognosis. Increasing attention is being given to PD psychosis. In this opinion review, we summarized and analyzed the identification, screening, epidemiology, mechanisms, risk factors, and therapeutic approaches of PD psychosis based on the current clinical evidence. PD psychosis tends to have a negative effect on patients' quality of life and increases the burden of family caregiving. Screening and identification in the early stage of disease is crucial for establishing tailored therapeutic strategies and predicting the long-term outcome. Development of PD psychosis is believed to involve a combination of exogenous and endogenous mechanisms including imbalance of neurotransmitters, structural and network changes, genetic profiles, cognitive impairment, and antiparkinsonian medications. The therapeutic strategy for PD psychosis includes reducing or ceasing the use of dopaminergic drug, antipsychotics, cholinesterase inhibitors, and non-pharmacological interventions. Ongoing clinical trials are expected to provide new insights for tailoring therapy for PD psychosis. Future research based on novel biomarkers and genetic factors may help inform individualized therapeutic strategies.
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Affiliation(s)
- Shuo Zhang
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Yan Ma
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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Dong H, Shen Y, Hao W. Assessing the mediating role of impulsivity between methamphetamine-induced psychotic disorders and increased gambling severity in methamphetamine-dependent individuals. Eur Arch Psychiatry Clin Neurosci 2022; 272:1109-1117. [PMID: 34398267 DOI: 10.1007/s00406-021-01320-5] [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: 04/12/2021] [Accepted: 08/11/2021] [Indexed: 11/26/2022]
Abstract
Pathological gambling (PG) and methamphetamine-induced psychotic disorders (MIPD) both frequently occurs in methamphetamine-dependent individuals. The current study examined whether impulsivity mediated the relationship between MIPD and gambling severity. The sample consisted of 320 pathological gamblers with methamphetamine dependence (mean age 32.6 years, ranging from 15 to 64 years) voluntarily recruited from three rehabilitation centers in Hunan, China. The semistructured clinical interview of DSM-IV-TR Axis I Disorders Patient Edition was used to diagnosis the presence of MIPD and PG by registered psychiatrists. The severity of gambling symptoms was assessed using the global assessment of functioning scale, and the Barratt Impulsiveness Scale-11 provided a measure of impulsivity. Of the sample, 53.4% of participants (n = 171) met diagnostic criteria for MIPD. Individuals with a dual diagnosis of MIPD were associated with higher levels of impulsivity and greater gambling severity. Notably, support for our hypothesized mediation model was found such that impulsivity mediated the association between MIPD and gambling severity. Our findings imply that impulsivity appears to be a transdiagnostic process, which may be targeted in treatment among pathological gamblers with a dual diagnosis of MIPD to reduce gambling behaviors. Limits and future directions for research are discussed.
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Affiliation(s)
- Huixi Dong
- Mental Health Institute of the Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders of Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yidong Shen
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
- National Clinical Research Center for Mental Disorders, Changsha, 410011, Hunan, China.
- National Technology Institute on Mental Disorders, Changsha, 410011, Hunan, China.
| | - Wei Hao
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
- National Clinical Research Center for Mental Disorders, Changsha, 410011, Hunan, China.
- National Technology Institute on Mental Disorders, Changsha, 410011, Hunan, China.
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Schmidt SD, Zinn CG, Cavalcante LE, Ferreira FF, Furini CRG, Izquierdo I, de Carvalho Myskiw J. Participation of Hippocampal 5-HT 5A, 5-HT 6 and 5-HT 7 Serotonin Receptors on the Consolidation of Social Recognition Memory. Neuroscience 2022; 497:171-183. [PMID: 35718219 DOI: 10.1016/j.neuroscience.2022.06.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 05/31/2022] [Accepted: 06/09/2022] [Indexed: 11/28/2022]
Abstract
Social recognition is the ability of animals to identify and recognize a conspecific. The consolidation of social stimuli in long-term memory is crucial for the establishment and maintenance of social groups, reproduction and species survival. Despite its importance, little is known about the circuitry and molecular mechanisms involved in the social recognition memory (SRM). Serotonin (5-hydroxytryptamine, 5-HT) is acknowledged as a major neuromodulator, which plays a key role in learning and memory. Focusing on the more recently described 5-HT receptors, we investigated in the CA1 region of the dorsal hippocampus the participation of 5-HT5A, 5-HT6 and 5-HT7 receptors in the consolidation of SRM. Male Wistar rats cannulated in CA1 were subjected to a social discrimination task. In the sample phase the animals were exposed to a juvenile conspecific for 1 h. Immediately after, they received different pharmacological treatments. Twenty-four hours later, they were submitted to a 5 min retention test in the presence of the previously presented juvenile (familiar) and a novel juvenile. The animals that received infusions of 5-HT5A receptor antagonist SB-699551 (10 µg/µL), 5-HT6 receptor agonist WAY-208466 (0.63 µg/µL) or 5-HT7 receptor agonist AS-19 (5 µg/µL) intra-CA1 were unable to recognize the familiar juvenile. This effect was blocked by the coinfusion of WAY-208466 plus 5-HT6 receptor antagonist SB-271046 (10 µg/µL) or AS-19 plus 5-HT7 receptor antagonist SB-269970 (5 µg/µL). The present study helps to clarify the neurobiological functions of the 5-HT receptors more recently described and extends our knowledge about mechanisms underlying the SRM.
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Affiliation(s)
- Scheila Daiane Schmidt
- Memory Center, Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690-2nd Floor, 90610-000 Porto Alegre, RS, Brazil.
| | - Carolina Garrido Zinn
- Memory Center, Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690-2nd Floor, 90610-000 Porto Alegre, RS, Brazil
| | - Lorena Evelyn Cavalcante
- Memory Center, Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690-2nd Floor, 90610-000 Porto Alegre, RS, Brazil
| | - Flávia Fagundes Ferreira
- Memory Center, Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690-2nd Floor, 90610-000 Porto Alegre, RS, Brazil
| | - Cristiane Regina Guerino Furini
- Memory Center, Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690-2nd Floor, 90610-000 Porto Alegre, RS, Brazil; National Institute of Translational Neuroscience (INNT), National Research Council of Brazil, Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil
| | - Ivan Izquierdo
- Memory Center, Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690-2nd Floor, 90610-000 Porto Alegre, RS, Brazil; National Institute of Translational Neuroscience (INNT), National Research Council of Brazil, Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil
| | - Jociane de Carvalho Myskiw
- Memory Center, Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690-2nd Floor, 90610-000 Porto Alegre, RS, Brazil; National Institute of Translational Neuroscience (INNT), National Research Council of Brazil, Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil; Psychobiology and Neurocomputation Laboratory (LPBNC), Department of Biophysics, Institute of Biosciences, Federal University of Rio Grande do Sul (UFRGS), Av. Bento Gonçalves, 9500, Building 43422, Room 208A, 91501-970 Porto Alegre, RS, Brazil.
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Identification of cerebrospinal fluid and serum metabolomic biomarkers in first episode psychosis patients. Transl Psychiatry 2022; 12:229. [PMID: 35665740 PMCID: PMC9166796 DOI: 10.1038/s41398-022-02000-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/18/2022] [Accepted: 05/26/2022] [Indexed: 11/24/2022] Open
Abstract
Psychotic disorders are currently diagnosed by examining the patient's mental state and medical history. Identifying reliable diagnostic, monitoring, predictive, or prognostic biomarkers would be useful in clinical settings and help to understand the pathophysiology of schizophrenia. Here, we performed an untargeted metabolomics analysis using ultra-high pressure liquid chromatography coupled with time-of-flight mass spectroscopy on cerebrospinal fluid (CSF) and serum samples of 25 patients at their first-episode psychosis (FEP) manifestation (baseline) and after 18 months (follow-up). CSF and serum samples of 21 healthy control (HC) subjects were also analyzed. By comparing FEP and HC groups at baseline, we found eight CSF and 32 serum psychosis-associated metabolites with non-redundant identifications. Most remarkable was the finding of increased CSF serotonin (5-HT) levels. Most metabolites identified at baseline did not differ between groups at 18-month follow-up with significant improvement of positive symptoms and cognitive functions. Comparing FEP patients at baseline and 18-month follow-up, we identified 20 CSF metabolites and 90 serum metabolites that changed at follow-up. We further utilized Ingenuity Pathway Analysis (IPA) and identified candidate signaling pathways involved in psychosis pathogenesis and progression. In an extended cohort, we validated that CSF 5-HT levels were higher in FEP patients than in HC at baseline by reversed-phase high-pressure liquid chromatography. To conclude, these findings provide insights into the pathophysiology of psychosis and identify potential psychosis-associated biomarkers.
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12
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Veselinović T, Neuner I. Progress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia. CNS Drugs 2022; 36:819-858. [PMID: 35831706 PMCID: PMC9345797 DOI: 10.1007/s40263-022-00935-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/06/2022] [Indexed: 12/11/2022]
Abstract
Cognitive impairments associated with schizophrenia (CIAS) represent a central element of the symptomatology of this severe mental disorder. CIAS substantially determine the disease prognosis and hardly, if at all, respond to treatment with currently available antipsychotics. Remarkably, all drugs presently approved for the treatment of schizophrenia are, to varying degrees, dopamine D2/D3 receptor blockers. In turn, rapidly growing evidence suggests the immense significance of systems other than the dopaminergic system in the genesis of CIAS. Accordingly, current efforts addressing the unmet needs of patients with schizophrenia are primarily based on interventions in other non-dopaminergic systems. In this review article, we provide a brief overview of the available evidence on the importance of specific systems in the development of CIAS. In addition, we describe the promising targets for the development of new drugs that have been used so far. In doing so, we present the most important candidates that have been investigated in the field of the specific systems in recent years and present a summary of the results available at the time of drafting this review (May 2022), as well as the currently ongoing studies.
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Affiliation(s)
- Tanja Veselinović
- Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany.
- Institute of Neuroscience and Medicine 4, INM-4, Forschungszentrum Jülich, Jülich, Germany.
| | - Irene Neuner
- Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
- Institute of Neuroscience and Medicine 4, INM-4, Forschungszentrum Jülich, Jülich, Germany
- JARA-BRAIN, Aachen, Germany
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13
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Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia-Relevance for Mental Diseases. Cells 2021; 10:cells10081902. [PMID: 34440670 PMCID: PMC8392445 DOI: 10.3390/cells10081902] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/16/2021] [Accepted: 07/23/2021] [Indexed: 12/28/2022] Open
Abstract
The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor-receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1-15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor-receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.
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14
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Ji JL, Helmer M, Fonteneau C, Burt JB, Tamayo Z, Demšar J, Adkinson BD, Savić A, Preller KH, Moujaes F, Vollenweider FX, Martin WJ, Repovš G, Cho YT, Pittenger C, Murray JD, Anticevic A. Mapping brain-behavior space relationships along the psychosis spectrum. eLife 2021; 10:e66968. [PMID: 34313219 PMCID: PMC8315806 DOI: 10.7554/elife.66968] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 06/14/2021] [Indexed: 12/29/2022] Open
Abstract
Difficulties in advancing effective patient-specific therapies for psychiatric disorders highlight a need to develop a stable neurobiologically grounded mapping between neural and symptom variation. This gap is particularly acute for psychosis-spectrum disorders (PSD). Here, in a sample of 436 PSD patients spanning several diagnoses, we derived and replicated a dimensionality-reduced symptom space across hallmark psychopathology symptoms and cognitive deficits. In turn, these symptom axes mapped onto distinct, reproducible brain maps. Critically, we found that multivariate brain-behavior mapping techniques (e.g. canonical correlation analysis) do not produce stable results with current sample sizes. However, we show that a univariate brain-behavioral space (BBS) can resolve stable individualized prediction. Finally, we show a proof-of-principle framework for relating personalized BBS metrics with molecular targets via serotonin and glutamate receptor manipulations and neural gene expression maps derived from the Allen Human Brain Atlas. Collectively, these results highlight a stable and data-driven BBS mapping across PSD, which offers an actionable path that can be iteratively optimized for personalized clinical biomarker endpoints.
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Affiliation(s)
- Jie Lisa Ji
- Department of Psychiatry, Yale University School of MedicineNew HavenUnited States
- Interdepartmental Neuroscience Program, Yale University School of MedicineNew HavenUnited States
| | - Markus Helmer
- Department of Psychiatry, Yale University School of MedicineNew HavenUnited States
| | - Clara Fonteneau
- Department of Psychiatry, Yale University School of MedicineNew HavenUnited States
| | | | - Zailyn Tamayo
- Department of Psychiatry, Yale University School of MedicineNew HavenUnited States
| | - Jure Demšar
- Department of Psychology, University of LjubljanaLjubljanaSlovenia
- Faculty of Computer and Information Science, University of LjubljanaLjubljanaSlovenia
| | - Brendan D Adkinson
- Department of Psychiatry, Yale University School of MedicineNew HavenUnited States
- Interdepartmental Neuroscience Program, Yale University School of MedicineNew HavenUnited States
| | | | - Katrin H Preller
- Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry ZurichZurichSwitzerland
| | - Flora Moujaes
- Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry ZurichZurichSwitzerland
| | - Franz X Vollenweider
- Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry ZurichZurichSwitzerland
| | - William J Martin
- The Janssen Pharmaceutical Companies of Johnson and JohnsonSan FranciscoUnited States
| | - Grega Repovš
- Department of Psychiatry, University of ZagrebZagrebCroatia
| | - Youngsun T Cho
- Department of Psychiatry, Yale University School of MedicineNew HavenUnited States
- Child Study Center, Yale University School of MedicineNew HavenUnited States
| | - Christopher Pittenger
- Department of Psychiatry, Yale University School of MedicineNew HavenUnited States
- Child Study Center, Yale University School of MedicineNew HavenUnited States
| | - John D Murray
- Department of Psychiatry, Yale University School of MedicineNew HavenUnited States
- Interdepartmental Neuroscience Program, Yale University School of MedicineNew HavenUnited States
- Department of Physics, Yale UniversityNew HavenUnited States
| | - Alan Anticevic
- Department of Psychiatry, Yale University School of MedicineNew HavenUnited States
- Interdepartmental Neuroscience Program, Yale University School of MedicineNew HavenUnited States
- Department of Psychology, Yale University School of MedicineNew HavenUnited States
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15
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16
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Colangeli R, Teskey GC, Di Giovanni G. Endocannabinoid-serotonin systems interaction in health and disease. PROGRESS IN BRAIN RESEARCH 2021; 259:83-134. [PMID: 33541682 DOI: 10.1016/bs.pbr.2021.01.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Endocannabinoid (eCB) and serotonin (5-HT) neuromodulatory systems work both independently and together to finely orchestrate neuronal activity throughout the brain to strongly sculpt behavioral functions. Surprising parallelism between the behavioral effects of 5-HT and eCB activity has been widely reported, including the regulation of emotional states, stress homeostasis, cognitive functions, food intake and sleep. The distribution pattern of the 5-HT system and the eCB molecular elements in the brain display a strong overlap and several studies report a functional interplay and even a tight interdependence between eCB/5-HT signaling. In this review, we examine the available evidence of the interaction between the eCB and 5-HT systems. We first introduce the eCB system, then we describe the eCB/5-HT crosstalk at the neuronal and synaptic levels. Finally, we explore the potential eCB/5-HT interaction at the behavioral level with the implication for psychiatric and neurological disorders. The precise elucidation of how this neuromodulatory interaction dynamically regulates biological functions may lead to the development of more targeted therapeutic strategies for the treatment of depressive and anxiety disorders, psychosis and epilepsy.
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Affiliation(s)
- Roberto Colangeli
- Section of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
| | - G Campbell Teskey
- Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Giuseppe Di Giovanni
- Laboratory of Neurophysiology, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Neuroscience Division, School of Biosciences, Cardiff University, Cardiff, United Kingdom
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Pokorny T, Duerler P, Seifritz E, Vollenweider FX, Preller KH. LSD acutely impairs working memory, executive functions, and cognitive flexibility, but not risk-based decision-making. Psychol Med 2020; 50:2255-2264. [PMID: 31500679 DOI: 10.1017/s0033291719002393] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Psychiatric and neurodegenerative illnesses are characterized by cognitive impairments, in particular deficits in working memory, decision-making, and executive functions including cognitive flexibility. However, the neuropharmacology of these cognitive functions is poorly understood. The serotonin (5-HT) 2A receptor might be a promising candidate for the modulation of cognitive processes. However, pharmacological studies investigating the role of this receptor system in humans are rare. Recent evidence demonstrates that the effects of Lysergic acid diethylamide (LSD) are mediated via agonistic action at the 5-HT2A receptor. Yet, the effects of LSD on specific cognitive domains using standardized neuropsychological test have not been studied. METHODS We examined the acute effects of LSD (100 µg) alone and in combination with the 5-HT2A antagonist ketanserin (40 mg) on cognition, employing a double-blind, randomized, placebo-controlled, within-subject design in 25 healthy participants. Executive functions, cognitive flexibility, spatial working memory, and risk-based decision-making were examined by the Intra/Extra-Dimensional shift task (IED), Spatial Working Memory task (SWM), and Cambridge Gambling Task (CGT) of the Cambridge Neuropsychological Test Automated Battery. RESULTS Compared to placebo, LSD significantly impaired executive functions, cognitive flexibility, and working memory on the IED and SWM, but did not influence the quality of decision-making and risk taking on the CGT. Pretreatment with the 5-HT2A antagonist ketanserin normalized all LSD-induced cognitive deficits. CONCLUSIONS The present findings highlight the role of the 5-HT2A receptor system in executive functions and working memory and suggest that specific 5-HT2A antagonists may be relevant for improving cognitive dysfunctions in psychiatric disorders.
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Affiliation(s)
- Thomas Pokorny
- Neuropsychopharmacology and Brain Imaging, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
- Heffter Research Center Zurich, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
| | - Patricia Duerler
- Neuropsychopharmacology and Brain Imaging, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
- Heffter Research Center Zurich, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
| | - Erich Seifritz
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
| | - Franz X Vollenweider
- Neuropsychopharmacology and Brain Imaging, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
- Heffter Research Center Zurich, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
| | - Katrin H Preller
- Neuropsychopharmacology and Brain Imaging, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
- Heffter Research Center Zurich, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
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Abstract
Schizophrenia is a major mental illness associated with profound disability. Current treatments for schizophrenia (antipsychotics) all have a similar mechanism of action and are primarily dopamine type 2 receptor (D2R) antagonists. Antipsychotics are not fully effective for the majority of schizophrenia patients, suggesting the need for alternative approaches. The primary focus of this review is to assess the evidence for the role of the serotonin type 2A receptor (5-HT2AR) in schizophrenia. Topics include an overview of 5-HT2AR physiology and pathophysiology in schizophrenia, 5-HT2AR interaction with other neurotransmitter systems, including the glutamatergic system, a review of the 5-HT2AR/d-lysergic acid diethylamide (LSD) model of schizophrenia, a contrast of the 5-HT2AR and glutamatergic models of schizophrenia, and finally, a review of Food and Drug Administration (FDA)-approved and investigational 5-HT2AR-modulating compounds. Recent studies with lumeteperone, pimavanserin, and roluperidone are highlighted.
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Green TA, Bardo MT. Opposite regulation of conditioned place preference and intravenous drug self-administration in rodent models: Motivational and non-motivational examples. Neurosci Biobehav Rev 2020; 116:89-98. [PMID: 32534899 DOI: 10.1016/j.neubiorev.2020.06.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 06/01/2020] [Accepted: 06/03/2020] [Indexed: 12/13/2022]
Abstract
Although developed from a common antecedent, conditioned place preference (CPP) and intravenous drug self-administration (SA) represent different behavioral paradigms, each with strong face validity. The field has treated results from these studies largely interchangeably; however, there is considerable evidence of opposite modulation of CPP vs. SA. This review outlines four manipulations that differentially affect CPP and SA based on alterations of motivation. These examples are contrasted with one example of differential CPP and SA results that can be explained by simple parallel shifts in dose-response functions. The final two examples have yet to be classified as motivation-based or parallel shifts. Important aspects, including motivation, volitional control of drug administration, reward, and the role of cues are discussed. One major conclusion of this paper is that explanations for apparent discrepancies between CPP and SA require full dose effect functions and assessment of PR breakpoints. Overall, this manuscript offers a more nuanced insight into how CPP and SA can be used to study different aspects of substance use disorders.
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Affiliation(s)
- Thomas A Green
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, United States.
| | - Michael T Bardo
- Department of Psychology, University of Kentucky, United States.
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Jones MT, Strassnig MT, Harvey PD. Emerging 5-HT receptor antagonists for the treatment of Schizophrenia. Expert Opin Emerg Drugs 2020; 25:189-200. [PMID: 32449404 DOI: 10.1080/14728214.2020.1773792] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION While antipsychotics have been generally successful in treating psychosis in schizophrenia, there is a major treatment gap for negative symptoms and cognitive deficits. Given that these aspects of the disease contribute to poor functional outcomes independently of positive symptoms, treatments would have profound implications for quality of life. The 5-HT2A- receptor has been considered a potential target for interventions aimed at negative and cognitive symptoms and multiple antagonists and inverse agonists of this receptor have been tested. AREAS COVERED Ritanserin and volinanserin, are historically important compounds in this area, while pimavanserin, roluperidone, and lumateperone are either newly approved, in late stages of development, or currently being tested for efficacy in schizophrenia-related features. The focus will be on their efficacy in the treatment of negative symptoms, with a limited secondary discussion of cognition. EXPERT OPINION In addition to their efficacy in treating negative symptoms and cognition, these compounds may also have a role in modulating antipsychotic-induced dopamine super-sensitivity and preventing relapse. They may also show efficacy in treating patients with milder symptoms such as patients with schizotypal personality disorder and attenuated psychosis syndrome. Their utility may also expand outside the spectrum of schizophrenia to encompass Parkinson's Disease psychosis, major depression, bipolar depression, and dementia-associated apathy.
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Affiliation(s)
| | | | - Philip D Harvey
- Miller School of Medicine, University of Miami , Miami, FL, USA
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Treatment of psychosis in Parkinson's disease and dementia with Lewy Bodies: A review. Parkinsonism Relat Disord 2020; 75:55-62. [PMID: 32480308 DOI: 10.1016/j.parkreldis.2020.05.026] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 05/21/2020] [Accepted: 05/23/2020] [Indexed: 12/16/2022]
Abstract
There is a considerable overlap between Parkinson's Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB). They present a challenge therapeutically, with regard to morbidity and mortality risk. In particular, symptoms of psychosis in these conditions augur a considerably increased burden. To date, there has been a myriad of prospective, retrospective and case studies examining the use of neuroleptics in the treatment of psychotic symptoms in PDD/DLB. Clozapine has the most robust evidence base however its use is limited by agranulocytosis risk and the associated need for frequent blood count monitoring. Quetiapine is more readily used, however, it has a more equivocal evidence base, in terms of efficacy. Other neuroleptics have thus far demonstrated mixed results with increased risk of extrapyramidal worsening. In addition to the atypical agents, the introduction of pimavanserin has provided another treatment option for Parkinson's Disease Psychosis (PDP), decreasing concern for deterioration in motor function. We await further research to confidently demonstrate its efficacy and safety in DLB psychosis. Cholinesterase inhibitors likely have a limited role in treating milder psychosis symptomatology in DLB and perhaps PDD. After review of the current literature for antipsychotic therapy in both PDD and DLB, we provide a logical framework for addressing psychotic symptoms in each condition.
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22
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Bucki A, Marcinkowska M, Śniecikowska J, Zagórska A, Jamrozik M, Pawłowski M, Głuch-Lutwin M, Siwek A, Jakubczyk M, Pytka K, Jastrzębska-Więsek M, Partyka A, Wesołowska A, Mierzejewski P, Kołaczkowski M. Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles targeting behavioral and psychological symptoms of dementia (BPSD). Eur J Med Chem 2020; 191:112149. [PMID: 32105980 DOI: 10.1016/j.ejmech.2020.112149] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 02/12/2020] [Accepted: 02/13/2020] [Indexed: 11/24/2022]
Abstract
Patients suffering from dementia experience cognitive deficits and 90% of them show non-cognitive behavioral and psychological symptoms of dementia (BPSD). The spectrum of BPSD includes agitation, depression, anxiety and psychosis. Antipsychotics, e.g. quetiapine, have been commonly used off-label to control the burdensome symptoms, though they cause serious side effects and further cognitive impairment. Therefore, the development of targeted therapy for BPSD, suitable for elderly patients, remains relevant. A multitarget-directed ligand, acting on serotonin 5-HT2A and dopamine D2 receptors (R) and thus exerting anti-aggressive and antipsychotic activity, as well as on 5-HT6Rs and 5-HT7Rs (potential pro-cognitive, antidepressant and anxiolytic activity), poses a promising strategy for the treatment of BPSD. Antitargeting muscarinic M3R and hERG channel is expected to reduce the risk of side effects. We obtained a series of stereoisomeric compounds by combining 6-fluoro-1,2-benzoxazole moiety and arylsulfonamide fragment through pyrrolidin-1-yl-propyl linker. N-[(3R)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-1-benzothiophene-2-sulfonamide showed a substantial affinity for the targets of interest (pKi = 8.32-9.35) and no significant interaction with the antitargets. Functional studies revealed its antagonist efficacy (pKB = 7.41-9.03). The lead compound showed a promising profile of antipsychotic-like activity in amphetamine- and MK-801-induced hyperlocomotion (MED = 2.5 mg/kg), antidepressant-like, as well as anxiolytic-like activity in mice (MED = 0.312 and 1.25 mg/kg in the forced swim and four-plate tests, respectively). Notably, the novel compound didn't affect spontaneous locomotor activity, nor induced catalepsy or memory deficits (step-through passive avoidance test) in therapeutically relevant doses, which proved its benign safety profile. The overall pharmacological characteristics of the lead compound outperformed the reference drug quetiapine, making it a promising option for evaluation in the treatment of BPSD.
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Affiliation(s)
- Adam Bucki
- Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland; Adamed Pharma S.A., Pienkow, 6A Mariana Adamkiewicza Street, 05-152, Czosnów, Poland.
| | - Monika Marcinkowska
- Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland; Adamed Pharma S.A., Pienkow, 6A Mariana Adamkiewicza Street, 05-152, Czosnów, Poland
| | - Joanna Śniecikowska
- Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland; Adamed Pharma S.A., Pienkow, 6A Mariana Adamkiewicza Street, 05-152, Czosnów, Poland
| | - Agnieszka Zagórska
- Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
| | - Marek Jamrozik
- Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
| | - Maciej Pawłowski
- Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
| | - Monika Głuch-Lutwin
- Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
| | - Agata Siwek
- Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
| | - Magdalena Jakubczyk
- Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
| | - Karolina Pytka
- Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
| | | | - Anna Partyka
- Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
| | - Anna Wesołowska
- Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
| | - Paweł Mierzejewski
- Institute of Psychiatry and Neurology, 9 Sobieskiego Street, 02-957, Warsaw, Poland
| | - Marcin Kołaczkowski
- Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland; Adamed Pharma S.A., Pienkow, 6A Mariana Adamkiewicza Street, 05-152, Czosnów, Poland
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An integrative analysis of 5HTT-mediated mechanism of hyperactivity to non-threatening voices. Commun Biol 2020; 3:113. [PMID: 32157156 PMCID: PMC7064530 DOI: 10.1038/s42003-020-0850-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 02/21/2020] [Indexed: 01/24/2023] Open
Abstract
The tonic model delineating the serotonin transporter polymorphism’s (5-HTTLPR) modulatory effect on anxiety points towards a universal underlying mechanism involving a hyper-or-elevated baseline level of arousal even to non-threatening stimuli. However, to our knowledge, this mechanism has never been observed in non-clinical cohorts exhibiting high anxiety. Moreover, empirical support regarding said association is mixed, potentially because of publication bias with a relatively small sample size. Hence, how the 5-HTTLPR modulates neural correlates remains controversial. Here we show that 5-HTTLPR short-allele carriers had significantly increased baseline ERPs and reduced fearful MMN, phenomena which can nevertheless be reversed by acute anxiolytic treatment. This provides evidence that the 5-HTT affects the automatic processing of threatening and non-threatening voices, impacts broadly on social cognition, and conclusively asserts the heightened baseline arousal level as the universal underlying neural mechanism for anxiety-related susceptibilities, functioning as a spectrum-like distribution from high trait anxiety non-patients to anxiety patients. Chen et al. apply a multi-level approach to show that serotonin signaling modulates neuronal responses to both threatening and non-threatening voices even in the pre-attentive stage. They show that 5-HTTLPR short-allele carriers had higher baseline event-related potentials and lower fearful mismatch negativity, which can be reversed by acute anxiolytic treatment.
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Karpouzian-Rogers T, Stocks J, Meltzer HY, Reilly JL. The effect of high vs. low dose lurasidone on eye movement biomarkers of prefrontal abilities in treatment-resistant schizophrenia. Schizophr Res 2020; 215:314-321. [PMID: 31706786 DOI: 10.1016/j.schres.2019.10.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/30/2019] [Accepted: 10/06/2019] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Eye movement (EM) measures can serve as biomarkers to evaluate pharmacological effects on brain systems involved in cognition. In recent onset schizophrenia, antipsychotic treatment can improve attentional control on the antisaccade task and exacerbate working memory impairment on the memory guided saccade task; effects in treatment-resistant schizophrenia (TRS) are less clear. This study evaluated the effects of high versus low dose lurasidone on EM performance in TRS. METHODS TRS patients completed EM testing: 1) at baseline, on existing medication regimen (n = 42), 2) after 6 weeks of low dose (80 mg) lurasidone (n = 38), 3) after 12 weeks following randomization to low (80 mg) or high dose (240 mg) lurasidone (n = 27), and 4) after 24 weeks of treatment (n = 23). EM testing included prosaccade, antisaccade, and memory guided saccade tasks. RESULTS Six weeks of lurasidone resulted in increased prosaccade saccade latency and reduced antisaccade errors, with no change in memory guided saccade accuracy. After randomization, prosaccade and antisaccade latencies increased in only the high dose group, with no change in antisaccade errors in both groups. Memory guided saccade error increased in the high dose group and remained stable in the low dose group. CONCLUSION Among TRS, stabilization on low dose lurasidone was associated with improved executive control of attention reflected by reduced antisaccade errors. High dose lurasidone resulted in prolonged speed of reflexive and executive shifts of attention and reduced spatial working memory relative to low dose. These findings indicate that EM measures are helpful biomarkers of dose-dependent antipsychotic treatment effects on executive cognitive abilities in TRS.
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Affiliation(s)
- Tatiana Karpouzian-Rogers
- Northwestern University Feinberg School of Medicine, Department of Psychiatry and Behavioral Sciences, 710 N Lake Shore Drive, Chicago, IL, 60611, USA.
| | - Jane Stocks
- Northwestern University Feinberg School of Medicine, Department of Psychiatry and Behavioral Sciences, 710 N Lake Shore Drive, Chicago, IL, 60611, USA
| | - Herbert Y Meltzer
- Northwestern University Feinberg School of Medicine, Department of Psychiatry and Behavioral Sciences, 710 N Lake Shore Drive, Chicago, IL, 60611, USA
| | - James L Reilly
- Northwestern University Feinberg School of Medicine, Department of Psychiatry and Behavioral Sciences, 710 N Lake Shore Drive, Chicago, IL, 60611, USA
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Sniecikowska J, Newman-Tancredi A, Kolaczkowski M. From Receptor Selectivity to Functional Selectivity: The Rise of Biased Agonism in 5-HT1A Receptor Drug Discovery. Curr Top Med Chem 2019; 19:2393-2420. [PMID: 31544717 DOI: 10.2174/1568026619666190911122040] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/27/2019] [Accepted: 08/28/2019] [Indexed: 02/08/2023]
Abstract
Despite extensive efforts to design serotonin 5-HT1A receptor compounds, there are currently no clinically available selective agonists to explore the therapeutic potential of activating this receptor. Commonly used drugs targeting 5-HT1A receptors, such as buspirone or other azapirone compounds, possess only limited selectivity over cross-reacting sites, act as partial agonists for 5-HT1A receptor activation, and are metabolically labile, generating active metabolites. In addition, drug discovery has been hampered by the multiplicity of 5-HT1A receptor subpopulations, expressed in different brain regions, that are coupled to distinct molecular signaling mechanisms and mediate a wide variety of physiological responses, both desired and undesired. In this context, advances in 5-HT1A receptor drug discovery have attracted attention of novel 'biased agonists' that are selective, efficacious and preferentially target the brain regions that mediate therapeutic activity without triggering side effects. The prototypical first-in-class compound NLX-101 (a.k.a. F15599; 3-chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl)amino]methyl]piperidin- 1-yl]methanone), preferentially activates 5-HT1A receptors in cortical regions and exhibits potent, rapidacting and sustained antidepressant-like and procognitive properties in animal models. Here the background has been reviewed that led to the discovery of the class of 1-(1-benzoylpiperidin-4- yl)methanamine derivatives, including NLX-101, as well as recent advances in discovery of novel 5-HT1A receptor biased agonists, notably aryloxyethyl derivatives of 1‑(1-benzoylpiperidin-4yl)methanamine which show promising pharmacological activity both in vitro and in vivo. Overall, the results suggest that opportunities exist for innovative drug discovery of selective 5-HT1A receptor biased agonists that may open new avenues for the treatment of CNS disorders involving dysfunction of serotonergic neurotransmission.
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Affiliation(s)
- Joanna Sniecikowska
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Chair of Pharmaceutical Chemistry, 9 Medyczna Street, 30-688 Krakow, Poland
| | | | - Marcin Kolaczkowski
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Chair of Pharmaceutical Chemistry, 9 Medyczna Street, 30-688 Krakow, Poland
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5-HT 2A receptor-dependent phosphorylation of mGlu 2 receptor at Serine 843 promotes mGlu 2 receptor-operated G i/o signaling. Mol Psychiatry 2019; 24:1610-1626. [PMID: 29858599 DOI: 10.1038/s41380-018-0069-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 02/19/2018] [Accepted: 03/13/2018] [Indexed: 12/31/2022]
Abstract
The serotonin 5-HT2A and glutamate mGlu2 receptors continue to attract particular attention, given their implication in psychosis associated with schizophrenia and the mechanism of action of atypical antipsychotics and a new class of antipsychotics, respectively. A large body of evidence indicates a functional crosstalk between both receptors in the brain, but the underlying mechanisms are not entirely elucidated. Here, we have explored the influence of 5-HT2A receptor upon the phosphorylation pattern of mGlu2 receptor in light of the importance of specific phosphorylation events in regulating G protein-coupled receptor signaling and physiological outcomes. Among the five mGlu2 receptor-phosphorylated residues identified in HEK-293 cells, the phosphorylation of Ser843 was enhanced upon mGlu2 receptor stimulation by the orthosteric agonist LY379268 only in cells co-expressing the 5-HT2A receptor. Likewise, administration of LY379268 increased mGlu2 receptor phosphorylation at Ser843 in prefrontal cortex of wild-type mice but not 5-HT2A-/- mice. Exposure of HEK-293 cells co-expressing mGlu2 and 5-HT2A receptors to 5-HT also increased Ser843 phosphorylation state to a magnitude similar to that measured in LY379268-treated cells. In both HEK-293 cells and prefrontal cortex, Ser843 phosphorylation elicited by 5-HT2A receptor stimulation was prevented by the mGlu2 receptor antagonist LY341495, while the LY379268-induced effect was abolished by the 5-HT2A receptor antagonist M100907. Mutation of Ser843 into alanine strongly reduced Gi/o signaling elicited by mGlu2 or 5-HT2A receptor stimulation in cells co-expressing both receptors. Collectively, these findings identify mGlu2 receptor phosphorylation at Ser843 as a key molecular event that underlies the functional crosstalk between both receptors.
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Serotonin 5-HT 1A, 5-HT 2A and dopamine D 2 receptors strongly influence prefronto-hippocampal neural networks in alert mice: Contribution to the actions of risperidone. Neuropharmacology 2019; 158:107743. [PMID: 31430459 DOI: 10.1016/j.neuropharm.2019.107743] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 07/22/2019] [Accepted: 08/13/2019] [Indexed: 12/26/2022]
Abstract
Atypical antipsychotic drugs (APDs) used to treat positive and negative symptoms in schizophrenia block serotonin receptors 5-HT2AR and dopamine receptors D2R and stimulate 5-HT1AR directly or indirectly. However, the exact cellular mechanisms mediating their therapeutic actions remain unresolved. We recorded neural activity in the prefrontal cortex (PFC) and hippocampus (HPC) of freely-moving mice before and after acute administration of 5-HT1AR, 5-HT2AR and D2R selective agonists and antagonists and atypical APD risperidone. We then investigated the contribution of the three receptors to the actions of risperidone on brain activity via statistical modeling and pharmacological reversal (risperidone + 5-HT1AR antagonist WAY-100635, risperidone + 5-HT2A/2CR agonist DOI, risperidone + D2R agonist quinpirole). Risperidone, 5-HT1AR agonism with 8-OH-DPAT, 5-HT2AR antagonism with M100907, and D2R antagonism with haloperidol reduced locomotor activity of mice that correlated with a suppression of neural spiking, power of theta and gamma oscillations in PFC and HPC, and reduction of PFC-HPC theta phase synchronization. By contrast, activation of 5-HT2AR with DOI enhanced high-gamma oscillations in PFC and PFC-HPC high gamma functional connectivity, likely related to its hallucinogenic effects. Together, power changes, regression modeling and pharmacological reversals suggest an important role of 5-HT1AR agonism and 5-HT2AR antagonism in risperidone-induced alterations of delta, beta and gamma oscillations, while D2R antagonism may contribute to risperidone-mediated changes in delta oscillations. This study provides novel insight into the neural mechanisms for widely prescribed psychiatric medication targeting the serotonin and dopamine systems in two regions involved in the pathophysiology of schizophrenia.
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Lord LD, Expert P, Atasoy S, Roseman L, Rapuano K, Lambiotte R, Nutt DJ, Deco G, Carhart-Harris RL, Kringelbach ML, Cabral J. Dynamical exploration of the repertoire of brain networks at rest is modulated by psilocybin. Neuroimage 2019; 199:127-142. [PMID: 31132450 DOI: 10.1016/j.neuroimage.2019.05.060] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 05/20/2019] [Accepted: 05/23/2019] [Indexed: 12/11/2022] Open
Abstract
Growing evidence from the dynamical analysis of functional neuroimaging data suggests that brain function can be understood as the exploration of a repertoire of metastable connectivity patterns ('functional brain networks'), which potentially underlie different mental processes. The present study characterizes how the brain's dynamical exploration of resting-state networks is rapidly modulated by intravenous infusion of psilocybin, a tryptamine psychedelic found in "magic mushrooms". We employed a data-driven approach to characterize recurrent functional connectivity patterns by focusing on the leading eigenvector of BOLD phase coherence at single-TR resolution. Recurrent BOLD phase-locking patterns (PL states) were assessed and statistically compared pre- and post-infusion of psilocybin in terms of their probability of occurrence and transition profiles. Results were validated using a placebo session. Recurrent BOLD PL states revealed high spatial overlap with canonical resting-state networks. Notably, a PL state forming a frontoparietal subsystem was strongly destabilized after psilocybin injection, with a concomitant increase in the probability of occurrence of another PL state characterized by global BOLD phase coherence. These findings provide evidence of network-specific neuromodulation by psilocybin and represent one of the first attempts at bridging molecular pharmacodynamics and whole-brain network dynamics.
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Affiliation(s)
| | - Paul Expert
- Centre for Mathematics of Precision Healthcare, Imperial College London, UK; Department of Mathematics, Imperial College London, UK
| | - Selen Atasoy
- Department of Psychiatry, University of Oxford, UK
| | - Leor Roseman
- Centre for Psychedelic Research, Department of Brain Sciences, Imperial College London, UK
| | | | | | - David J Nutt
- Centre for Psychedelic Research, Department of Brain Sciences, Imperial College London, UK
| | - Gustavo Deco
- Center for Brain and Cognition, Universitat Pompeu Fabra, Spain; Institució Catalana de la Recerca i Estudis Avançats (ICREA), Universitat Pompeu Fabra, Spain
| | - Robin L Carhart-Harris
- Centre for Psychedelic Research, Department of Brain Sciences, Imperial College London, UK
| | - Morten L Kringelbach
- Department of Psychiatry, University of Oxford, UK; Centre for Music in the Brain, Department of Clinical Medicine, Aarhus University, Denmark; Institut d'Études Avancées de Paris, France; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Portugal
| | - Joana Cabral
- Department of Psychiatry, University of Oxford, UK; Centre for Music in the Brain, Department of Clinical Medicine, Aarhus University, Denmark; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Portugal.
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The allosteric dopamine D1 receptor potentiator, DETQ, ameliorates subchronic phencyclidine-induced object recognition memory deficits and enhances cortical acetylcholine efflux in male humanized D1 receptor knock-in mice. Behav Brain Res 2019; 361:139-150. [DOI: 10.1016/j.bbr.2018.12.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 11/30/2018] [Accepted: 12/01/2018] [Indexed: 12/13/2022]
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Antipsychotics with similar association kinetics at dopamine D 2 receptors differ in extrapyramidal side-effects. Nat Commun 2018; 9:3577. [PMID: 30177830 PMCID: PMC6120954 DOI: 10.1038/s41467-018-04489-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Accepted: 04/30/2018] [Indexed: 12/22/2022] Open
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Davies W. SULFATION PATHWAYS: The steroid sulfate axis and its relationship to maternal behaviour and mental health. J Mol Endocrinol 2018; 61:T199-T210. [PMID: 29440314 DOI: 10.1530/jme-17-0219] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 11/16/2017] [Indexed: 12/14/2022]
Abstract
Steroid hormones can exist in functionally dissociable sulfated and non-sulfated (free) forms and can exert profound effects on numerous aspects of mammalian physiology; the ratio of free-to-sulfated steroids is governed by the antagonistic actions of steroid sulfatase (STS) and sulfotransferase (SULT) enzymes. Here, I examine evidence from human and animal model studies, which suggests that STS and its major substrate (dehydroepiandrosterone sulfate, DHEAS) and product (DHEA) can influence brain function, behaviour and mental health, before summarising how the activity of this axis varies throughout mammalian pregnancy and the postpartum period. I then consider how the steroid sulfate axis might impact upon normal maternal behaviour and how its dysfunction might contribute towards risk of postpartum psychiatric illness. Understanding the biological substrates underlying normal and abnormal maternal behaviour will be important for maximising the wellbeing of new mothers and their offspring.
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Affiliation(s)
- William Davies
- School of PsychologyCardiff University, Cardiff, UK
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical NeurosciencesSchool of Medicine, Cardiff University, Cardiff, UK
- Neuroscience and Mental Health Research InstituteCardiff University, Cardiff, UK
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32
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Sommer IEC, Kleijer H, Visser L, van Laar T. Successful treatment of intractable visual hallucinations with 5-HT 2A antagonist ketanserin. BMJ Case Rep 2018; 2018:bcr-2018-224340. [PMID: 29950360 DOI: 10.1136/bcr-2018-224340] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Hallucinations, visual, auditory or in another sensory modality, often respond well to treatment in patients with schizophrenia. Some, however, do not and can be very chronic and debilitating. We present a patient with schizophrenia with intractable hallucinations despite state of the art care, including high-dose clozapine and transcranial magnetic stimulation. Based on the possible role of the 5-HT2A receptor in hallucinations, we treated her with the antihypertensive drug ketanserin, a 5-HT2A receptor antagonist.This significantly reduced her visual but not her auditory hallucinations, suggesting a possible role of the 5HT2A receptor in the pathophysiology of specifically visual hallucinations. This is the first time ketanserin has been described to successfully reduce visual hallucinations in a patient with schizophrenia.
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Affiliation(s)
- Iris E C Sommer
- Department of Psychiatry and Department of Neuroscience, Rijksuniversiteit Groningen (RUG), Universitair Medisch Centrum Groningen (UMCG), Groningen, The Netherlands.,Department of Psychology, Universitetet i Bergen Det Psykologiske Fakultet, Bergen, Norway
| | - Hidde Kleijer
- Department of Psychiatry and Department of Neuroscience, Rijksuniversiteit Groningen (RUG), Universitair Medisch Centrum Groningen (UMCG), Groningen, The Netherlands.,Department of Psychiatry, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
| | - Lucy Visser
- Department of Psychiatry, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
| | - Teus van Laar
- Department of Neurology, Universitair Medisch Centrum Groningen, Groningen, The Netherlands
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Kim HS, Cassetta BD, Hodgins DC, Tomfohr-Madsen LM, McGrath DS, Tavares H. Assessing the Relationship between Disordered Gamblers with Psychosis and Increased Gambling Severity: The Mediating Role of Impulsivity. CANADIAN JOURNAL OF PSYCHIATRY. REVUE CANADIENNE DE PSYCHIATRIE 2018; 63:370-377. [PMID: 28884607 PMCID: PMC5971405 DOI: 10.1177/0706743717730825] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Recent research suggests that disordered gambling and psychosis co-occur at higher rates than expected in the general population. Gamblers with psychosis also report greater psychological distress and increased gambling severity. However, the mechanism by which psychosis leads to greater gambling symptomology remains unknown. The objective of the present research was to test whether impulsivity mediated the relationship between comorbid psychosis and gambling severity. METHOD The sample consisted of 394 disordered gamblers voluntarily seeking treatment at a large university hospital in São Paulo, Brazil. A semistructured clinical interview (Mini-International Neuropsychiatric Interview) was used to diagnosis the presence of psychosis by registered psychiatrists. Severity of gambling symptoms was assessed using the Gambling Symptom Assessment Scale, and the Barratt Impulsiveness Scale-11 provided a measure of impulsivity. RESULTS Of the sample, 7.2% met diagnostic criteria for psychosis. Individuals with a dual diagnosis of psychosis did not report greater gambling severity. Conversely, dual diagnoses of psychosis were associated with greater levels of impulsivity. Higher levels of impulsivity were also associated with greater gambling severity. Importantly, support for our hypothesised mediation model was found such that impulsivity mediated the association between disordered gambling and psychosis and gambling severity. CONCLUSION Impulsivity appears to be a transdiagnostic process that may be targeted in treatment among disordered gamblers with a dual diagnosis of psychosis to reduce problematic gambling behaviours.
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Affiliation(s)
- Hyoun S. Kim
- Department of Psychology, University of Calgary, Calgary, Alberta
| | | | - David C. Hodgins
- Department of Psychology, University of Calgary, Calgary, Alberta
| | | | | | - Hermano Tavares
- Impulse Control Disorders Outpatient Unit, Institute and Department of Psychiatry, University of São Paulo, Butantã, São Paulo, Brazil
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Jastrzębska-Więsek M, Partyka A, Rychtyk J, Śniecikowska J, Kołaczkowski M, Wesołowska A, Varney MA, Newman-Tancredi A. Activity of Serotonin 5-HT 1A Receptor Biased Agonists in Rat: Anxiolytic and Antidepressant-like properties. ACS Chem Neurosci 2018; 9:1040-1050. [PMID: 29266914 DOI: 10.1021/acschemneuro.7b00443] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Although serotonin 5-HT1A receptors constitute attractive therapeutic targets, there is a lack of potential clinical candidates that have a high degree of selectivity and full agonist efficacy. Recently, novel 5-HT1A receptor "biased agonists" F15599 (also known as NLX-101) and F13714 have been reported that exhibit distinctive properties for in vitro signaling, neurochemical, electrophysiological effects, and in brain imaging. The present study characterized their effects in rat models of anxiety (elevated plus-maze, EPM, and Vogel tests), in depressive-like behavior (forced swim test), and on the induction of the three serotonergic behaviors (forepaw treading, flat body posture, and lower lip retraction). The prototypical 5-HT1A receptor ligands (±)8-OH-DPAT and buspirone were tested as comparators. In the elevated plus-maze, F15599, F13714, and (±)8-OH-DPAT dose-dependently increased the amount and percentage of time spent in the open arms with minimal effective doses (MED) of 5 mg/kg p.o., 2.5 mg/kg p.o. and 1.25 mg/kg s.c., respectively. The effects of the three agonists were abolished by pretreatment with the selective 5-HT1A receptor antagonist, WAY100635 (0.63 mg/kg s.c.). Buspirone did not show significant activity in the EPM. In contrast, in the Vogel test only buspirone was active, significantly increasing the number of licks and shocks accepted (active dose: 1.25 mg/kg s.c.). However, WAY100635 failed to reverse the effects of buspirone in this test, suggesting that they were not 5-HT1A receptor-mediated. In the forced swim test, F15599, F13714, and (±)8-OH-DPAT were potently active, abolishing immobility (MED: 0.63 mg/kg p.o., 0.63 mg/kg p.o. and 0.16 mg/kg s.c., respectively). Buspirone was not active. In measures of serotonergic behavior, F13714 and (±)8-OH-DPAT robustly elicited all three signs of serotonergic behaviors, whereas F15599 and buspirone elicited only lower-lip retraction. Taken together, these observations highlight the distinct profiles of activity of 5-HT1A agonists and suggest that the novel biased agonist F15599 combines pronounced activity in a test of anxiety (elevated plus-maze) with potent antidepressant-like effects and low propensity to induce serotonergic behaviors. These data suggest that selective biased agonists could constitute promising pharmacotherapeutics for mood disorders.
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Affiliation(s)
| | - Anna Partyka
- Jagiellonian University, Medical College, Medyczna 9 St., 30-688 Krakow, Poland
| | - Joanna Rychtyk
- Jagiellonian University, Medical College, Medyczna 9 St., 30-688 Krakow, Poland
| | - Joanna Śniecikowska
- Jagiellonian University, Medical College, Medyczna 9 St., 30-688 Krakow, Poland
| | - Marcin Kołaczkowski
- Jagiellonian University, Medical College, Medyczna 9 St., 30-688 Krakow, Poland
| | - Anna Wesołowska
- Jagiellonian University, Medical College, Medyczna 9 St., 30-688 Krakow, Poland
| | - Mark A. Varney
- Neurolixis Inc., 34145 Pacific Coast Highway #504, Dana Point, California 92629, United States
| | - Adrian Newman-Tancredi
- Neurolixis Inc., 34145 Pacific Coast Highway #504, Dana Point, California 92629, United States
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Abstract
PURPOSE OF REVIEW Hallucinations are common and often stressful experiences, occurring in all sensory modalities. They frequently complicate many disorders or situations, such as Parkinson's disease, schizophrenia, hearing or vision loss, intoxications and delirium. Although psychoeducation, coping techniques and psychotherapy may be broadly applicable, they do not address a specific underlying brain mechanism. Pharmacotherapy may effectively alleviate hallucinations if the corresponding mechanism is present, whereas in its absence, may only cause harmful side effects. Therefore, pharmacotherapy needs input about underlying brain mechanisms. RECENT FINDINGS Recent findings suggest new underlying neurobiological mechanisms as possible therapeutic targets in selected patients, for example increased glutamate levels. In addition, neuronavigation can guide repetitive transcranial magnetic stimulation treatment of auditory verbal hallucinations to target-specific cortical regions. SUMMARY We propose the use of neuroimaging methods to better understand the interaction of different mechanisms underlying hallucinations and to use this knowledge to guide pharmacotherapy or focal brain stimulation in a personalized manner. In addition, we suggest evidence from various imaging modalities should converge to answer a research question. We believe this 'convergence of evidence' avoids the problem of overreliance on single and isolated findings.
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Soto CA, Shashack MJ, Fox RG, Bubar MJ, Rice KC, Watson CS, Cunningham KA, Gilbertson SR, Anastasio NC. Novel Bivalent 5-HT 2A Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo. ACS Chem Neurosci 2018; 9:514-521. [PMID: 29111677 DOI: 10.1021/acschemneuro.7b00309] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
The 5-HT2A receptor (5-HT2AR) plays an important role in various neuropsychiatric disorders, including substance use disorder and schizophrenia. Homodimerization of this receptor has been suggested, but tools that allow direct assessment of the relevance of the 5-HT2AR:5-HT2AR homodimer in these disorders are necessary. We chemically modified the selective 5-HT2AR antagonist M100907 to synthesize a series of homobivalent ligands connected by ethylene glycol linkers of varying lengths that may be useful tools for probing 5-HT2AR:5-HT2AR homodimer function. We tested these molecules for 5-HT2AR antagonist activity in a cell line stably expressing the functional 5-HT2AR and quantified a downstream signaling target, activation (phosphorylation) of extracellular regulated kinases 1/2 (ERK1/2), in comparison to in vivo efficacy of altering spontaneous or cocaine-evoked locomotor activity in rats. All of the synthetic compounds inhibited 5-HT-mediated phosphorylation of ERK1/2 in the cellular signaling assay; the potency of the bivalent ligands varied as a function of linker length, with the intermediate linker lengths being the most potent. The Ki values for the binding of bivalent ligands to 5-HT2AR were only slightly lower than the values for the parent (+)-M100907 compound, but significant selectivity for 5-HT2AR over 5-HT2BR or 5-HT2CR binding was retained. In addition, the 11-atom-linked bivalent 5-HT2AR antagonist (2 mg/kg, intraperitoneally) demonstrated efficacy on par with that of (+)-M100907 in inhibiting cocaine-evoked hyperactivity. As we develop further strategies for ligand-evoked receptor assembly and analyses of diverse signaling and functional roles, these novel homobivalent 5-HT2AR antagonist ligands will serve as useful in vitro and in vivo probes of 5-HT2AR structure and function.
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Affiliation(s)
| | | | | | | | - Kenner C. Rice
- Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Bethesda, Maryland 20892, United States
| | | | | | - Scott R. Gilbertson
- Department of Chemistry, University of Houston, Houston, Texas 77004, United States
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Eum S, Lee AM, Bishop JR. Pharmacogenetic tests for antipsychotic medications: clinical implications and considerations. DIALOGUES IN CLINICAL NEUROSCIENCE 2017. [PMID: 27757066 PMCID: PMC5067149 DOI: 10.31887/dcns.2016.18.3/jbishop] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Optimizing antipsychotic pharmacotherapy is often challenging due to significant variability in effectiveness and tolerability. Genetic factors influencing pharmacokinetics and pharmacodynamics may contribute to some of this variability. Research studies have characterized these pharmacogenetic relationships, and some genetic markers are now available as clinical tests. These advances in pharmacogenetics research and test availability have great potential to improve clinical outcomes and quality of life in psychiatric patients. For clinicians considering using pharmacogenetics, it is important to understand the clinical implications and also the limitations of markers included in currently available tests. This review focuses on pharmacokinetic and pharmacodynamic gene variants that are currently available in commercial genetic testing panels. Associations of these variants with clinical efficacy and adverse effects, as well as other clinical implications, in antipsychotic pharmacotherapy are discussed.
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Affiliation(s)
- Seenae Eum
- College of Pharmacy, Department of Experimental and Clinical Pharmacology; University of Minnesota, Minneapolis, Minnesota, USA
| | - Adam M Lee
- College of Pharmacy, Department of Experimental and Clinical Pharmacology; University of Minnesota, Minneapolis, Minnesota, USA
| | - Jeffrey R Bishop
- College of Pharmacy, Department of Experimental and Clinical Pharmacology; College of Medicine, Department of Psychiatry; University of Minnesota, Minneapolis, Minnesota, USA
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Newman-Tancredi A, Martel JC, Cosi C, Heusler P, Lestienne F, Varney MA, Cussac D. Distinctive in vitro signal transduction profile of NLX-112, a potent and efficacious serotonin 5-HT1A receptor agonist. J Pharm Pharmacol 2017; 69:1178-1190. [DOI: 10.1111/jphp.12762] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 05/13/2017] [Indexed: 12/13/2022]
Abstract
Abstract
Objectives
NLX-112 (befiradol, F13640) is a selective serotonin 5-HT1A receptor agonist. Although it has been tested in vivo, little has been reported on its in vitro signal transduction profile.
Methods
NLX-112 was tested on G-protein activation, inhibition of adenylyl cyclase, ERK1/2 phosphorylation (pERK) and receptor internalization in recombinant cell lines. NLX-112 was also tested on G-protein activation in rat hippocampal membranes. Gα subunit mRNA expression in cell lines and rat brain tissue was quantified by quantitative PCR.
Key findings
For all signalling measures, NLX-112 exhibited agonist efficacy greater than for reference compounds ((±)8-OH-DPAT or buspirone), but similar to the endogenous agonist, serotonin, and was more potent for pERK than other responses. In rat hippocampal membranes, NLX-112 stimulated ‘total G-proteins' but, unlike (±)8-OH-DPAT and buspirone, was more potent for Gαo activation. Cell lines predominantly expressed Gαi1 and Gαi2 mRNA, with low levels of Gαo, whereas in rat brain Gαo subunits showed highest mRNA expression.
Conclusions
Unlike reference compounds, NLX-112 was a highly efficacious agonist in vitro, preferentially activating pERK in cell lines and Gαo proteins in rat hippocampal membranes. However, Gα subunit mRNA levels differ markedly between rat brain and cell lines, warranting caution when extrapolating from recombinant systems to native tissues.
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Sarva H, Henchcliffe C. Evidence for the use of pimavanserin in the treatment of Parkinson's disease psychosis. Ther Adv Neurol Disord 2016; 9:462-473. [PMID: 27800022 PMCID: PMC5066530 DOI: 10.1177/1756285616664300] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder with both motor and nonmotor symptoms (NMS), leading to significant morbidity and caregiver burden. Psychosis is common but is under recognized by physicians. When present, it increases the patient's risk of hospitalization and nursing home placement and caregiver burden. Although the atypical antipsychotic agent, clozapine, has been considered the gold standard treatment, severe agranulocytosis in 0.38% of patients and more commonly milder leukopenia, resulting in frequent blood testing, limit its use. Pimavanserin, a 5HT2A receptor inverse agonist, has been shown to reduce psychosis in PD without worsening motor symptoms. It is therefore a welcome therapeutic option for this devastating NMS.
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Affiliation(s)
- Harini Sarva
- Division of Neurology, Maimonides Medical Center, 883 65 Street, Brooklyn, NY 11220, USA
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Nikolic K, Mavridis L, Djikic T, Vucicevic J, Agbaba D, Yelekci K, Mitchell JBO. Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies. Front Neurosci 2016; 10:265. [PMID: 27375423 PMCID: PMC4901078 DOI: 10.3389/fnins.2016.00265] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 05/25/2016] [Indexed: 11/13/2022] Open
Abstract
HIGHLIGHTS
Many CNS targets are being explored for multi-target drug design New databases and cheminformatic methods enable prediction of primary pharmaceutical target and off-targets of compounds QSAR, virtual screening and docking methods increase the potential of rational drug design The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer‘s disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug-discovery programs. A probabilistic method, the Parzen-Rosenblatt Window approach, was used to build a “predictor” model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands targeting AChE/MAO-A/MAO-B and also D1-R/D2-R/5-HT2A-R/H3-R are promising novel drug candidates with improved efficacy and beneficial neuroleptic and procognitive activities in treatment of Alzheimer's and related neurodegenerative diseases. Structural information for drug targets permits docking and virtual screening and exploration of the molecular determinants of binding, hence facilitating the design of multi-targeted drugs. The crystal structures and models of enzymes of the monoaminergic and cholinergic systems have been used to investigate the structural origins of target selectivity and to identify molecular determinants, in order to design MTDLs.
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Affiliation(s)
- Katarina Nikolic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade Belgrade, Serbia
| | - Lazaros Mavridis
- School of Biological and Chemical Sciences, Queen Mary University of London London, UK
| | - Teodora Djikic
- Department of Bioinformatics and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University Istanbul, Turkey
| | - Jelica Vucicevic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade Belgrade, Serbia
| | - Danica Agbaba
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade Belgrade, Serbia
| | - Kemal Yelekci
- Department of Bioinformatics and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University Istanbul, Turkey
| | - John B O Mitchell
- EaStCHEM School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews St Andrews, UK
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Cascio MG, Zamberletti E, Marini P, Parolaro D, Pertwee RG. The phytocannabinoid, Δ⁹-tetrahydrocannabivarin, can act through 5-HT₁A receptors to produce antipsychotic effects. Br J Pharmacol 2016; 172:1305-18. [PMID: 25363799 DOI: 10.1111/bph.13000] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 10/22/2014] [Accepted: 10/28/2014] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND AND PURPOSE This study aimed to address the questions of whether Δ(9)-tetrahydrocannabivarin (THCV) can (i) enhance activation of 5-HT1 A receptors in vitro and (ii) induce any apparent 5-HT₁A receptor-mediated antipsychotic effects in vivo. EXPERIMENTAL APPROACH In vitro studies investigated the effect of THCV on targeting by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) of 5-HT₁A receptors in membranes obtained from rat brainstem or human 5-HT₁A CHO cells, using [(35)S]-GTPγS and 8-[(3)H]-OH-DPAT binding assays. In vivo studies investigated whether THCV induces signs of 5-HT₁A receptor-mediated antipsychotic effects in rats. KEY RESULTS THCV (i) potently, albeit partially, displaced 8-[(3) H]-OH-DPAT from specific binding sites in rat brainstem membranes; (ii) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of receptors in these membranes; (iii) produced concentration-related increases in 8-[(3)H]-OH-DPAT binding to specific sites in membranes of human 5-HT₁A receptor-transfected CHO cells; and (iv) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of these human 5-HT₁A receptors. In phencyclidine-treated rats, THCV, like clozapine (i) reduced stereotyped behaviour; (ii) decreased time spent immobile in the forced swim test; and (iii) normalized hyperlocomotor activity, social behaviour and cognitive performance. Some of these effects were counteracted by the 5-HT₁A receptor antagonist, WAY100635, or could be reproduced by the CB₁ antagonist, AM251. CONCLUSIONS AND IMPLICATIONS Our findings suggest that THCV can enhance 5-HT₁A receptor activation, and that some of its apparent antipsychotic effects may depend on this enhancement. We conclude that THCV has therapeutic potential for ameliorating some of the negative, cognitive and positive symptoms of schizophrenia.
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Affiliation(s)
- Maria Grazia Cascio
- School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
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Kaczor AA, Targowska-Duda KM, Budzyńska B, Biała G, Silva AG, Castro M. In vitro, molecular modeling and behavioral studies of 3-{[4-(5-methoxy-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]methyl}-1,2-dihydroquinolin-2-one (D2AAK1) as a potential antipsychotic. Neurochem Int 2016; 96:84-99. [PMID: 26964765 DOI: 10.1016/j.neuint.2016.03.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 03/02/2016] [Accepted: 03/05/2016] [Indexed: 12/29/2022]
Abstract
Antipsychotics currently available to treat schizophrenia suffer several limitations: (1) they are efficient against positive but not negative and cognitive symptoms of the disease; (2) they help only a half of patients; (3) they have severe side effects including neurological and metabolic side effects. Thus, novel drugs to treat schizophrenia are highly demanded. We identified a novel dopamine D2 receptor antagonist, D2AAK1, with Ki of 58 nM using structure-based virtual screening. D2AAK1 possesses additional nanomolar or low micromolar affinity to D1, D3, 5-HT1A and 5-HT2A receptors, making it an ideal candidate for a multi-target drug. Here we present homology modeling, molecular docking and molecular dynamics of D2AAK1 and its molecular targets and animal studies of D2AAK1 as a potential antipsychotic. The main contact of D2AAK1 and all the receptors studied is the electrostatic interaction between the protonable nitrogen atom of the ligand and the conserved Asp(3.32) as typical for orthosteric ligands of aminergic GPCRs. We confirmed antagonistic/partial agonistic properties of D2AAK1 towards all the receptors in in vitro essays and in in silico studies as the ligand stabilizes the ionic lock interaction. We also demonstrated neuroleptic, anxiolytic and, importantly, procognitive properties of D2AAK1 in mouse models.
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Affiliation(s)
- Agnieszka A Kaczor
- Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
| | - Katarzyna M Targowska-Duda
- Department of Biopharmacy, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland
| | - Barbara Budzyńska
- Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland
| | - Grażyna Biała
- Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland
| | - Andrea G Silva
- Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, E-15782 Santiago de Compostela, Spain
| | - Marián Castro
- Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, E-15782 Santiago de Compostela, Spain
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Abstract
Despite a lack of recent progress in the treatment of schizophrenia, our understanding of its genetic and environmental causes has considerably improved, and their relationship to aberrant patterns of neurodevelopment has become clearer. This raises the possibility that 'disease-modifying' strategies could alter the course to - and of - this debilitating disorder, rather than simply alleviating symptoms. A promising window for course-altering intervention is around the time of the first episode of psychosis, especially in young people at risk of transition to schizophrenia. Indeed, studies performed in both individuals at risk of developing schizophrenia and rodent models for schizophrenia suggest that pre-diagnostic pharmacotherapy and psychosocial or cognitive-behavioural interventions can delay or moderate the emergence of psychosis. Of particular interest are 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder. This Review aims to provide a broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia.
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Sahlholm K, Zeberg H, Nilsson J, Ögren SO, Fuxe K, Århem P. The fast-off hypothesis revisited: A functional kinetic study of antipsychotic antagonism of the dopamine D2 receptor. Eur Neuropsychopharmacol 2016; 26:467-76. [PMID: 26811292 DOI: 10.1016/j.euroneuro.2016.01.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 12/02/2015] [Accepted: 01/11/2016] [Indexed: 11/28/2022]
Abstract
Newer, "atypical" antipsychotics carry a lower risk of motor side-effects than older, "typical" compounds. It has been proposed that a ~100-fold faster dissociation from the dopamine D2 receptor (D2R) distinguishes atypical from typical antipsychotics. Furthermore, differing antipsychotic D2R affinities have been suggested to reflect differences in dissociation rate constants (koff), while association rate constants (kon) were assumed to be similar. However, it was recently demonstrated that lipophilic accumulation of ligand in the cell interior and/or membrane can cause underestimation of koff, and as high-affinity D2R antagonists are frequently lipophilic, this may have been a confounding factor in previous studies. In the present work, a functional electrophysiology assay was used to measure the recovery of dopamine-mediated D2R responsivity from antipsychotic antagonism, using elevated concentrations of dopamine to prevent the potential bias of re-binding of lipophilic ligands. The variability of antipsychotic kon was also reexamined, capitalizing on the temporal resolution of the assay. kon was estimated from the experimental recordings using a simple mathematical model assumed to describe the binding process. The time course of recovery from haloperidol (typical antipsychotic) was only 6.4- to 2.5-fold slower than that of the atypical antipsychotics, amisulpride, clozapine, and quetiapine, while antipsychotic kons were found to vary more widely than previously suggested. Finally, affinities calculated using our kon and koff estimates correlated well with functional potency and with affinities reported from radioligand binding studies. In light of these findings, it appears unlikely that typical and atypical antipsychotics are primarily distinguished by their D2R binding kinetics.
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Affiliation(s)
- Kristoffer Sahlholm
- Department of Neuroscience, Karolinska Institutet, Retzius väg 8, SE-171 77 Stockholm, Sweden.
| | - Hugo Zeberg
- Department of Neuroscience, Karolinska Institutet, Retzius väg 8, SE-171 77 Stockholm, Sweden
| | - Johanna Nilsson
- Department of Neuroscience, Karolinska Institutet, Retzius väg 8, SE-171 77 Stockholm, Sweden
| | - Sven Ove Ögren
- Department of Neuroscience, Karolinska Institutet, Retzius väg 8, SE-171 77 Stockholm, Sweden
| | - Kjell Fuxe
- Department of Neuroscience, Karolinska Institutet, Retzius väg 8, SE-171 77 Stockholm, Sweden
| | - Peter Århem
- Department of Neuroscience, Karolinska Institutet, Retzius väg 8, SE-171 77 Stockholm, Sweden
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Franke RT, Tarland E, Fink H, Pertz HH, Brosda J. 2-Bromoterguride-a potential atypical antipsychotic drug without metabolic effects in rats. Psychopharmacology (Berl) 2016; 233:3041-50. [PMID: 27317020 PMCID: PMC4933731 DOI: 10.1007/s00213-016-4356-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 06/03/2016] [Indexed: 01/12/2023]
Abstract
RATIONALE Recently, we showed that 2-bromoterguride acted as a dopamine D2 receptor partial agonist, a serotonin 5-HT2A and α2C-adrenergic receptor antagonist, and exhibited antidopaminergic efficacy in amphetamine-induced locomotion (AIL) in rats without inducing catalepsy. OBJECTIVE To extend our knowledge on the antipsychotic effects of 2-bromoterguride, we used convergent preclinical animal models and tests; i.e., conditioned avoidance response (CAR), predictive of antipsychotic-like effects; Fos protein expression, a molecular marker for (atypical) antipsychotic activity; wet dog shake behavior, a test for the in vivo effects of drugs acting on central 5-HT2A receptors; and investigated metabolic changes as a common side effect of atypical antipsychotic drugs (APDs). RESULTS Acute treatment with 2-bromoterguride (0.1 and 0.3 mg/kg) decreased the CAR at 30, 90, and 270 min post-injection in rats without inducing escape failures at any time. Fos protein expression, as shown by Western blotting, was enhanced by 2-bromoterguride in the nucleus accumbens (NAc), the dorsolateral striatum (dStr), and the medial prefrontal cortex (mPFC). (±)-2,5-Dimethoxy-4-iodoamphetamine (DOI)-induced wet dog shakes in rats were reduced by 2-bromoterguride. Chronic treatment with 2-bromoterguride did not affect metabolic parameters such as body weight development and body fat composition as well as behavioral parameters such as food intake and locomotor activity. CONCLUSIONS Our data suggest that 2-bromoterguride is a promising candidate in the treatment of schizophrenia due to its atypical antipsychotic-like activity and its inability to induce weight gain.
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Affiliation(s)
- Robert T. Franke
- />Institute of Pharmacology and Toxicology, School of Veterinary Medicine, Freie Universität Berlin, 14195 Berlin, Germany
| | - Emilia Tarland
- />Institute of Pharmacology and Toxicology, School of Veterinary Medicine, Freie Universität Berlin, 14195 Berlin, Germany
| | - Heidrun Fink
- />Institute of Pharmacology and Toxicology, School of Veterinary Medicine, Freie Universität Berlin, 14195 Berlin, Germany
| | - Heinz H. Pertz
- />Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2, 14195 Berlin, Germany
| | - Jan Brosda
- Institute of Pharmacology and Toxicology, School of Veterinary Medicine, Freie Universität Berlin, 14195, Berlin, Germany.
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Kleene R, Chaudhary H, Karl N, Katic J, Kotarska A, Guitart K, Loers G, Schachner M. Interaction between CHL1 and serotonin receptor 2c regulates signal transduction and behavior in mice. J Cell Sci 2015; 128:4642-52. [PMID: 26527397 DOI: 10.1242/jcs.176941] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 10/28/2015] [Indexed: 02/05/2023] Open
Abstract
The serotonergic system plays important roles in multiple functions of the nervous system and its malfunctioning leads to neurological and psychiatric disorders. Here, we show that the cell adhesion molecule close homolog of L1 (CHL1), which has been linked to mental disorders, binds to a peptide stretch in the third intracellular loop of the serotonin 2c (5-HT2c) receptor through its intracellular domain. Moreover, we provide evidence that CHL1 deficiency in mice leads to 5-HT2c-receptor-related reduction in locomotor activity and reactivity to novelty, and that CHL1 regulates signaling pathways triggered by constitutively active isoforms of the 5-HT2c receptor. Furthermore, we found that the 5-HT2c receptor and CHL1 colocalize in striatal and hippocampal GABAergic neurons, and that 5-HT2c receptor phosphorylation and its association with phosphatase and tensin homolog (PTEN) and β-arrestin 2 is regulated by CHL1. Our results demonstrate that CHL1 regulates signal transduction pathways through constitutively active 5-HT2c receptor isoforms, thereby altering 5-HT2c receptor functions and implicating CHL1 as a new modulator of the serotonergic system.
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Affiliation(s)
- Ralf Kleene
- Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany
| | - Harshita Chaudhary
- Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany
| | - Nicole Karl
- Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany
| | - Jelena Katic
- Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany
| | - Agnieszka Kotarska
- Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany
| | - Kathrin Guitart
- Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany
| | - Gabriele Loers
- Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany
| | - Melitta Schachner
- Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ 08854, USA Center for Neuroscience, Shantou University Medical College, 22 Xin Ling Road, Shantou, Guangdong 515041, China
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Citrome L, Stensbøl TB, Maeda K. The preclinical profile of brexpiprazole: what is its clinical relevance for the treatment of psychiatric disorders? Expert Rev Neurother 2015; 15:1219-29. [PMID: 26402059 DOI: 10.1586/14737175.2015.1086269] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Brexpiprazole is a serotonin-dopamine activity modulator in clinical development for schizophrenia, adjunctive treatment of major depressive disorder, agitation in Alzheimer's disease and post-traumatic stress disorder. It is a partial agonist at 5-HT1A and D2 receptors with similar potency, and an antagonist at 5-HT2A and adrenergic α1B/2C receptors. Compared with aripiprazole, brexpiprazole is more potent at 5-HT1A receptors and displays less intrinsic activity at D2 receptors. This unique serotonin and dopamine modulatory activity has shown robust antipsychotic, antidepressant-like and anxiolytic activities, and limited extrapyramidal symptom liability with pro-cognitive efficacy in animal models. Phase III clinical trials have been successfully completed in schizophrenia and adjunctive use in major depressive disorder, with the US FDA approval obtained for these uses; Phase III studies in Alzheimer's disease and post-traumatic stress disorder are ongoing.
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Affiliation(s)
| | | | - Kenji Maeda
- c 3 Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan
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Bristow GC, Bostrom JA, Haroutunian V, Sodhi MS. Sex differences in GABAergic gene expression occur in the anterior cingulate cortex in schizophrenia. Schizophr Res 2015; 167:57-63. [PMID: 25660468 PMCID: PMC4524801 DOI: 10.1016/j.schres.2015.01.025] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 01/15/2015] [Accepted: 01/17/2015] [Indexed: 01/30/2023]
Abstract
GABAergic dysfunction has been strongly implicated in the pathophysiology of schizophrenia. In this study, we analyzed the expression levels of several GABAergic genes in the anterior cingulate cortex (ACC) of postmortem subjects with schizophrenia (n=21) and a comparison group of individuals without a history of psychiatric illness (n=18). Our analyses revealed a significant sex by diagnosis effect, along with significant differences in GABAergic gene expression based on medication status. Analyses revealed that in male groups, the expression of GABAergic genes was generally lower in schizophrenia cases compared to the controls, with significantly lower expression levels of GABA-Aα5, GABA-Aβ1, and GABA-Aε. In females, the expression of GABAergic genes was higher in the schizophrenia cases, with significantly higher expression of the GABA-Aβ1 and GAD67 genes. Analysis of the effect of medication in the schizophrenia subjects revealed significantly higher expression of GABA-Aα1-3, GABA-Aβ2, GABA-Aγ2, and GAD67 in the medicated group compared to the unmedicated group. These data show that sex differences in the expression of GABAergic genes occur in the ACC in schizophrenia. Therefore, our data support previous findings of GABAergic dysfunction in schizophrenia and emphasize the importance of considering sex in analyses of the pathophysiology of schizophrenia. Sex differences in the GABAergic regulation of ACC function may contribute to the differences observed in the symptoms of male and female patients with schizophrenia. In addition, our findings indicate that antipsychotic medications may alter GABAergic signaling in the ACC, supporting the potential of GABAergic targets for the development of novel antipsychotic medication.
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Affiliation(s)
- Greg C. Bristow
- Department of Pharmacy Practice and Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago IL 60607, USA.,Corresponding author: Dr. Greg Bristow, Department of Pharmacy Practice, University of Illinois at Chicago, 900 S. Ashland Ave., MC870, Chicago IL 60607-4067, USA. Tel: +1-312-996-1413, Fax: +1-312-413-9303,
| | - John A. Bostrom
- Department of Pharmacy Practice and Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago IL 60607, USA
| | - Vahram Haroutunian
- Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA
| | - Monsheel S. Sodhi
- Department of Pharmacy Practice and Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago IL 60607, USA.,Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA
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Castañé A, Kargieman L, Celada P, Bortolozzi A, Artigas F. 5-HT2A receptors are involved in cognitive but not antidepressant effects of fluoxetine. Eur Neuropsychopharmacol 2015; 25:1353-61. [PMID: 25914158 DOI: 10.1016/j.euroneuro.2015.04.006] [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: 10/15/2014] [Revised: 03/24/2015] [Accepted: 04/01/2015] [Indexed: 10/23/2022]
Abstract
The prefrontal cortex (PFC) plays a crucial role in cognitive and affective functions. It contains a rich serotonergic (serotonin, 5-HT) innervation and a high density of 5-HT receptors. Endogenous 5-HT exerts robust actions on the activity of pyramidal neurons in medial PFC (mPFC) via excitatory 5-HT2A and inhibitory 5-HT1A receptors, suggesting the involvement of 5-HT neurotransmission in cortical functions. However, the underlying mechanisms must be elucidated. Here we examine the role of 5-HT2A receptors in the processing of emotional and cognitive signals evoked by increasing the 5-HT tone after acute blockade of the 5-HT transporter. Fluoxetine (5-20mg/kg i.p.) dose-dependently reduced the immobility time in the tail-suspension test in wild-type (WT) and 5-HT2Aknockout (KO2A) mice, with non-significant differences between genotypes. Fluoxetine (10mg/kg i.p.) significantly impaired mice performance in the novel object recognition test 24h post-administration in WT, but not in KO2A mice. The comparable effect of fluoxetine on extracellular 5-HT in the mPFC of both genotypes suggests that presynaptic differences are not accountable. In contrast, single unit recordings of mPFC putative pyramidal neurons showed that fluoxetine (1.8-7.2mg/kg i.v.) significantly increased neuronal discharge in KO2A but not in WT mice. This effect is possibly mediated by an altered excitatory/inhibitory balance in the PFC in KO2A mice. Overall, the present results suggest that 5-HT2A receptors play a detrimental role in long-term memory deficits mediated by an excess 5-HT in PFC.
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Affiliation(s)
- Anna Castañé
- Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
| | - Lucila Kargieman
- Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Barcelona, Spain; Laboratory of Experimental Psychology & Neuroscience, Institute of Cognitive Neurology, Favaloro University, Buenos Aires, Argentina; UDP-INECO Foundation Core on Neuroscience, Diego Portales University, Santiago, Chile
| | - Pau Celada
- Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Analía Bortolozzi
- Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Francesc Artigas
- Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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