DOCSLIB.ORG

82803295.Pdf

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
82803295.Pdf CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Neuron Article Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior Javier Gonza´ lez-Maeso,1,7 Noelia V. Weisstaub,3,4,5,7 Mingming Zhou,4 Pokman Chan,1 Lidija Ivic,1 Rosalind Ang,1 Alena Lira,4 Maria Bradley-Moore,4 Yongchao Ge,1,2 Qiang Zhou,1 Stuart C. Sealfon,1,2,* and Jay A. Gingrich4,5,6 1 Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA 2 Center for Translational Systems Biology, Mount Sinai School of Medicine, New York, NY 10029, USA 3 Department of Biological Sciences, Columbia University, New York, NY 10032, USA 4 Department of Psychiatry, Columbia University, New York, NY 10032, USA 5 Sackler Institute Laboratories, New York State Psychiatric Institute, New York, NY 10032, USA 6 Lieber Center for Schizophrenia Research, New York State Psychiatric Institute, New York, NY 10032, USA 7 These authors contributed equally to this work. *Correspondence: [email protected] DOI 10.1016/j.neuron.2007.01.008 SUMMARY tors (2AR) (Gonzalez-Maeso and Sealfon, 2006; Roth et al., 1998). Genetic or pharmacological inactivation of Hallucinogens, including mescaline, psilocybin, 2AR signaling blocks the behavioral effects of HCs in and lysergic acid diethylamide (LSD), profoundly a variety of species, including mice, rats, and humans affect perception, cognition, and mood. All (Fiorella et al., 1995; Gonzalez-Maeso et al., 2003; Vollen- weider et al., 1998). Taken together, these findings indi- known drugs of this class are 5-HT2A receptor (2AR) agonists, yet closely related 2AR agonists cate that 2AR activation is necessary for the psychoactive such as lisuride lack comparable psychoactive effects of HCs. The demonstration that HCs elicit their psychoactive properties. Why only certain 2AR agonists are effects via 2AR activation has not resolved the fundamen- hallucinogens and which neural circuits mediate tal paradox that 2AR activation is a universally shared their effects are poorly understood. By geneti- property of HCs and that 2AR activation is required for cally expressing 2AR only in cortex, we show HC effects, but yet not all 2AR agonists exhibit hallucino- that 2AR-regulated pathways on cortical neu- genic activity. Indeed, nonhallucinogenic compounds rons are sufficient to mediate the signaling pat- (NHCs) such as lisuride and ergotamine share significant tern and behavioral response to hallucinogens. structural similarities and comparable agonist activities Hallucinogenic and nonhallucinogenic 2AR at 2AR (Egan et al., 1998), but lack psychoactive proper- agonists both regulate signaling in the same ties (Pieri et al., 1978). 2AR-expressing cortical neurons. However, 2AR is expressed widely in the central nervous system the signaling and behavioral responses to the (CNS) and is expressed in structures involved in psycho- sis—the ventral striatum and ventral tegmental area (Li hallucinogens are distinct. While lisuride and et al., 2004; Lopez-Gimenez et al., 1997, 2001; Nocjar LSD both act at 2AR expressed by cortex et al., 2002; Pazos et al., 1985). Several of these structures neurons to regulate phospholipase C, LSD re- have also been implicated in HC effects (Nielsen and sponses also involve pertussis toxin-sensitive Scheel-Kruger, 1986; Vetulani et al., 1979; Willins and heterotrimeric Gi/o proteins and Src. These Meltzer, 1997). However, the neuronal substrates that studies identify the long-elusive neural and sig- mediate hallucinogen effects remain obscure. naling mechanisms responsible for the unique Our previous study of two HCs, lysergic acid di- effects of hallucinogens. ethylamide (LSD) and 1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane (DOI), suggests the hypothesis that HCs induce a characteristic, 2AR-dependent regulation of gene INTRODUCTION expression in mouse somatosensory cortex (SSC) (Gon- zalez-Maeso et al., 2003). By extending our previous Throughout history, naturally occurring hallucinogenic biochemical studies to a large group of diverse chemicals, substances such as psilocybin and mescaline have been we provide a basis for predicting hallucinogenic potential recognized for their capacity to alter perception, emotion, from effects in mouse. We find that HC and NHC 2AR and cognition (Nichols, 2004). All such hallucinogenic agonists differ in their regulation of signaling and physiol- compounds (HCs) exhibit high affinity for 5-HT2A recep- ogy in the same neurons in vivo and in vitro. By using Neuron 53, 439–452, February 1, 2007 ª2007 Elsevier Inc. 439 Neuron Hallucinogen Signalling in Cortical Neurons a genetic strategy to restore specifically 2AR-signaling penetrate the CNS after systemic administration. How- capacity to cortical neurons in htr2AÀ/À mice, we show ever, only the drugs with hallucinogenic potential in that the unique signaling and neurobehavioral effects of humans (Nichols, 2004) activated a significant HTR in HCs do not result from their previously proposed regula- htr2A+/+ mice, but not in htr2AÀ/À mice (Figure 1A). The tion of subcortical-cortical circuits, but are intrinsic to NHC 2AR agonists (ergotamine, R-lisuride, and S-lisuride) 2AR-expressing cortical pyramidal neurons. We formulate were inactive in both genotypes (Figure 1A). Thus, the a new model for the mechanism of action of HCs. HTR was used as a mouse behavioral proxy of human hallucinogenic potential in subsequent studies. RESULTS HCs Elicit a 2AR Signaling Response Distinct HCs Are 2AR Ligands in the Mouse from NHCs The responses to HC and NHC 2AR agonists have pre- Consistent with psychoactive effects of certain 2AR dominantly been studied in rats, primates, and humans. agonists in humans, the HTR was produced only by the The effects of these drugs in mice have been less well HCs, a subset of drugs with 2AR agonist properties. To studied. Because hallucinogens require 2AR activation, explain this finding, we reasoned that HCs might interact we sought to verify that HCs and NHCs exhibit affinities with 2AR to recruit specific signaling pathways not to mouse 2AR that are comparable with those seen in activated by NHCs. other experimental models. When assayed by displace- To test this hypothesis, we compared HC- and NHC- ment of [3H]ketanserin from membranes prepared from activation of multiple signal transduction pathways. Be- mouse cortex (see Figure S1 in the Supplemental Data), cause signal transduction cascades ultimately regulate all agonists displayed affinities that were consistent with gene transcription (Ruf and Sealfon, 2004), we assessed rat and human values (Hoyer et al., 1994). Thus, the 2AR HC and NHC signaling by measuring the ‘‘downstream’’ signaling system in mice presents a tractable model transcriptome responses elicited by HCs and NHCs in system to study the effects of HCs. mouse SSC, a responsive and reliable tissue for assessing the cellular responses of HCs (Gonzalez-Maeso et al., Acute Behavioral Responses Induced by HCs 2003; Scruggs et al., 2000). We quantified the in vivo in- Behavioral animal models cannot capture the perturba- duction of 19 transcripts regulated by HCs and NHCs in tions of perception, cognition, and mood produced by htr2A+/+ and htr2AÀ/À mice (Tables S3 and S4). Each ago- HCs in humans. However, rodents might exhibit behav- nist elicited a differential and reproducible response. To ioral proxies of human hallucinogenic effects. Systemic assess the predictive value of these gene induction re- administration of HCs in rats and nonhuman primates sponses on behavior, we used principal components anal- elicits several unconditioned effects: changes in explor- ysis (PCA) to reduce a 19-dimensional signaling space atory behavior (Adams and Geyer, 1985a), grooming (reflected by gene transcripts) to two axes (Figure 1B). (Trulson and Howell, 1984), interruption of operant re- Plotted in this way, the transcriptome responses of HCs sponding (Mokler and Rech, 1984), head twitch response and NHCs predicted their behavioral effects in htr2A+/+ (HTR), ear scratch response (ESR), and hyperthermia and htr2AÀ/À mice and their hallucinogenic potential in (Corne and Pickering, 1967; Darmani et al., 1990; Maj human (Figure 1B). We selected the most informative et al., 1977; Silva and Calil, 1975). signaling response markers for distinguishing 2AR activa- To identify a mouse model of acute hallucinogenic po- tion, as well as HC from NHC by statistical significance tential, we examined a variety of responses produced by (Tables S5 and S6). Regulation of c-fos tracked with ago- several HCs and NHCs (Figure S2). Among the behavioral nist activity at 2AR, and induction of egr-2 and egr-1 measures assayed, only two were elicited by HCs and most robustly predicted behavioral activity of HCs in not NHCs: the ESR and HTR. Other measures such as loco- mouse (Figure 1C and Tables S7 and S8). motion, rearing, grooming, and basal body temperature changes were inconsistently affected by HCs and NHCs Activation of Transcriptome Response in Neurons (Figure S2 and Tables S1 and S2 in the Supplemental Data). that Express 2AR The HTR and ESR were both dependent upon the pres- The effects of HCs and NHCs on transcriptome activation ence of 2AR signaling capacity, even at a high dose of DOI indicated that these compounds interact with 2AR to (Figure S2). However, the ESR was not elicited by every activate distinct signaling pathways. This interpretation HC and was not normally distributed among individual implies that the genes induced
Load more

Recommended publications
  • Dopamine D1 Rather Than D2 Receptor Agonists Disrupt Prepulse Inhibition of Startle in Mice
    Neuropsychopharmacology (2003) 28, 108–118 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 www.neuropsychopharmacology.org Dopamine D1 Rather than D2 Receptor Agonists Disrupt Prepulse Inhibition of Startle in Mice 1 2 ,2 Rebecca J Ralph-Williams , Virginia Lehmann-Masten and Mark A Geyer* 1 2 Alcohol and Drug Abuse Research Center, Harvard Medical School and McLean Hospital, Belmont, MA, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA Although substantial literature describes the modulation of prepulse inhibition (PPI) by dopamine (DA) in rats, few reports address the effects of dopaminergic manipulations on PPI in mice. We characterized the effects of subtype-specific DA agonists in the PPI paradigm to further delineate the specific influences of each DA receptor subtype on sensorimotor gating in mice. The mixed D1/D2 agonist apomorphine and the preferential D1-family agonists SKF82958 and dihydrexidine significantly disrupted PPI, with differing or no effects on startle. In contrast to findings in rats, the D2/D3 agonist quinpirole reduced startle but had no effect on PPI. Pergolide, which has affinity for D2/D3 and D1-like receptors, reduced both startle and PPI, but only at the higher, nonspecific doses. In addition, the D1-family receptor antagonist SCH23390 blocked the PPI-disruptive effects of apomorphine on PPI, but the D2-family receptor antagonist raclopride failed to alter the disruptive effect of apomorphine. These studies reveal potential species differences in the DA receptor modulation of PPI between rats and mice, where D1-family receptors may play a more prominent and independent role in the modulation of PPI in mice than in rats.
    [Show full text]
  • Dopamine: a Role in the Pathogenesis and Treatment of Hypertension
    Journal of Human Hypertension (2000) 14, Suppl 1, S47–S50 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh Dopamine: a role in the pathogenesis and treatment of hypertension MB Murphy Department of Pharmacology and Therapeutics, National University of Ireland, Cork, Ireland The catecholamine dopamine (DA), activates two dis- (largely nausea and orthostasis) have precluded wide tinct classes of DA-specific receptors in the cardio- use of D2 agonists. In contrast, the D1 selective agonist vascular system and kidney—each capable of influenc- fenoldopam has been licensed for the parenteral treat- ing systemic blood pressure. D1 receptors on vascular ment of severe hypertension. Apart from inducing sys- smooth muscle cells mediate vasodilation, while on temic vasodilation it induces a diuresis and natriuresis, renal tubular cells they modulate sodium excretion. D2 enhanced renal blood flow, and a small increment in receptors on pre-synaptic nerve terminals influence nor- glomerular filtration rate. Evidence is emerging that adrenaline release and, consequently, heart rate and abnormalities in DA production, or in signal transduc- vascular resistance. Activation of both, by low dose DA tion of the D1 receptor in renal proximal tubules, may lowers blood pressure. While DA also binds to alpha- result in salt retention and high blood pressure in some and beta-adrenoceptors, selective agonists at both DA humans and in several animal models of hypertension. receptor classes have been studied in the treatment of
    [Show full text]
  • TECHNISCHE UNIVERSITÄT MÜNCHEN Large Scale
    TECHNISCHE UNIVERSITÄT MÜNCHEN Lehrstuhl für Genomorientierte Bioinformatik Large Scale Knowledge Extraction from Biomedical Literature Based on Semantic Role Labeling Thorsten Barnickel Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzende: Univ.‐Prof. Dr. I. Antes Prüfer der Dissertation: 1. Univ.‐Prof. Dr. H.‐W. Mewes 2. Univ.‐Prof. Dr. R. Zimmer (Ludwig‐Maximilians‐Universität München) Die Dissertation wurde am 30. Juli bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 25. November 2009 angenommen. ACKNOWLEDGEMENTS First and foremost, I would like to express my deep gratitude to my promoter Dr. Volker Stümpflen. Without his continuing, stimulating encouragement and his excellent background in Enterprise technologies still being predominantly used in the IT-industry rather than in academic research, I would not have been able to finish my doctorate in the presented form. Facing the tremendous amount of data that was generated by gathering the positional information of millions of biomedical terms, I was close to cutting the project down to a notably smaller version compared to the text mining system presented in this thesis. Volkers knowledge on database servers and performance tuning significantly contributed to the development of a database schema finally being able to cope with the immense amount of data. I would also like to cordially thank Prof. Dr. Hans-Werner Mewes, head of the Institute for Bioinformatics and Systems Biology (IBIS), for giving me the opportunity to do my doctorate at his institute and for his friendly support and encouragement all along my time at IBIS.
    [Show full text]
  • Title Structure of the Human Histamine H1 Receptor Complex With
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Kyoto University Research Information Repository Structure of the human histamine H1 receptor complex with Title doxepin. Shimamura, Tatsuro; Shiroishi, Mitsunori; Weyand, Simone; Tsujimoto, Hirokazu; Winter, Graeme; Katritch, Vsevolod; Author(s) Abagyan, Ruben; Cherezov, Vadim; Liu, Wei; Han, Gye Won; Kobayashi, Takuya; Stevens, Raymond C; Iwata, So Citation Nature (2011), 475(7354): 65-70 Issue Date 2011-07-07 URL http://hdl.handle.net/2433/156845 © 2011 Nature Publishing Group, a division of Macmillan Right Publishers Limited. Type Journal Article Textversion author Kyoto University Title: Structure of the human histamine H1 receptor in complex with doxepin. Authors Tatsuro Shimamura 1,2,3*, Mitsunori Shiroishi 1,2,4*, Simone Weyand 1,5,6, Hirokazu Tsujimoto 1,2, Graeme Winter 6, Vsevolod Katritch7, Ruben Abagyan7, Vadim Cherezov3, Wei Liu3, Gye Won Han3, Takuya Kobayashi 1,2‡, Raymond C. Stevens3‡and So Iwata1,2,5,6,8‡ 1. Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. 2. Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-Ku, Kyoto 606-8501, Japan. 3. Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. 4. Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. 5. Division of Molecular Biosciences, Membrane Protein Crystallography Group, Imperial College, London SW7 2AZ, UK. 6. Diamond Light Source, Harwell Science and Innovation Campus, Chilton, Didcot, Oxfordshire OX11 0DE, UK.
    [Show full text]
  • Antagonism of Dopamine D2 Receptor/Я-Arrestin 2 Interaction Is a Common Property of Clinically Effective Antipsychotics
    Antagonism of dopamine D2 receptor/␤-arrestin 2 interaction is a common property of clinically effective antipsychotics Bernard Masri, Ali Salahpour, Michael Didriksen*, Valentina Ghisi, Jean-Martin Beaulieu†, Raul R. Gainetdinov‡, and Marc G. Caron§ Departments of Cell Biology, Medicine and Neurobiology, Duke University Medical Center, Durham, NC 27710 Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved July 8, 2008 (received for review April 10, 2008) Since the unexpected discovery of the antipsychotic activity of beit with different potency, on the dopamine (DA) system. It has chlorpromazine, a variety of therapeutic agents have been devel- been demonstrated that clinical efficacy of essentially all anti- oped for the treatment of schizophrenia. Despite differences in psychotic drugs (including traditional and newer antipsychotics) their activities at various neurotransmitter systems, all clinically is directly correlated with dopamine D2 receptor (D2R) binding effective antipsychotics share the ability to interact with D2 class affinity and their capacity to antagonize this receptor (5, 6). It dopamine receptors (D2R). D2R mediate their physiological effects is commonly believed that the D2R, which belongs to the G via both G protein-dependent and independent (␤-arrestin 2- protein-coupled receptor (GPCR) family, mediates the major dependent) signaling, but the role of these D2R-mediated signaling part of its signaling and functions by coupling to Gi/o proteins to events in the actions of antipsychotics remains unclear. We dem- negatively regulate cAMP production. Thus, studies aimed at onstrate here that while different classes of antipsychotics have assessing the efficacy of antipsychotics on D2R signaling have complex pharmacological profiles at G protein-dependent D2R classically been mainly concerned with measuring Gi/o-mediated long isoform (D2LR) signaling, they share the common property of inhibition of cAMP.
    [Show full text]
  • Repeated Quinpirole Treatment Increases Camp-Dependent Protein
    Neuropsychopharmacology (2004) 29, 1823–1830 & 2004 Nature Publishing Group All rights reserved 0893-133X/04 $30.00 www.neuropsychopharmacology.org Repeated Quinpirole Treatment Increases cAMP-Dependent Protein Kinase Activity and CREB Phosphorylation in Nucleus Accumbens and Reverses Quinpirole-Induced Sensorimotor Gating Deficits in Rats 1 1 3 ,1,2 Kerry E Culm , Natasha Lugo-Escobar , Bruce T Hope and Ronald P Hammer Jr* 1 2 Departments of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA; Neuroscience, Anatomy 3 and Psychiatry, Tufts University School of Medicine, Boston, MA, USA; Behavioral Neuroscience Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA Sensorimotor gating, which is severely disrupted in schizophrenic patients, can be measured by assessing prepulse inhibition of the acoustic startle response (PPI). Acute administration of D -like receptor agonists such as quinpirole reduces PPI, but tolerance occurs 2 upon repeated administration. In the present study, PPI in rats was reduced by acute quinpirole (0.1 mg/kg, s.c.), but not following repeated quinpirole treatment once daily for 28 days. Repeated quinpirole treatment did not alter the levels of basal-, forskolin- (5 mM), or SKF 82958- (10 mM) stimulated adenylate cyclase activity in the nucleus accumbens (NAc), but significantly increased cAMP- dependent protein kinase (PKA) activity. Phosphorylation of cAMP response element-binding protein (CREB) was significantly greater in the NAc after repeated quinpirole treatment than after repeated saline treatment with or without acute quinpirole challenge. Activation of PKA by intra-accumbens infusion of the cAMP analog, Sp-cAMPS, prevented acute quinpirole-induced PPI disruption, similar to the behavioral effect observed following repeated quinpirole treatment.
    [Show full text]
  • Repeated Administration of Aripiprazole Produces A
    University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Faculty Publications, Department of Psychology Psychology, Department of 2015 Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor- mediated behavioral function Jun Gao University of Nebraska–Lincoln Rongyin Qin University of Nebraska–Lincoln Ming Li University of Nebraska-Lincoln, [email protected] Follow this and additional works at: http://digitalcommons.unl.edu/psychfacpub Part of the Applied Behavior Analysis Commons, Experimental Analysis of Behavior Commons, and the Health Psychology Commons Gao, Jun; Qin, Rongyin; and Li, Ming, "Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function" (2015). Faculty Publications, Department of Psychology. 681. http://digitalcommons.unl.edu/psychfacpub/681 This Article is brought to you for free and open access by the Psychology, Department of at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Faculty Publications, Department of Psychology by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Published in Journal of Psychopharmacology 29:4 (2015), pp. 390–400; doi: 10.1177/0269881114565937 Copyright © 2014 Jun Gao, Rongyin Qin, and Ming Li. Published by SAGE Publications. Used by permission. digitalcommons.unl.edudigitalcommons.unl.edu Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function Jun Gao,1 Rongyin Qin,1,2,3 and Ming Li1 1 Department of Psychology, University of Nebraska–Lincoln, Lincoln, NE, USA 2 Department of Neurology, The Clinical Medical College of Yangzhou University, Yangzhou, PR China 3 Department of Neurology, Changzhou No.
    [Show full text]
  • GPCR/G Protein
    Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com GPCR/G Protein G Protein Coupled Receptors (GPCRs) perceive many extracellular signals and transduce them to heterotrimeric G proteins, which further transduce these signals intracellular to appropriate downstream effectors and thereby play an important role in various signaling pathways. G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a GPCR. Upon receptor stimulation by a ligand, G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. These effects include activating the MAPK and PI3K pathways, as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels. Most human GPCRs can be grouped into five main families named; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin, forming the GRAFS classification system. A series of studies showed that aberrant GPCR Signaling including those for GPCR-PCa, PSGR2, CaSR, GPR30, and GPR39 are associated with tumorigenesis or metastasis, thus interfering with these receptors and their downstream targets might provide an opportunity for the development of new strategies for cancer diagnosis, prevention and treatment. At present, modulators of GPCRs form a key area for the pharmaceutical industry, representing approximately 27% of all FDA-approved drugs. References: [1] Moreira IS. Biochim Biophys Acta. 2014 Jan;1840(1):16-33.
    [Show full text]
  • Natural Psychoplastogens As Antidepressant Agents
    molecules Review Natural Psychoplastogens As Antidepressant Agents Jakub Benko 1,2,* and Stanislava Vranková 1 1 Center of Experimental Medicine, Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia; [email protected] 2 Faculty of Medicine, Comenius University, 813 72 Bratislava, Slovakia * Correspondence: [email protected]; Tel.: +421-948-437-895 Academic Editor: Olga Pecháˇnová Received: 31 December 2019; Accepted: 2 March 2020; Published: 5 March 2020 Abstract: Increasing prevalence and burden of major depressive disorder presents an unavoidable problem for psychiatry. Existing antidepressants exert their effect only after several weeks of continuous treatment. In addition, their serious side effects and ineffectiveness in one-third of patients call for urgent action. Recent advances have given rise to the concept of psychoplastogens. These compounds are capable of fast structural and functional rearrangement of neural networks by targeting mechanisms previously implicated in the development of depression. Furthermore, evidence shows that they exert a potent acute and long-term positive effects, reaching beyond the treatment of psychiatric diseases. Several of them are naturally occurring compounds, such as psilocybin, N,N-dimethyltryptamine, and 7,8-dihydroxyflavone. Their pharmacology and effects in animal and human studies were discussed in this article. Keywords: depression; antidepressants; psychoplastogens; psychedelics; flavonoids 1. Introduction 1.1. Depression Depression is the most common and debilitating mental disease. Its prevalence and burden have been steadily rising in the past decades. For example, in 1990, the World Health Organization (WHO) projected that depression would increase from 4th to 2nd most frequent cause of world-wide disability by 2020 [1].
    [Show full text]
  • Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor
    pharmaceuticals Review Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor Qing Wang 1,2 , Yu Zhou 2 , Jianhui Huang 1 and Niu Huang 2,3,* 1 School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China; [email protected] (Q.W.); [email protected] (J.H.) 2 National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China; [email protected] 3 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China * Correspondence: [email protected]; Tel.: +86-10-80720645 Abstract: Since the first characterization of the 5-hydroxytryptamine 2B receptor (5-HT2BR) in 1992, significant progress has been made in 5-HT2BR research. Herein, we summarize the biological function, structure, and small-molecule pharmaceutical ligands of the 5-HT2BR. Emerging evidence has suggested that the 5-HT2BR is implicated in the regulation of the cardiovascular system, fibrosis disorders, cancer, the gastrointestinal (GI) tract, and the nervous system. Eight crystal complex structures of the 5-HT2BR bound with different ligands provided great insights into ligand recognition, activation mechanism, and biased signaling. Numerous 5-HT2BR antagonists have been discovered and developed, and several of them have advanced to clinical trials. It is expected that the novel 5-HT2BR antagonists with high potency and selectivity will lead to the development of first-in-class drugs in various therapeutic areas. Keywords: GPCR; 5-HT2BR; biased signaling; agonist; antagonist Citation: Wang, Q.; Zhou, Y.; Huang, J.; Huang, N. Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor. 1. Introduction Pharmaceuticals 2021, 14, 76.
    [Show full text]
  • A Double-Blind Placebo-Controlled Study of Fluvoxamine and Imipramine in Out-Patients with Primary Depression T.M
    Br. J. clin. Pharmac. (1983), 15, 433S-438S A DOUBLE-BLIND PLACEBO-CONTROLLED STUDY OF FLUVOXAMINE AND IMIPRAMINE IN OUT-PATIENTS WITH PRIMARY DEPRESSION T.M. ITIL, R.K. SHRIVASTAVA, S. MUKHERJEE, B.S. COLEMAN' & S.T. MICHAEL New York Institute for Research into Contemporary Medicine, Tarrytown, N.Y., affiliated with the Department of Psychiatry, New York Medical College, Valhalla, N.Y. and 'Kali-Duphar Laboratories, Inc., Columbus, Ohio 43229, U.S.A. 1 A double-blind placebo-controlled study of fluvoxamine and imipramine was performed in a group of depressed patients. Twenty-two patients received fluvoxamine (mean dose 101 mg/day), 25 received imipramine (mean dose 127 mg/day) and 22 received placebo. 2 Apart from an increase in the SGOT and SGPT values offour imipramine patients, no statistically significant changes in haematology or urinalysis were judged to be medically relevant. Fluvoxamine exhibited fewer anticholinergic side effects than imipramine. 3 Both fluvoxamine treated patients and imipramine-treated patients exhibited a statistically sig- nificant improvement at the end ofthe 28-day treatment period with respect to the placebo patients, as measured using the Hamilton Rating Scale for Depression, and the Clinical Global Impression Scale. Evaluations ofthe results of the Beck Depression Inventory and the Profile ofMood States revealed a statistically significant improvement for imipramine patients with respect to placebo at week 4, but not for fluvoxamine patients. It is postulated on the basis of quantitative pharmaco-EEG findings, that the slight superiority of imipramine over fluvoxamine was due to underdosing of the latter. Introduction Despite the development of a series of new anti- study in human volunteers (Menon & Vijvers, 1974) depressants, there is still a need to develop an anti- confirmed the absence of anticholinergic effects.
    [Show full text]
  • Mypgx Abstract Booklet
    MyPGx® Abstract booklet July 2018 Version number: 003 Content I. General information abstracts – Pharmacogenetics (PGx), single nucleotide polymorphisms (SNPs) and adverse drug reactions (ADRs) 2 II. Psychiatry - MyPSY 10 III. Rheumatology - MyRHUMA 14 IV. Neuology – MyNEURO 16 V. Oncology – MyONCO 18 VI. Cardiology– MyCARDIO 21 VII. APPENDIX 1: U.S.Food & Drug administration (FDA) PGx Biomarker in drug labelling 26 VIII. APPENDIX 2: Genetic biomarkers associated with inter-individual differences in drug pharmacokinetic or pharmacodynamics parameters 42 © 2018 SYNLAB International GmbH. All rights reserved. MyPGx® is a registered trade mark of SYNLAB International GmbH. 1 I. General information abstracts – Pharmacogenetics (PGx), single nucleotide polymorphisms (SNPs) and adverse drug reactions (ADRs) A Survey on Polypharmacy and Use of Inappropriate Medications Rambhade, S., Chakarborty, A., Shrivastava, A., Patil, U. K., & Rambhade, A. (2012). A survey on polypharmacy and use of inappropriate medications. Toxicology international, 19(1), 68. In the past, polypharmacy was referred to the mixing of many drugs in one prescription. Today polypharmacy implies to the prescription of too many medications for an individual patient, with an associated higher risk of adverse drug reactions (ADRs) and interactions. Situations certainly exist where the combination therapy or polytherapy is the used for single disease condition. Polypharmacy is a problem of substantial importance, in terms of both direct medication costs and indirect medication costs resulting from drug-related morbidity. Polypharmacy increases the risk of side effects and interactions. Moreover it is a preventable problem. A retrospective study was carried out at Bhopal district (Capital of Madhya Pradesh, India) in the year of September-November 2009 by collecting prescriptions of consultants at various levels of health care.
    [Show full text]