DOCSLIB.ORG

From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia J

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia J REVIEW The Neuropsychopharmacology of Phencyclidine: From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia J. David Jentsch, Ph.D., and Robert H. Roth, Ph.D. Administration of noncompetitive NMDA/glutamate effects of these drugs are discussed, especially with regard to receptor antagonists, such as phencyclidine (PCP) and differing profiles following single-dose and long-term ketamine, to humans induces a broad range of exposure. The neurochemical effects of NMDA receptor schizophrenic-like symptomatology, findings that have antagonist administration are argued to support a contributed to a hypoglutamatergic hypothesis of neurobiological hypothesis of schizophrenia, which includes schizophrenia. Moreover, a history of experimental pathophysiology within several neurotransmitter systems, investigations of the effects of these drugs in animals manifested in behavioral pathology. Future directions for suggests that NMDA receptor antagonists may model some the application of NMDA receptor antagonist models of behavioral symptoms of schizophrenia in nonhuman schizophrenia to preclinical and pathophysiological research subjects. In this review, the usefulness of PCP are offered. [Neuropsychopharmacology 20:201–225, administration as a potential animal model of schizophrenia 1999] © 1999 American College of is considered. To support the contention that NMDA Neuropsychopharmacology. Published by Elsevier receptor antagonist administration represents a viable Science Inc. model of schizophrenia, the behavioral and neurobiological KEY WORDS: Ketamine; Phencyclidine; Psychotomimetic; widely from the administration of purportedly psychot- Memory; Catecholamine; Schizophrenia; Prefrontal cortex; omimetic drugs (Snyder 1988; Javitt and Zukin 1991; Cognition; Dopamine; Glutamate Jentsch et al. 1998a), to perinatal insults (Lipska et al. Biological psychiatric research has seen the develop- 1993; El-Khodor and Boksa 1997; Moore and Grace ment of many putative animal models of schizophrenia. 1997; Bertolino et al. 1997), to chronic social isolation or The etiological bases of these models have varied stress (Jones et al. 1990), and beyond. The administra- tion of psychotomimetic drugs to humans and animals represents probably the most widely accepted and uti- lized class of schizophrenia models. These “pharmaco- From the Neuropsychopharmacology Research Unit (JDJ, RHR), logical” models seem to represent methods for the in- Section of Neurobiology (JDJ), and Departments of Psychiatry (RHR) duction of psychopathology in humans and aberrant and Pharmacology (RHR), Yale University School of Medicine, New Haven, Connecticut. (potentially related) behavior in animals. Address correspondence to: Dr. J. David Jentsch, Section of Neu- At the behavioral level, there seems to be some heter- robiology, Yale University School of Medicine, P.O. Box 208001, ogeneity in the effects of different psychotomimetic New Haven, Connecticut 06520-8001. Received 25 March 1998; revised 22 May 1998; accepted 13 June drug classes. The psychomotor stimulants, such as am- 1998. phetamine and cocaine, can clearly induce a form of NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3 © 1999 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(98)00060-8 202 J.D. Jentsch and R.H. Roth NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3 paranoid psychosis in human subjects after high-dose because of the overtly neurotoxic effects of this drug as or long-term administration, but evidence regarding determined by studies in rodents (Olney et al. 1989; the ability of these agents to induce “deficit” state 1991; Olney and Farber 1995). Nevertheless, scientists symptoms is conflicting (Angrist and Gershon 1970; have recently utilized a PCP congener, ketamine, to Everitt et al., 1997); moreover, there is evidence that am- produce a model of psychosis in humans. This drug, phetamine may actually alleviate negative and cognitive which (like PCP) noncompetitively blocks NMDA re- symptoms in schizophrenic patients (Angrist et al. 1982; ceptors, also simulates schizophrenic psychopathology Goldberg et al. 1991; Carter et al. 1997). Psychotomi- in normal humans (Krystal et al. 1994; Malhotra et al. metic indoleamines, such as lysergic acid diethylamide, 1996) and exacerbates symptoms in schizophrenic pa- can induce profound sensory hallucinations without tients (Lahti et al. 1994; Malhotra et al. 1997a). Although causing any apparent deficit state in normal subjects it seems that ketamine can induce many of the effects of (Geyer and Markou 1994) and without precipitating PCP in humans, it should be noted that ketamine is far symptomatology in schizophrenic patients (Cohen et al. less potent for inducing psychotomimetic reactions, es- 1962). In contrast, the noncompetitive antagonists of the pecially after chronic use (Rainey and Crowder 1974). N-methyl-D-aspartate (NMDA)/glutamate receptor, in- Several reports have demonstrated that competitive cluding phencyclidine (PCP) and ketamine, seem to be NMDA receptor antagonists are also psychotomimetic capable of inducing both positive and negative symp- in humans (Bunney et al. 1994; Grotta et al. 1995; Tam- toms of schizophrenia, including cognitive dysfunction minga 1998). in normal humans (Snyder 1980; Javitt and Zukin 1991; It is important to summarize the primary symptoms Tamminga 1998); these drugs also profoundly exacer- of schizophrenia that may be “modeled” in a drug- bate both positive and negative symptoms in schizo- treated individual. Many of the “positive” symptoms of phrenic patients (Itil et al. 1967; Lahti et al. 1994; Mal- schizophrenia, including paranoia, hallucinations, im- hotra et al. 1997a). pulsivity, formal thought disorder, delusions, and vio- Because of the more comprehensive psychopathol- lent behavior, are characteristic of psychotomimetic ogy induced by PCP, many researchers have studied drug-induced psychopathology (Angrist and Gershon the effects of NMDA receptor antagonists in humans 1970; Javitt and Zukin 1991; Ellison 1995), but PCP and animals to gain insights into the neurobiology of seems to be unique among psychostimulants because of schizophrenia. In this review, the validity of NMDA re- its ability to produce “negative” or deficit state symp- ceptor antagonist-induced models of schizophrenia in toms of schizophrenia, such as emotional lability and humans and animals are considered, and the applicabil- social withdrawal. In addition, PCP/ketamine adminis- ity of acute versus chronic administration of PCP as a tration can lead to profound cognitive dysfunction more precise model is assessed. The neurobiological (Luby et al. 1959; Cohen et al. 1962; Pearlson 1981; Javitt substrates of the observed behavioral effects in acute and Zukin 1991), including impaired performance of and chronic NMDA receptor antagonist models are re- the Wisconsin Card Sort and continuous performance viewed. Finally, new directions for use of PCP/ket- vigilance tasks and deficits in delayed recall, free recall, amine administration as a model of schizophrenia are recognition memory, and verbal fluency (Krystal et al. offered. 1994; Malhotra et al. 1996). Many of these deficits impli- cate frontal lobe dysfunction (Krystal et al. 1994), which is critical for the validity of a PCP model of schizophre- nia, because frontal cortical deficits are clearly a compo- BASIS OF THE PCP/KETAMINE MODELS OF nent of the schizophrenic disease process (Fey 1951; SCHIZOPHRENIA IN HUMANS Robbins 1990; Goldman-Rakic 1991; Weinberger and Berman 1996; Goldman-Rakic and Selemon 1997). Nearly 40 years ago, it was first reported that acute ad- Although the initial observations of NMDA receptor ministration of the noncompetitive NMDA-sensitive antagonist-induced psychosis were made in humans in glutamate receptor antagonist PCP to normal humans small, controlled studies of the effects of single-dose ex- induced a psychopathology with “impressive similarity posure, PCP became a popular drug-of-abuse within [to] . certain primary symptoms of the schizophrenic certain subcultures by the early 1960s. In addition to the process” (Luby et al. 1959, p. 367). This finding has been “toxic psychosis” induced by single-dose administra- replicated over the intervening years (Davies and Beech tion, it has also been noted that repeated use of PCP by 1960; Cohen et al. 1962), and in addition, it has been humans induces a more persistent schizophrenic symp- found that PCP likewise exacerbates the primary symp- tomatology, including psychosis, hallucinations, flat- toms of chronic schizophrenic patients (Luby et al. 1959; tened affect, delusions, formal thought disorder, cogni- Itil et al. 1967). tive dysfunction, and social withdrawal (Rainey and Controlled studies of the effects of PCP in normal Crowder 1975; Allen and Young 1978; Pearlson 1981; and schizophrenic humans are now prohibited, in part, Javitt and Zukin 1991; Cosgrove and Newell 1991). NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3 NMDA Antagonist Models of Schizophrenia 203 DO ACUTE AND LONG-TERM PCP EXPOSURE social judgment, poor attention span and concentration, HAVE SIMILAR CONSEQUENCES? poor interpersonal relationships, and social maladjust- ment” (American Psychiatric Association 1989, p. 1217). An important question pertains to whether the differ- These findings provide support for the argument that ence between the behavioral and biological effects of long-term PCP abuse is
Load more

Recommended publications
  • INVESTIGATION of NATURAL PRODUCT SCAFFOLDS for the DEVELOPMENT of OPIOID RECEPTOR LIGANDS by Katherine M
    INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS By Katherine M. Prevatt-Smith Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. _________________________________ Chairperson: Dr. Thomas E. Prisinzano _________________________________ Dr. Brian S. J. Blagg _________________________________ Dr. Michael F. Rafferty _________________________________ Dr. Paul R. Hanson _________________________________ Dr. Susan M. Lunte Date Defended: July 18, 2012 The Dissertation Committee for Katherine M. Prevatt-Smith certifies that this is the approved version of the following dissertation: INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS _________________________________ Chairperson: Dr. Thomas E. Prisinzano Date approved: July 18, 2012 ii ABSTRACT Kappa opioid (KOP) receptors have been suggested as an alternative target to the mu opioid (MOP) receptor for the treatment of pain because KOP activation is associated with fewer negative side-effects (respiratory depression, constipation, tolerance, and dependence). The KOP receptor has also been implicated in several abuse-related effects in the central nervous system (CNS). KOP ligands have been investigated as pharmacotherapies for drug abuse; KOP agonists have been shown to modulate dopamine concentrations in the CNS as well as attenuate the self-administration of cocaine in a variety of species, and KOP antagonists have potential in the treatment of relapse. One drawback of current opioid ligand investigation is that many compounds are based on the morphine scaffold and thus have similar properties, both positive and negative, to the parent molecule. Thus there is increasing need to discover new chemical scaffolds with opioid receptor activity.
    [Show full text]
  • Emulated Clinical Trials from Longitudinal Real-World Data Efficiently Identify Candidates for Neurological Disease Modification
    medRxiv preprint doi: https://doi.org/10.1101/2020.08.11.20171447; this version posted November 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Emulated Clinical Trials from Longitudinal Real-World Data Efficiently Identify Candidates for Neurological Disease Modification: Examples from Parkinson's Disease Daphna Laifenfeld, PhD1,a,†, Chen Yanover, PhD2,b,†, Michal Ozery-Flato, PhD3,†, Oded Shaham, PhD2,c, Michal Rozen-Zvi, PhD3,4,*, Nirit Lev, MD/PhD1,d,‡ , Yaara Goldschmidt, PhD2,e,‡, Iris Grossman, PhD1,f,‡ 1Formerly Teva Pharmaceuticals Research & Development, Petach Tikva, Israel; 2Formerly IBM Research – Haifa, Israel; 3IBM Research – Haifa, Israel; 4Faculty of Medicine, The HeBrew University, Jerusalem, Israel; aPresent Address: Ibex Medical Analytics, Tel Aviv, Israel; bPresent Address: KI Research Institute, Kfar Malal, Israel; cPresent Address: MeMed Dx, Haifa, Israel; dPresent Address: Meir Medical Center and Sackler Faculty of Medicine Tel Aviv University, Tel Aviv, Israel; ePresent Address: K Health, Tel Aviv, Israel; fPresent Address: Gross Advantage, Brookline, MA, USA; † These authors contriButed equally and share first authorship. ‡ These authors contriButed equally to this work. * Corresponding author: Michal Rosen-Zvi [email protected] Haifa University Campus, Mount Carmel Haifa, 3498825, Israel Tel: (972) 04-8296517 Keywords: Real World Data; Clinical Evidence; Parkinson’s disease; Artificial Intelligence; Causal Inference; Rasagiline; Zolpidem; Disease Modifying Therapeutics; Repurposing. NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
    [Show full text]
  • A Guide to Glutamate Receptors
    A guide to glutamate receptors 1 Contents Glutamate receptors . 4 Ionotropic glutamate receptors . 4 - Structure ........................................................................................................... 4 - Function ............................................................................................................ 5 - AMPA receptors ................................................................................................. 6 - NMDA receptors ................................................................................................. 6 - Kainate receptors ............................................................................................... 6 Metabotropic glutamate receptors . 8 - Structure ........................................................................................................... 8 - Function ............................................................................................................ 9 - Group I: mGlu1 and mGlu5. .9 - Group II: mGlu2 and mGlu3 ................................................................................. 10 - Group III: mGlu4, mGlu6, mGlu7 and mGlu8 ............................................................ 10 Protocols and webinars . 11 - Protocols ......................................................................................................... 11 - Webinars ......................................................................................................... 12 References and further reading . 13 Excitatory synapse pathway
    [Show full text]
  • Hallucinogens - LSD, Peyote, Psilocybin, and PCP
    Information for Behavioral Health Providers in Primary Care Hallucinogens - LSD, Peyote, Psilocybin, and PCP What are Hallucinogens? Hallucinogenic compounds found in some plants and mushrooms (or their extracts) have been used— mostly during religious rituals—for centuries. Almost all hallucinogens contain nitrogen and are classified as alkaloids. Many hallucinogens have chemical structures similar to those of natural neurotransmitters (e.g., acetylcholine-, serotonin-, or catecholamine-like). While the exact mechanisms by which hallucinogens exert their effects remain unclear, research suggests that these drugs work, at least partially, by temporarily interfering with neurotransmitter action or by binding to their receptor sites. This InfoFacts will discuss four common types of hallucinogens: LSD (d-lysergic acid diethylamide) is one of the most potent mood-changing chemicals. It was discovered in 1938 and is manufactured from lysergic acid, which is found in ergot, a fungus that grows on rye and other grains. Peyote is a small, spineless cactus in which the principal active ingredient is mescaline. This plant has been used by natives in northern Mexico and the southwestern United States as a part of religious ceremonies. Mescaline can also be produced through chemical synthesis. Psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine) is obtained from certain types of mushrooms that are indigenous to tropical and subtropical regions of South America, Mexico, and the United States. These mushrooms typically contain less than 0.5 percent psilocybin plus trace amounts of psilocin, another hallucinogenic substance. PCP (phencyclidine) was developed in the 1950s as an intravenous anesthetic. Its use has since been discontinued due to serious adverse effects. How Are Hallucinogens Abused? The very same characteristics that led to the incorporation of hallucinogens into ritualistic or spiritual traditions have also led to their propagation as drugs of abuse.
    [Show full text]
  • Profil D'effets Indésirables Des Antagonistes R-NMDA
    Profil d’effets indésirables des antagonistes R-NMDA : analyse de clusters des signaux de disproportionnalité extraits de Vigibase® Nhan-Taï Pierre Ly To cite this version: Nhan-Taï Pierre Ly. Profil d’effets indésirables des antagonistes R-NMDA : analyse de clusters des signaux de disproportionnalité extraits de Vigibase®. Sciences pharmaceutiques. 2019. dumas- 03039996 HAL Id: dumas-03039996 https://dumas.ccsd.cnrs.fr/dumas-03039996 Submitted on 4 Dec 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. AVERTISSEMENT Ce document est le fruit d'un long travail approuvé par le jury de soutenance et mis à disposition de l'ensemble de la communauté universitaire élargie. Il n’a pas été réévalué depuis la date de soutenance. Il est soumis à la propriété intellectuelle de l'auteur. Ceci implique une obligation de citation et de référencement lors de l’utilisation de ce document. D’autre part, toute contrefaçon, plagiat, reproduction illicite encourt une poursuite pénale. Contact au SID de Grenoble : [email protected] LIENS LIENS Code
    [Show full text]
  • Cerebellar Toxicity of Phencyclidine
    The Journal of Neuroscience, March 1995, 75(3): 2097-2108 Cerebellar Toxicity of Phencyclidine Riitta N&kki, Jari Koistinaho, Frank Ft. Sharp, and Stephen M. Sagar Department of Neurology, University of California, and Veterans Affairs Medical Center, San Francisco, California 94121 Phencyclidine (PCP), clizocilpine maleate (MK801), and oth- Phencyclidine (PCP), dizocilpine maleate (MK801), and other er NMDA antagonists are toxic to neurons in the posterior NMDA receptor antagonistshave attracted increasing attention cingulate and retrosplenial cortex. To determine if addition- becauseof their therapeutic potential. These drugs have neuro- al neurons are damaged, the distribution of microglial ac- protective properties in animal studies of focal brain ischemia, tivation and 70 kDa heat shock protein (HSP70) induction where excitotoxicity is proposedto be an important mechanism was studied following the administration of PCP and of neuronal cell death (Dalkara et al., 1990; Martinez-Arizala et MK801 to rats. PCP (10-50 mg/kg) induced microglial ac- al., 1990). Moreover, NMDA antagonists decrease neuronal tivation and neuronal HSP70 mRNA and protein expression damage and dysfunction in other pathological conditions, in- in the posterior cingulate and retrosplenial cortex. In ad- cluding hypoglycemia (Nellgard and Wieloch, 1992) and pro- dition, coronal sections of the cerebellar vermis of PCP (50 longed seizures(Church and Lodge, 1990; Faingold et al., 1993). mg/kg) treated rats contained vertical stripes of activated However, NMDA antagonists are toxic to certain neuronal microglial in the molecular layer. In the sagittal plane, the populations in the brain. Olney et al. (1989) demonstratedthat microglial activation occurred in irregularly shaped patch- the noncompetitive NMDA antagonists,PCP, MK801, and ke- es, suggesting damage to Purkinje cells.
    [Show full text]
  • Interactions Between Nitrous Oxide and Tissue Plasminogen Activator in a Rat Model of Thromboembolic Stroke
    Interactions between Nitrous Oxide and Tissue Plasminogen Activator in a Rat Model of Thromboembolic Stroke Benoît Haelewyn, Ph.D.,* He´le` ne N. David, Ph.D.,† Nathalie Colloc’h, Ph.D., D.Sc.,‡ Denis G. Colomb, Jr., Ph.D.,§ Jean-Jacques Risso, Ph.D., D.Sc.,ʈ Jacques H. Abraini, Ph.D., D.Sc., Psy.D.# Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/115/5/1044/452771/0000542-201111000-00027.pdf by guest on 25 September 2021 ABSTRACT What We Already Know about This Topic • Whether nitrous oxide, like xenon, reduces of ischemic brain Background: Preclinical evidence in rodents has suggested damage in the setting of thrombolysis for thromboembolic that inert gases, such as xenon or nitrous oxide, may be prom- stroke is unknown. ising neuroprotective agents for treating acute ischemic stroke. This has led to many thinking that clinical trials could be initiated in the near future. However, a recent study has What This Article Tells Us That Is New shown that xenon interacts with tissue-type plasminogen ac- • In rats, when administrated during the ischemic period, nitrous tivator (tPA), a well-recognized approved therapy of acute oxide dose-dependently inhibited tPa-induced thrombolysis and subsequent reduction of ischemic brain damage. How- * Research Engineer and Head, Universite´ de Caen - Basse Nor- ever, in contrast to xenon, postischemic nitrous oxide in- mandie, Centre Universitaire de Ressources Biologiques, Caen, France. creased brain hemorrhage and barrier dysfunction. † Research Scientist, Universite´ Laval, Centre Hospitalier Universitaire Affilie´Hoˆtel-Dieu Le´vis, Le´vis, Que´bec, Canada; Universite´ Laval, Cen- tre de Recherche Universite´ Laval Robert-Giffard, Que´bec, Que´bec, Canada.
    [Show full text]
  • Interplay Between Gating and Block of Ligand-Gated Ion Channels
    brain sciences Review Interplay between Gating and Block of Ligand-Gated Ion Channels Matthew B. Phillips 1,2, Aparna Nigam 1 and Jon W. Johnson 1,2,* 1 Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA; [email protected] (M.B.P.); [email protected] (A.N.) 2 Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA * Correspondence: [email protected]; Tel.: +1-(412)-624-4295 Received: 27 October 2020; Accepted: 26 November 2020; Published: 1 December 2020 Abstract: Drugs that inhibit ion channel function by binding in the channel and preventing current flow, known as channel blockers, can be used as powerful tools for analysis of channel properties. Channel blockers are used to probe both the sophisticated structure and basic biophysical properties of ion channels. Gating, the mechanism that controls the opening and closing of ion channels, can be profoundly influenced by channel blocking drugs. Channel block and gating are reciprocally connected; gating controls access of channel blockers to their binding sites, and channel-blocking drugs can have profound and diverse effects on the rates of gating transitions and on the stability of channel open and closed states. This review synthesizes knowledge of the inherent intertwining of block and gating of excitatory ligand-gated ion channels, with a focus on the utility of channel blockers as analytic probes of ionotropic glutamate receptor channel function. Keywords: ligand-gated ion channel; channel block; channel gating; nicotinic acetylcholine receptor; ionotropic glutamate receptor; AMPA receptor; kainate receptor; NMDA receptor 1. Introduction Neuronal information processing depends on the distribution and properties of the ion channels found in neuronal membranes.
    [Show full text]
  • (NMDA) Receptor Encephalitis Is an Autoimmune Seizures and Autonomic Dysfunction
    Nonprofit Organization U.S. Postage PAID Twin Cities, MN VOLUME 23, NUMBER 4 200 University Ave. E. Permit No. 5388 St. Paul, MN 55101 651-291-2848 ADDRESSwww.gillettechildrens.org SERVICE REQUESTED VOLUME 23, NUMBER 4 2014 A Pediatric Perspective focuses on specialized topics in pediatrics, orthopedics, neurology, neurosurgery and rehabilitation medicine. Diagnosing and Treating Anti- KEY INSIGHTS To subscribe to or unsubscribe from A Pediatric Perspective, please send an email to [email protected]. N-Methyl-D-Aspartate (NMDA) ■ Anti-NMDA receptor encephalitis Editor-in-Chief – Steven Koop, M.D. is a relatively common and treatable Editor – Ellen Shriner Receptor Encephalitis cause of encephalitis in pediatric Designers – Becky Wright, Kim Goodness patients. Photographers – Anna Bittner, Amanda Moen, M.D., pediatric neurologist Paul DeMarchi ■ Common symptoms include person- Copyright 2014. Gillette Children’s Specialty ality change, abnormal movements, Amanda Moen, M.D. Healthcare. All rights reserved. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune seizures and autonomic dysfunction. condition in which the body produces antibodies that act against receptors in ■ If these symptoms are present, an the brain, resulting in both neurologic and psychiatric symptoms. Common urgent child neurology evaluation is symptoms include personality change, psychosis, abnormal movements, indicated and an evaluation for anti- To make a referral, call 651-325-2200 or seizures and autonomic dysfunction. The antibodies associated with this NMDA receptor encephalitis should Pediatric neurologist Amanda Moen, M.D., treats children 855-325-2200 (toll-free). condition were first identified in 2005, and since then it has become recognized be initiated. who have epilepsy and other neurological conditions.
    [Show full text]
  • From Sacred Plants to Psychotherapy
    From Sacred Plants to Psychotherapy: The History and Re-Emergence of Psychedelics in Medicine By Dr. Ben Sessa ‘The rejection of any source of evidence is always treason to that ultimate rationalism which urges forward science and philosophy alike’ - Alfred North Whitehead Introduction: What exactly is it that fascinates people about the psychedelic drugs? And how can we best define them? 1. Most psychiatrists will define psychedelics as those drugs that cause an acute confusional state. They bring about profound alterations in consciousness and may induce perceptual distortions as part of an organic psychosis. 2. Another definition for these substances may come from the cross-cultural dimension. In this context psychedelic drugs may be recognised as ceremonial religious tools, used by some non-Western cultures in order to communicate with the spiritual world. 3. For many lay people the psychedelic drugs are little more than illegal and dangerous drugs of abuse – addictive compounds, not to be distinguished from cocaine and heroin, which are only understood to be destructive - the cause of an individual, if not society’s, destruction. 4. But two final definitions for psychedelic drugs – and those that I would like the reader to have considered by the end of this article – is that the class of drugs defined as psychedelic, can be: a) Useful and safe medical treatments. Tools that as adjuncts to psychotherapy can be used to alleviate the symptoms and course of many mental illnesses, and 1 b) Vital research tools with which to better our understanding of the brain and the nature of consciousness. Classifying psychedelic drugs: 1,2 The drugs that are often described as the ‘classical’ psychedelics include LSD-25 (Lysergic Diethylamide), Mescaline (3,4,5- trimethoxyphenylathylamine), Psilocybin (4-hydroxy-N,N-dimethyltryptamine) and DMT (dimethyltryptamine).
    [Show full text]
  • United States Patent (19) 11 Patent Number: 5,902,815 Olney Et Al
    USOO5902815A United States Patent (19) 11 Patent Number: 5,902,815 Olney et al. (45) Date of Patent: May 11, 1999 54 USE OF 5HT2A SEROTONIN AGONISTS TO Hougaku, H. et al., “Therapeutic effect of lisuride maleate on PREVENT ADVERSE EFFECTS OF NMDA post-stroke depression” Nippon Ronen Igakkai ZaSShi 31: RECEPTOR HYPOFUNCTION 52-9 (1994) (abstract). Kehne, J.H. et al., “Preclinical Characterization of the Poten 75 Inventors: John W. Olney, Ladue; Nuri B. tial of the Putative Atypical Antipsychotic MDL 100,907 as Farber, University City, both of Mo. a Potent 5-HT2A Antagonist with a Favorable CNS Saftey Profile.” The Journal of Pharmacology and Experimental 73 Assignee: Washington University, St. Louis, Mo. Therapuetics 277: 968–981 (1996). Maurel-Remy, S. et al., “Blockade of phencyclidine-induced 21 Appl. No.: 08/709,222 hyperlocomotion by clozapine and MDL 100,907 in rats reflects antagonism of 5-HT2A receptors' European Jour 22 Filed: Sep. 3, 1996 nal of Pharmacology 280: R9–R11 (1995). 51) Int. Cl. ........................ A61K 31/445; A61K 31/54; Olney, J.W., et al., “NMDAantagonist neurotoxicity: Mecha A61K 31/135 nism and prevention,” Science 254: 1515–1518 (1991). 52 U.S. Cl. .......................... 514/285; 514/315; 514/318; Olney, J.W., et al., “Glutamate receptor dysfunction and 514/646 schizophrenia.” Arch. Gen. Psychiatry 52:998-1007 (1995). 58 Field of Search ............................. 514/285; 314/315, Pulvirenti, L. et al., “Dopamine receptor agonists, partial 314/318, 646 agonists and psychostimulant addiction' Trends Pharmacol Sci 15: 374-9 (1994). 56) References Cited Robles, R.G. et al., “Natriuretic Effects of Dopamine Agonist Drugs in Models of Reduced Renal Mass” Journal of U.S.
    [Show full text]
  • Inhibits Dyskinesia Expression and Normalizes Motor Activity in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Treated Primates
    The Journal of Neuroscience, October 8, 2003 • 23(27):9107–9115 • 9107 Behavioral/Systems/Cognitive 3,4-Methylenedioxymethamphetamine (Ecstasy) Inhibits Dyskinesia Expression and Normalizes Motor Activity in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Treated Primates Mahmoud M. Iravani, Michael J. Jackson, Mikko Kuoppama¨ki, Lance A. Smith, and Peter Jenner Neurodegenerative Disease Research Centre, Guy’s, King’s, and St. Thomas’ School of Biomedical Sciences, King’s College, London SE1 1UL, United Kingdom Ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] was shown to prolong the action of L-3,4-dihydroxyphenylalanine (L-DOPA) while suppressing dyskinesia in a single patient with Parkinson’s disease (PD). The clinical basis of this effect of MDMA is unknown but may relate to its actions on either dopaminergic or serotoninergic systems in brain. In normal, drug-naive common marmosets, MDMA administration suppressed motor activity and exploratory behavior. In 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-treated, L-DOPA-primedcommonmarmosets,MDMAtransientlyrelievedmotordisability but over a period of 60 min worsened motor symptoms. When given in conjunction with L-DOPA, however, MDMA markedly decreased dyskinesia by reducing chorea and to a lesser extent dystonia and decreased locomotor activity to the level observed in normal animals. MDMA similarly alleviated dyskinesia induced by the selective dopamine D2/3 agonist pramipexole. The actions of MDMA appeared to be mediated through 5-HT mechanisms because its effects were fully blocked by the selective serotonin reuptake inhibitor fluvoxamine. Furthermore,theeffectofMDMAon L-DOPA-inducedmotoractivityanddyskinesiawaspartiallyinhibitedby5-HT1a/bantagonists.The ability of MDMA to inhibit dyskinesia results from its broad spectrum of action on 5-HT systems.
    [Show full text]