Markus Heilig, MD, PhD, Chief
Section of Molecular Pathophysiology, LCTS
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
10 Center Drive, Room 10-CRC/1E-5334: MSC 1108
Bethesda MD 20892-1108
telephone: 301.435.9386
e-mail: markus.heilig@mail.nih.gov
What we do
The MP section was created in 2004. We do the basic science that is aimed at discovering novel molecular targets for treatment of alcoholism. Once identified, these can feed into early human studies carried out by other components of the LCTS. The MP section focuses on long-term neuroadaptations in the central nervous system, and on stress-systems that mediate negative affective states in addiction. Although initial drug use is driven by rewarding drug effects, over time drugs lose their reward value. Instead negative affect and increased sensitivity to stress are experienced in the absence of drug, and compulsive drug use is mainatained by relief of negative affect.
Our discovery work typically starts out with rodent models of alcoholism and related behaviors, such as anxiety and stress responses. We use rat and mouse paradigms to model excessive voluntary alcohol intake and relapse to alcohol seeking triggered by stress. Various methods, such as e.g. DNA microarrays, are used to screen for differential gene expression within brain areas important for negative emotions and stress, in order to discover candidate treatment targets. These are confirmed through quantitative expression analysis and anatomical mapping using in situ hybridization, Real-Time PCR, protein analyses, receptor binding or receptor signaling analysis. The functional role of confirmed candidate targets is finally examined by going back to the animal models, and using pharmacological or molecular approaches to determine whether blocking or otherwise interfering with a confirmed candidate target will reduced excessive alcohol intake, or relapse-like behavior.
Current staff
|
|
Annika Thorsell, PhD
Staff Scientist
telephone: 301.451.6960
annika.thorsell@mail.nih.gov
Dr. Thorsell is responsible for the day-to-day management of our section. Starting out with a masters degree in biochemistry and molecular biology from Gothenburg University, Sweden, she obtained a PhD in experimental psychiatry at the Karolinska Institute in Stockholm . Following post-doctoral training at the Scripps Research Institute in La Jolla, CA, she joined the NIAAA in 2005. Her own research interests have been centered around neuropeptide Y (NPY) and Corticotropine-Releasing Hormone (CRH), and their role in stress-related neuroadaptations in alcoholism.
|
|
|
Erick Singley
Chemist
telephone: 301.496.4936
erick.singley@mail.nih.gov
Erick Singley is a chemist and runs our analytical core, which involves everything from measuring blood alcohol levels in humans as well as experimental animals, through HPLC analyses of monoamines and their metabolites in cerebrospinal fluid, to analyses of neuropeptides using immune-based methods. In addition, he is responsible for the maintenance of equipment, including property management and the procurement of equipment and supplies for LCTS.
|
|
|
Hui Sun, MD
Staff Scientist
telephone: 301.451.5059 hui.sun@mail.nih.gov
Dr. Sun runs a range of molecular methods in the laboratory, ranging from genotyping of human research subjects, non-human primate variants and mutant mice, through expression analysis using Real-Time PCR, reporter assays and other methods, to functional analysis such as expression of neurotransmitter receptor variants.
|
|
|
Robert Eskay, PhD
Research Physiologist
telephone: 301.496.4690
bob.eskay@mail.nih.gov
Dr. Eskay studies biochemical and neurotransmitter systems involved in alcohol-induced neurotoxicity, as well as neuroprotective mechanisms. He also has a long standing interest in brain neuropeptide systems and their role in alcohol-related mechanisms. In a collaboration with the NIHGR Center for Chemical Genomics, he is currently involved in efforts to develop ligands for a novel neuropeptide receptor that would enable our lab to evaluate this receptor as a candidate treatment target.
|
|
|
Ruslan Damadzic, MD
Research Fellow
telephone: 301.451.9472
ruslan.damadzic@mail.nih.gov
Dr. Damadzic works with the research team to better understand the consequences of excessive ethanol consumption on the brain, studies of stress, and alcoholism and alcohol related behaviors. His research efforts are focused on understanding the brain’s biological changes that lead to excessive alcohol consumption and the neurochemical changes that occur with alcohol dependence.
|
|
|
Melanie Schwandt, PhD
Research Fellow
telephone: 301.451.6960
melanie.schwandt@nih.gov
Dr. Schwandt came to NIH after receiving her PhD in physical anthropology with a focus on non-human primates studies from Arizona State University. She conducted research with rhesus macaques for several years at the NIH Animal Facility in Poolesville, MD, before coming to the section of Molecular Pathophysiology in 2008. In addition to continuing work with archived non-human primate data, she helps curate and manage the LCTS clinical databases. Her research interests include environmental and genetic influences on development, behavior, stress reactivity, and alcohol consumption.
|
|
|
Estelle Barbier, PhD
Visiting Fellow
telephone: 301.451.7605
estelle.barbier@nih.gov
Dr. Barbier joined LCTS in September 2008. She previously obtained her PhD in Neuroscience in a research group focusing on alcohol and dependence to drugs, the “Groupe de Recherche sur l’Alcool et les Pharmacodépendances” at Picardie Jules Verne University (France). Dr. Barbier currently studies the potential effect of ethanol exposure on DNA methylation and acetylation using a “post dependent” rat model.
|
|
|
Andrea Cippitelli, MD
Visiting Fellow
telephone: 301.443.3754
andrea.cippitelli@nih.gov
Dr. Cippitelli came to LCTS in 2006 from the laboratory of our long standing collaborator, Dr. Roberto Ciccocioppo at Camerino University . He studies how dependence interacts with stress to induce excessive alcohol self-administration and relapse-like behavior in rat models. His current focus is on several stress-related neuropeptides: CRH, NPY and nociceptin.
|
|
|
Jesse Schank, PhD
Post-Doc IRTA
telephone: 301.594.0633
jesse.schank@nih.gov
Dr. Schank’s work explores the role of neuropeptides in alcohol dependence and alcohol seeking behavior. Specific systems that are assessed include substance P/NK1 and endogenous opioids. Using preclinical animal models, he studies the way in which these systems influence the expression of behaviors induced by alcohol dependence, with the ultimate goal of contributing to the development of novel pharmacotherapies for alcoholism. To further explore the specific mechanisms involved in these treatments, Dr. Schank plans to study the interaction of these systems with monoamine neurotransmitters and neuropeptides involved in stress responses, such as CRH.
|
|
|
Michael Brunnquell
Post-Bacc IRTA
telephone: 301.443.0745
mike.brunnquell@nih.gov
Mike Brunnquell joined NIAAA in investigating the role of stress and the CRH system on alcohol seeking behavior. Currently he is assisting in in-situ and immuno-histochemistry work studying brain changes due to alcohol consumption and leading to alcohol dependence.
|
|
|
Logan Christensen
Post-Bacc IRTA
telephone: 301.451.6969
logan.christensen@nih.gov
Logan Cristensen works with Dr. Barbier studying the effects of alcohol dependence on epigenetic changes in the rat brain.
|
|
|
Kathryn Frankola
Post-Bacc IRTA
telephone: 301.443.3754
kate.frankola@nih,gov
Kate Frankola, like Andrea Goldstein, is currently assisting the post docs with rat behavior experiments involving the effects of various pharmacological compounds, targeting stress and reward systems, on alcohol-seeking behaviors. Recent behavior experiments evaluated the degree to which LY379268, an mGlu2/3 receptor agonist, diminished the degree of alcohol-induced memory impairments and anxiety.
|
|
|
|
Andrea Goldstein
Post-Bacc IRTA
telephone: 301.496.8855
andrea.goldstein@nih.gov
Andrea Goldstein, like Kate Frankola, is currently assisting the post docs with rat behavior experiments involving the effects of various pharmacological compounds, targeting stress and reward systems, on alcohol-seeking behaviors. Recent behavior experiments evaluated the degree to which LY379268, an mGlu2/3 receptor agonist, diminished the degree of alcohol-induced memory impairments and anxiety.
|
|
|
|
Derek Passer
Post-Bacc IRTA
telephone: 301.451.8923
derek.passer@nih.gov
|
Selected Publications
ORIGINAL PAPERS
Karlsson RM, Tanaka K, Heilig M, Holmes A. Loss of glial glutamate and aspartate transporter (excitatory amino acid transporter 1) causes locomotor hyperactivity and exaggerated responses to psychotomimetics: rescue by haloperidol and metabotropic glutamate 2/3 agonist. Biol Psychiat 2008, November; 64(9):810-4. PDF
Economidou D, Hansson AC, Weiss F, Terasmaa A, Sommer WH, Cippitelli A, Fedeli A, Martin-Fardon R, Massi M, Ciccocioppo R, Heilig M. Dysregulation of nociceptin/orphanin FQ activity in the amygdala is linked to excessive alcohol drinking in the rat. Biol Psychiat 2008, August 1; 64(3):211-8. PDF
Hansson AC, Rimondini R, Neznanova O, Sommer WH, Heilig M. Neuroplasticity in brain reward circuitry following a history of ethanol dependence. Eur J Neurosci. 2008, April 27; 27(8):1912-22. PDF
Barr CS, Schwandt ML, Lindell SG, Higley D, Maestripieri D, Goldman D, Suomi SJ, Heilig M. Variation at the Mu-Opioid Receptor Gene (OPRM1) Influences Attachment Behavior in Infant Primates. PNAS. 2008, April 1; 105(13):5277-81. PDF
Björk K, Rimondini R, Hansson AC, Terasmaa A, Hyytiä P, Heilig M, Sommer WH. Modulation of voluntary ethanol consumption by beta-arrestin 2. FASEB J. 2008, March 26; 22(7):2552-60. PDF
George DT, Gilman J, Hersh J, Thorsell A, Herion D, Geyer C, Peng X, Kielbasa W, Rawlings R, Brandt JE, Gehlert DR, Tauscher JT, Hunt SP, Hommer D, Heilig M. Neurokinin 1 Receptor Antagonism as a Possible Therapy for Alcoholism. Science. 2008, March 14; 319: 1536-39. PDF
Sommer WH, Rimondini R, Hansson AC, Hipskind PA, Gehlert DR, Barr CS, Heilig M. Upregulation of Voluntary Alcohol Intake, Behavioral Sensitivity to Stress, and Amygdala Crhr1 Expression Following a History of Dependence. Biol Psychiatry 2008, January 15; 63(2): 139-45. PDF
Kakko J, von Wachenfeldt J, Svanborg KD, Lidstrom J, Barr CS, Heilig M. Mood and neuroendocrine response to a chemical stressor, metyrapone, in buprenorphine-maintained heroin dependence. Biol Psychiatry 2008, January 15; 63(2):172-7. PDF
Karlsson RM, Choe JS, Cameron HA, Thorsell A, Crawley JN, Holmes A, Heilig M. The neuropeptide Y Y1 receptor subtype is necessary for the anxiolytic-like effects of neuropeptide Y, but not the antidepressant-like effects of fluoxetine, in mice. Psychopharmacology (Berl) 2008, January;195(4):547-57. PDF
Barr CS, Schwandt M, Lindell SG, Chen SA, Goldman D, Suomi SJ, Higley JD, Heilig M. Association of a functional polymorphism in the mu-opioid receptor gene with alcohol response and consumption in male rhesus macaques. Arch Gen Psychiatry 2007;64(3):369-76. PDF
Ciccocioppo R, Economidou D, Rimondini R, Sommer W, Massi M, Heilig M. Buprenorphine Reduces Alcohol Drinking Through Activation of the Nociceptin/Orphanin FQ-NOP Receptor System. Biol Psychiatry 2007;61(1):4-12. PDF
Gehlert DR, Cippitelli A, Thorsell A, Le AD, Hipskind PA, Hamdouchi C, Lu J, Hembre EJ, Cramer J, Song M, McKinzie D, Morin M, Ciccocioppo R, Heilig M. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl- imidazo[1,2-b]pyridazine: a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism. J Neurosci 2007;27(10):2718-26. PDF
Hansson AC, Bermudez-Silva FJ, Malinen H, Hyytia P, Sanchez-Vera I, Rimondini R, Rodriguez de FF, Kunos G, Sommer WH, Heilig M. Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference. Neuropsychopharmacology 2007;32(1):117-26. PDF
Kakko J, Gronbladh L, Svanborg KD, von Wachenfeldt J, Ruck C, Rawlings R, Nilsson LH, Heilig M. A stepped care strategy utilizing buprenorphine and methadone vs. conventional methadone maintenance in heroin dependence: A randomized controlled trial. Am J Psychiatry 2007;164(5):797-803. PDF
Sommer WH, Rimondini R, Marquitz M, Lidström J, Siems WE, Bader M, Heilig M. Plasticity and impact of the central renin-angiotensin system during development of ethanol dependence. J Mol Med 2007;85(10):1089-97. PDF
Thorsell A, Johnson J, Heilig M. Effect of the adenosine A2a receptor antagonist 3, 7-dimethyl-propargylxanthine on anxiety- and depression-like behavior and alcohol consumption in Wistar rats. Alcohol Clin Exp Res 2007;31(8):1302-7. PDF
Hansson AC, Cippitelli A, Sommer WH, Fedeli A, Bjork K, Soverchia L, Terasmaa A, Massi M, Heilig M, Ciccocioppo R. Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress. Proc Natl Acad Sci U S A 2006;103(41):15236-41. PDF
Rydmark I, Wahlberg K, Ghatan PH, Modell S, Nygren A, Ingvar M, Asberg M, Heilig M. Neuroendocrine, Cognitive and Structural Imaging Characteristics of Women on Longterm Sickleave with Job Stress-Induced Depression. Biol Psychiatry 2006;60(8):867-73. PDF
Bart G, Kreek MJ, Ott J, LaForge KS, Proudnikov D, Pollak L, Heilig M. Increased attributable risk related to a functional mu-opioid receptor gene polymorphism in association with alcohol dependence in central Sweden. Neuropsychopharmacology 2005;30(2):417-22. PDF
REVIEWS
Heilig M, Koob GF. A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci 2007;30(8):399-406. PDF
Heilig M, Egli M. Pharmacological treatment of alcohol dependence: Target symptoms and target mechanisms. Pharm Therap 2006;111(3):855-76. PDF
Thorsell A, Karlsson RM, Heilig M. NPY in alcoholism and psychiatric disorders. EXS 2006;(95):183-92. PDF
Heilig M, Thiele TE. Neuropeptide Y antagonists: a perspective. In: Spanagel R, Mann K, editors. Drugs for Relapse Prevention of Alcoholism.Basel: Birkhaüser; 2005. p. 189-205. PDF
Heilig M, Egli M. Models for alcohol dependence: A clinical perspective. Drug Discov Today: Dis Models 2005;2(4):313-8. PDF
Alcohol publications can also be found using the ETOH Database
FIND PUBLICATIONS USING PubMed
FIND ANNUAL REPORT PROJECTS USING NIDB Resources
SAMPLE Search Instructions: Under "Option 1" click box beside each "Year" of interest, then click "Free Text Search" - in BOX under "Enter some Keywords", type HEILIG M
NIH Research and Training Opportunities
Updated: March 2009