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: 301.451.6966
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: 301.443.0747
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.
|
|
|
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.
|
|
|
Karl Björk
Pre-Doc IRTA
telephone: 301.451.6964
karl.bjoerk@mail.nih.gov
Karl Björk is a graduate student in the NIH – Karolinska Graduate Partnership Program. He studies genetic variation at candidate gene loci in genetically selected preferring rat lines, and its role for gene expression and function. He has identified functional variants in the CRH, the GSTA4, and the beta-arrestin-2 genes, and linked these to gene expression levels.
|
|
|
Rose-Marie Karlsson, MSc
Pre-Doc IRTA
telephone: 301 .433.2674
rosie.karlsson@mail.nih.gov
Rose-Marie Karlsson is a graduate student in the NIH – Karolinska Graduate Partnership Program. She studies the role of several stress related neurotransmitter systems, with a current focus on glutamate, in modulating anxiety, stress, and alcohol-related behaviors using genetically modified mice. She is the liason for our lab in our collaboration on mouse models with the laboratory of Dr. Andrew Holmes at the NIAAA.
|
|
|
Lindsay Eisenberg
Post-Bacc IRTA
telephone: 301.496.8855
eisenbel@mail.nih.gov
Lindsay Eisenberg uses rodent models of alcohol dependence to investigate molecular targets for pharmacological treatments.
|
|
|
|
J. Elliott Robinson
Post-Bacc IRTA
telephone: 301.443.3754
robinsonjo@mail.nih,gov
Elliott Robinson is doing pre-clinical testing of possible pharmacotherapies for the treatment of alcoholism using rat models. His B.S. is in Biology from Georgetown University and he will be attending Georgetown University School of Medicine next year.
|
|
|
|
Derek Passer
Post-Bacc IRTA
telephone: 301.451.8923
derek.passer@nih.gov
|
|
|
Naz Moaddab
Special Volunteer
telephone: 301.443.3754
|
Selected Publications
ORIGINAL PAPERS
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; 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; 63(2): 139-45. PDF
Kakko J, von WJ, 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; 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;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: April 2008