Heads of Laboratories
Senior Attending Physician
Patrick E. and Beatrice M. Haggerty Professor
Laboratory of the Biology of Addictive Diseases
An estimated 25 to 33 percent of people who take a short-acting opiate drug such as heroin develop an addiction to it. This suggests some people are naturally more vulnerable to addiction than others, and that genetics may play a role in the condition. Mary Jeanne Kreek investigates how specific genetic factors, as well as drug-induced molecular neurobiological alterations, factor into addictive diseases such as opiate, cocaine, alcohol, nicotine, and marijuana addictions.
Kreek investigates the biological basis of addictive diseases as well as existing and novel treatments for these conditions. Her lab also researches the medical complications of drug abuse, such as hepatitis C and AIDS. In 1984, her group discovered that the second most common risk group for HIV-1/AIDS is parenteral drug users.
Kreek’s research focuses on the endogenous opioid system, which modulates stress, pain, and reward, and the roles that specific opioid peptides and their receptors play in normal and abnormal circumstances. Heroin and morphine, as well as cocaine and alcohol, activate these different opiate receptors either directly or indirectly. Kreek and her colleagues are examining gene expression changes in rodents that are given a drug of abuse, or are allowed to self-administer it, to study how this exposure impacts the brain’s neurochemistry, neurobiology, and circuitry, and to identify targets for potential new treatments. The lab also studies the epigenetic, physiologic, and behavioral effects of drug self-administration on the endogenous opioid system and related signaling networks. They perform microdialysis in rats and mice for dynamic studies of neurotransmitter release and peptide processing in the brain.
The lab studies the roles of the μ and κ opioid receptor systems and the CRF/CRFR1 and vasopressin/V1b receptor systems in “binge”-like alcohol drinking models using rats and inbred strains, and genetically modified mice. Additionally, since illicit oxycodone use in adolescence has become a major public health problem, the lab is investigating behavioral and neurobiological changes in adolescent versus adult mice during and after self-administration of oxycodone. The researchers are also working on the synthesis and study of new chemicals, primarily κ opioid receptor ligands, which could become new treatments for specific addictive diseases and co-occurring depression.
Kreek’s team is also conducting clinical studies in cocaine- and alcohol-addicted people, and in former heroin addicts in treatment with long-term methadone or buprenorphine-naloxone, focusing on the neurobiology components of these addictive diseases. In these studies, gene polymorphisms that may play a role in addiction, or genes that may alter responses to medications (pharmacogenetics) and affect normal physiology (physiogenetics), are identified. For example, Kreek identified and characterized a functional single-nucleotide polymorphism (A118G) in the μ opioid receptor that increases vulnerability to developing opioid and alcohol addictions and significantly alters stress responsiveness in healthy humans; a mouse model of this variant is currently used in studies.
Kreek is well known for her pioneering 1960s work developing methadone maintenance therapy for heroin addiction. The therapy has been documented to be the most effective treatment for any addiction, and is now commonly used to treat opiate addiction throughout the world, with 1.4 million people in daily treatment. Kreek was also one of the first to document, in 1985, that drugs of abuse significantly alter the expression of specific genes in certain brain regions, resulting in neurochemical and behavioral changes.
Columbia University College of Physicians and Surgeons
Internship in medicine, 1962–1963
Assistant Residency in medicine, 1963–1964
New York Hospital
Attending Physician, 1971–
Clinical Assistant Professor, 1971–1977
Weill Cornell Medical College
Assistant Professor, 1967–1972
Senior Research Associate, 1972–1983
Associate Professor, 1983–1994
The Rockefeller University
Associate Physician, 1964–1972
Senior Physician, 1994–
The Rockefeller University Hospital
Betty Ford Award, 1996
Specific Recognition Award for Research in the Science of Addiction, Executive Office of the President, 1998
R. Brinkley Smithers Distinguished Scientist Award, 1999
Nathan B. Eddy Memorial Award, 1999
Lifetime Science Award, National Institute on Drug Abuse, 2014
Valenza, M. et al. Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats. Psychopharmacology (Berl.) 234, 2219–2231 (2017).
Zhou, Y. et al. Synergistic blockade of alcohol escalation drinking in mice by a combination of novel kappa opioid receptor agonist Mesyl Salvinorin B and naltrexone. Brain Res. 1662, 75–86 (2017).
Zhang, Y. et al. Adolescent oxycodone self administration alters subsequent oxycodone-induced conditioned place preference and anti-nociceptive effect in C57BL/6J mice in adulthood. Neuropharmacology 111, 314–322 (2016).
Levran, O. et al. Glutamatergic and GABAergic susceptibility loci for heroin and cocaine addiction in subjects of African and European ancestry. Prog. Neuropsychopharmacol. Biol. Psychiatry 64, 118–123 (2016).
Zhang, Y. et al. Mouse model of the OPRM1 (A118G) polymorphism: differential heroin self-administration behavior compared with wild-type mice. Neuropsychopharmacology 40, 1091–1100 (2015).