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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.