Laboratory on the Biology of Addictive Diseases
Mary Jeanne Kreek
Laboratory of the Biology of Addictive Diseases
The primary goal of our laboratory is to elucidate the biological basis of three addictive diseases: opiate addiction, cocaine dependency, and alcoholism. Related goals are to determine the biological correlates of addictive diseases and existing or novel treatments thereof, and to expand information concerning the major medical complications of drug abuse, primarily hepatitis B, C, and delta, tuberculosis, and AIDS. Our basic laboratory and clinical studies are focused on determining the role of the endogenous opioid system in addictive diseases and the roles of various specific opioid peptides and receptors in the normal and abnormal physiology of the neuroendocrine, immune, and gastrointestinal systems.
Laboratory work currently includes studies of the molecular biology, cell biology, neurobiology, chemistry, and biochemistry of the endogenous opioid system and the physiological and behavioral effects of the endogenous opioid peptides and related neuropeptides in rats, mice and guinea pigs under basal conditions, and after acute and chronic administration of a drug of abuse or a potential treatment agent. A major effort is focused upon determining the effects of cocaine on the endogenous opioid system and the relevant interrelationships of the dopaminergic, serotonergic, and noradrenergic systems. The technique of solution hybridization protection assays, modified to enhance precision and sensitivity, is used to measure gene expression (mRNA levels) of opioid peptides, opioid receptors, and related neuropeptides, transporters, and receptors in specific brain regions, as well as in specific endocrine and gastrointestinal regions. Levels of specific opioid peptides derived from initial peptide gene products, proenkephalin, prodynorphin, and proopioimelanocortin, are also determined. New techniques using laser desorption mass spectrometry for studies of neuropeptide processing are under development in a collaborative effort with the Chait laboratory, with emphasis at this time on dynorphin biotransformations. Relative densities and affinity of specific opioid receptor subtypes are measured by quantitative autoradiography and in vitro binding techniques. Microdialysis is used for dynamic studies of neurotransmitter release and peptide processing in specific brain regions. Continuous behavioral measurements under controlled conditions are also made in rats and transgenic "knockout" mice.
Clinical research studies of neuroendocrine-neurotransmitter function and the effects of selected neuropeptides in cocaine addicts, heroin addicts, former addicts in methadone maintenance or other treatment, and in alcoholics are in progress. Effects of specific natural opioid peptides and neuroendocrine function are in progress. The possible role of abnormal responsivity to stress in initiation, perpetuation, and relapse to cocaine and opiate addiction and alcoholism is under study, with emphasis on elucidating the role of the endogenous opioid system in such responses.