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Faculty
George Koob
COMMITTEE CHAIR
Committee On The Neurobiology Of Addictive Disorders
TSRI - 1983
Education
Pennsylvania State University, B.S., Zoology (1969); Johns Hopkins University, Ph.D., Behavioral Physiology (1972)
Awards & Activities
Phi Sigma Society; Alpha Zeta Fraternity; Outstanding Faculty Teaching Award, Revelle College, University of California, San Diego (1988); Outstanding Faculty Teaching Award, Muir College, University of California, San Diego (1989); Outstanding Faculty Teaching Award, Warren College, University of California, San Diego (1992, 1993, 1995); Commencement Speaker, Warren College, University of California, San Diego (1993); Boots Distinguished Neuroscientist, Louisiana State University Medical Center (1989); Grass Foundation Lecturer, Society for Neuroscience, Indianapolis Chapter (1990); Grass Foundation Lecturer, Society for Neuroscience, Central New York Chapter (1990); Grass Foundation Lecturer, Society for Neuroscience, South Carolina Chapter (1992); Grass Foundation Lecturer, Society for Neuroscience, West Virginia Chapter (1993); Grass Foundation Lecturer, Society for Neuroscience, Northern Rocky Mountain Chapter (1994); John C. Forbes Honors, School of Basic Health Sciences, Virginia Commonwealth University (1991); Daniel H. Efron Award, Excellence in Research in Neuropsychopharmacology, American College of Neuropsychopharmacology (1991); Wendy and Stanley March Endowed Lectureship, Texas Tech University Health Sciences Center, Amarillo (1999); Bowles Lectureship, Center for Alcohol Studies, University of North Carolina (2000); Jellinek Lectureship, Substance Abuse Treatment Unit, Yale University School of Medicine (2000); Highly Cited Researcher, Institute for Scientific Information (2001)
Research Focus
Studies on the neurobiology of addiction continue to be focused on how the multiple neurochemical systems within the extended amygdala basal forebrain neurocircuitry change with the development of addiction and retain those changes to convey vulnerability to relapse. Animal models of the longterm changes in the brain produced by patterns of drug use associated with addiction and associated with vulnerability to relapse continue to be developed and refined. Recent developments include establishment of changes in the pattern of intravenous self-administration of heroin and nicotine with continuous access. Animals allowed continuous daily access to heroin compared to those with limited 2hour access showed a dramatic escalation in heroin intake such that responding moves into the normally inactive phase of the light-dark cycle. These studies suggest that prolonged exposure to drugs of abuse increase drug taking behavior. The brain circuit responsible for the aversive effects of opiate withdrawal hypothesized to be changed in the development of dependence is the same extended amygdala circuit hypothesized previously to be responsible for acute positive reinforcing effects of opiates. Opiate withdrawal-induced Fos immunoreactivity in the rat extended amygdala paralleled the development of conditioned place aversion. Functional interaction between opioid and cannabinoid receptors in drug self-administration have also been demonstrated. The neurochemical basis for the escalation in drug intake associated with dependence is under current investigation with a focus on neuropeptidergic mechanisms.
Previous studies of alcohol dependent, opiate dependent and cocaine dependent animals during acute withdrawal have shown enhanced stress-like responses that are reversed by selective competitive corticotropin-releasing factor (CRF) antagonists. Studies with animals exposed to chronic administration of cocaine, alcohol and cannabinoids have shown increases in CRF activity in the amygdala as measured by in vivo microdialysis. Even more exciting are results showing that CRF antagonists gain the ability to reduce alcohol drinking in animals with a history of dependence, but are inactive in animals with no history of dependence. These results suggest that the increased drug intake associated with drug dependence may involve not only decreases in the function of transmitter systems that are associated with the acute reinforcing (rewarding) effects of drugs of abuse (previous work from our group), but also with the recruitment of the brain neuropeptide systems associated with behavioral and neurobiological responses to stressors.
As a result of these studies, the neurochemical and neurobiological changes associated with addiction have been conceptualized in an allostatic framework as opposed to a homeostatic framework. Allostasis is defined as stability through change and in the present context refers to dysregulation of brain reward circuits including decreases in function of brain reward neurotransmitters and recruitment of brain stress systems. The brain is hypothesized to maintain this dysregulation of brain reward circuits by continued overactivity in the brain stress circuits and activation of the compulsive behavior circuit of the cortical-thalamic-striatal systems. The persistence of a residual allostatic load in the brain reward systems lends a vulnerability to reinstatement of drug taking and addiction even in subjects during prolonged drug free states post acute withdrawal.
Neuropeptides and Stress
Studies continue to be directed at exploring the functional significance of neuropeptides and receptors associated with the CRF-like neuropeptides in the brain. CRF-binding protein ligand inhibitors have been shown to have performance-enhancing effects presumably reflecting modest increases in availability of synaptic CRF. Injections of the CRF related neuropeptide urocortin into the hypothalamic paraventricular nucleus potently decreased food intake suggesting a site for the appetite suppressing effects of CRF related neuropeptides. The ability of urocortin to bind to the CRF-2 receptor as well as the CRF-1 receptor lends further support to the hypothesis that the CRF-2 receptor has an important role in the appetite suppressing effect of CRF related neuropeptides. These results continue to support the hypothesis that there are multiple CRF neuropeptide systems interacting within specific brain structures that may utilize more than one receptor system in mediating behavioral responses to stressors.
Selected References
Ahmed, S.H. and Koob, G.F. Transition from moderate to excessive drug intake: Change in hedonic set point, Science, 1998, 282:298-300.
Koob G.F. Allostatic view of motivation: implications for psychopathology. In: Bevins RA, Bardo MT (Eds.), Motivational Factors in the Etiology of Drug Abuse (series title: Nebraska Symposium on Motivation, vol. 50), University of Nebraska Press, Lincoln NE, 2004, pp. 1-18.
Koob G.F. Alcoholism: allostasis and beyond, Alcoholism: Clinical and Experimental Research, 2003, 27:232-243.
Zorrilla, E.P. and Koob, G.F. The therapeutic potential of CRF1 antagonists for anxiety, Expert Opinion on Investigational Drugs, 13 (2004) 799-828.
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