Kari J. Buck
Associate Professor, Behavioral Neuroscience, Oregon Health & Science University
e-mail: buckk@ohsu.edu
Major Areas
Biological (genetic) factors and neural circuits involved in complex behaviors, including risk factors for dependence on a variety of drugs of abuse.
Previous Positions
Assistant Professor, Department of Behavioral Neuroscience (previously Medical Psychology), OHSU
Postdoctoral Fellow, University of Colorado Health Sciences Center
Postdoctoral Fellow, Vollum Institute, OHSU
Education
B.S. (1984) University of Minnesota
Ph.D. (1990) University of Colorado
Research Interests
Sedative-hypnotic drugs such as benzodiazepines (Rohypnol, "roofies"), ?-hydroxybutyrate (GHB, "liquid ecstasy"), barbiturates, and alcohol are widely abused for their euphoric and sedative effects. A host of biological (genetic) and environment factors interact in a complex manner throughout the addictive process to influence drug use/abuse and contributes to relapse. Unfortunately, the identification of genes that influence these behaviors has been very limited. Thus, the use of preclinical (animal) models of drug physiological dependence and associated withdrawal episodes; and to evaluate their roles in motivation to use/abuse drugs and relapse.
Recently, we have identified several chromosomal regions that contain genes that jointly have a major influence on severity of drug dependence and withdrawal. These chromosomal regions are called quantitative trait loci (QTLs). Some of the QTLs have been narrowed to regions that contain only a few genes. Some of the most useful tools we have developed thus far are congenic strains for these QTLs. Each possess a small chromosomal segment from the donor strain superimposed on a genetic background that is ~99% from the background strain. As expected, congenic mice have reduced drug withdrawal severity. Because of the near elimination of genetic "noise" from loci elsewhere in the genome, congenic vs. background strain comparisons are invaluable in evaluating genes in the QTL intervals (and their protein products) and the neural circuits affected by the QTLs to assess their role in drug dependence and withdrawal.
Mdpz is apparently one of the genes responsible for genetic differences in predisposition to drug dependence and withdrawal. This gene codes for the multiple PDZ domain protein (MPDZ). Currently little is known about its function and the mechanism by which MPDZ affects drug withdrawal. MPDZ is widely expressed in the brain, and it interacts with GABAB, Sheraton, neuropteran, and other receptors. It is likely that MPDZ affects drug withdrawal by altering signal transduction mediated by one or more of the receptors with which it interacts. We are developing an Mpdz transgenic model to directly test its role in a variety of behavioral responses to drugs of abuse as well correlated responses. Finally, a recent work in the Buck laboratory implicates extended basal ganglia and limbic circuits in drug dependence and withdrawal. This suggests that MPDZ interaction with GABAB receptors, which regulate glutamate and GABA release in the former circuit, is a plausible mechanism that warrants further investigation.
Selected Recent Publications
Shirley RL, Walter NA, Reilly MT, Fehr C, Buck KJ (2004) Mpdz is a quantitative trait gene for drug withdrawal seizures. Nature Neuroscience. 7:699-700.
Churchill GA, et al; Complex Trait Consortium (2004) The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nature Genetics. 36:1133-1137.
Buck KJ, Reilly MT, Rogers LM, Szeliga K, Grant K, Brodie MS (2004) Serotonin 5-HT2 receptors and alcohol: Reward, withdrawal, and discrimination. Alcoholism: Clinical and Experimental Research. 28:211-216.
Hitzemann R, Reed C, Malmanger B, Lawler M, Hitzemann B, Cunningham B, Belknap J, Buck K, Phillips T, Crabbe J (2004) On the integration of alcohol-related QTLs and gene expression. Alcoholism: Clin Exp Ther. 28:1437-1448.
Abiola O, Angel JM, Avner P, Bachmanov AA, Belknap JK, Bennett B, Blankenhorn EP, Blizard DA, Bolivar V, Brockmann B, Buck KJ, et al (2003) A community's view on the nature and identification of quantitative trait loci (QTLs). Nature Genetics Review. 4:911-916.
Hitzemann R, Malmanger B, Reed C, Lawler M, Hitzemann B, Coulombe S, Buck K, et al (2003) A strategy for the integration of QTL, gene expression and sequence analyses. Mammalian Genome. 14:733-747.
Fehr C, Shirley RL, Metten P, Kosobud AEK, Belknap JK, Crabbe JC, Buck KJ (2004) Potential pleiotropic effects of Mpdz on vulnerability to seizures. Genes, Brain and Behavior. 2:1-12.
Buck KJ, Rademacher BLS, Metten P, Crabbe JC (2002) Mapping murine loci for physical dependence on ethanol. Psychopharmacology. 160:398-407.
Buck KJ, Finn DA (2001) Genetic factors in addiction: QTL mapping and candidate gene studies implicate GABAergic genes in alcohol and barbiturate withdrawal in mice. Addiction. 96:139-149.
Hood HM, Buck KJ (2000) Allelic variation in the GABAA receptor γ2 subunit is associated with genetic susceptibility to ethanol-induced motor incoordination and hypothermia, conditioned taste aversion, and withdrawal in BXD/Ty recombinant inbred mice. Alcoholism: Clinical and Experimental Therapeutics. 24:1327-1334.
Buck K, Lischka T, Dorow J, Crabbe J (2000) Mapping quantitative trait loci that regulate sensitivity and tolerance to quinpirole, a dopamine mimetic selective for D2/D3 receptors. American Journal of Medical Genetics (Neuropsychiatric Genetics). 96:696-705.