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Summary of Current Research

Sedative-hypnotic (SH) drugs are widely abused. A host of biological and environmental factors interact in a complex manner throughout the addictive process to influence SH use/abuse. Physical dependence on associated withdrawal episodes are thought to constitute a powerful motivational force that perpetuates SH use/abuse and contributes to relapse. In humans, the identification of genes that influence SH dependence and withdrawal has been limited, and the use of preclinical (animal) models that closely approximate the clinical situation has been critical to elucidate gene networks involved.

We have established that there is a great deal of common genetic influence on withdrawal from SH drugs including alcohol, barbiturates, benzodiazepines, and inhalants. Quantitative trait loci (QTLs) are chromosome sites containing genes that affect complex traits like behavior. My lab has detected and confirmed QTLs that affect SH withdrawal and consumption on chromosomes 1, 2, 4, 9, 11, and 19 in mice. Recently, we identified two genes, Mpdz (which encodes the multi-PDZ protein) and Kcnj9 (which encodes a member of the GIRK channel family, GIRK3) as QTL genes with large effects on risk for SH withdrawal. Both genes are also associated with SH preference/consumption, sensitivity and tolerance. This convergence suggests that Kcnj9 and Mpdz play important roles in diverse SH responses and withdrawal and makes them important targets. Furthermore, the human homologs of these genes are associated with SH dependence, so these are promising candidate genes for loci detected in human studies of SH dependence (including alcoholism).

Currently, there is limited information available about MPDZ and GIRK3 function and how this relates to SH withdrawal. Using immunohistochemical methods to assess induction of immediate early gene expression, my lab identified an extended limbic-basal ganglia circuit associated with SH withdrawal that is affected by Mpdz and Kcnj9. Lesions showed that the caudolateral substantia nigra pars reticulata (SNpr) is crucially involved in SH withdrawal. Currently, we are using neurophysiological and neurochemical methods to test the hypothesis that GIRK3 and MPDZ influence SH withdrawal via their regulation of GABAB and/or 5HT2C receptors in SNpr. Using viral mediated gene transfer and RNAi approaches, we plan to directly test the role of Mpdz and Kcnj9 in this circuit on withdrawal. Site-directed microinjections to pharmacologically manipulate brain regions will provide mechanistic information about MPDZ and GIRK3 actions on SH withdrawal.

An innovative feature of my research is to combine robust behavioral models of SH withdrawal with state-of-the-art strategies to elucidate QTL mechanisms of action. Some of the most useful tools we have developed and used are novel Mpdz transgenic (overexpression) and hemizygote (knockdown) models, and Kcnj9 knockouts. As expected, Mpdz hemizygotes display more severe SH withdrawal vs. wildtype littermates, Mpdz transgenics have less severe SH withdrawal vs. wildtype littermates, and Kcnj9 null mutants have less severe withdrawal vs. wildtype littermates. We are now expanding our analyses of these genetic animal models to assess SH preference/consumption, sensitivity and tolerance, and conditioned preference and aversion.

Recent Publications

Buck KJ, Rademacher BLS, Metten P, Crabbe JC (2002). Mapping murine loci for physical dependence on ethanol.  Psychopharmacology 160: 398-407.

Shirley RS, Walter NAR, Reilly MT, Fehr C, Buck KJ (2004).  Mpdz is a quantitative trait gene for drug withdrawal seizures.  Nature Neuroscience 7: 699-700.

Kliethermes CL, Metten P, Belknap JK, Buck KJ, Crabbe JC (2004). Selection for pentobarbital withdrawal severity: Correlated differences in withdrawal from other sedative drugs.  Brain Res 1009: 17-25.

Hood HM, Metten P, Koyama A, Crabbe JC, Buck KJ (2006).  Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11. Genes Brain Behav 5:1-10.

Walter NAR, McWeeney SK, Peters S, Belknap JK, Hitzemann R, Buck KJ (2007). SNPs matter: impact on detection of differential expression. Nature Methods 4: 679-680.

 Kozell LB, Belknap JK, Hofstetter JR, Mayeda A, Buck KJ (2008). Mapping a locus for alcohol physical dependence and associated withdrawal to a 1.1 Mb interval of mouse chromosome 1 syntenic with human chromosome 1q23.2-23.3. Genes Brain Behav 7:560-7.

 Denmark DL, Buck KJ (2008). Molecular analyses and identification of promising candidate genes for an alcohol withdrawal locus on mouse chromosome 1. Genes Brain Behav 7:599-608.

Chen G, Kozell LB, Hitzemann R, Buck KJ (2008) Involvement of the limbic basal ganglia in ethanol withdrawal convulsivity in mice is influenced by a chromosome 4 locus. J Neurosci 28: 9840-9849.

Education

B.S. (1984) University of Minnesota
Ph.D. (1990) University of Colorado
Postdoctoral Fellow (1994) Vollum Institute, OHSU

Positions

1995-2002                   Assistant Professor, Behavioral Neuroscience/Medical Psychology, OHSU
2002-2008                   Associate Professor, Behavioral Neuroscience, OHSU, Portland, OR
2002-present               VA Research Scientist/Pharmacologist, VAMC-Portland, OR
2008-present               Professor, Behavioral Neuroscience, OHSU, Portland, OR

Non-Academic Interests

Relaxing and playing with my children, husband, family and friends; biking, kayaking, skiing, reading