Graduate Studies Faculty

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Major Areas

• Gene and neural networks involved in CNS depressant drug dependence and associated withdrawal. 
• Quantitative trait gene (QTG) identification -- using fine-mapping, microarrays and RNASeq, weighted gene co-expression network analysis (WGCNA), and novel animal models (RNA interference, knockout and transgenic models).
• Mpdz (multi-PDZ domain protein) and the mechanism by which it affects drug withdrawal and consumption.
• Kcnj9 (G-protein coupled K+ channel [GIRK3) and the mechanism by which it affects drug response and withdrawal.
• A gene network crucially involved in cellular and oxidative stress and implicated in ethanol response and withdrawal.

Summary of Current Research

My research combines robust behavioral models and state-of-the-art methods to identify drug response QTGs and elucidate their mechanism of action CNS depressant drugs are widely abused for their sedative-hypnotic and euphoric actions. A host of biological and environmental factors interact in a complex manner throughout the addictive process to influence their use/abuse. Physical dependence on associated withdrawal episodes are thought to constitute a powerful motivational force that perpetuates their use/abuse and contributes to relapse. My lab uses preclinical (animal) models that closely approximate aspects of the human clinical situation in order to elucidate the gene and neural networks involved in drug response.

We and others have established that there is a great deal of common genetic influence on withdrawal from CNS depressant including alcohol, barbiturates, benzodiazepines, and inhalants in mice. Quantitative trait loci (QTLs) are chromosome sites containing genes that affect complex traits like drug dependence. We have detected and confirmed QTLs that affect drug withdrawal and/or consumption on chromosomes 1, 2, 4, 9, 11, and 19. We have identified two genes, Mpdz (multi-PDZ protein) and Kcnj9 (K+ channel GIRK3), as QTGs for withdrawal that also affect drug preference/consumption, sensitivity and/or tolerance. This convergence suggests that Mpdz and Kcnj9 play important roles in drug dependence and makes them important targets. Furthermore, recent studies find that the human MPDZ gene is associated with alcohol dependence. 

Currently, there is limited information available about Mpdz and Kcnj9 function and how this relates to drug actions. Using inducible transcription factor (cFos) expression, we have identified neural circuits associated with these QTGs. Site-directed lesions (electrolytic and chemical) confirm crucial roles for the substantia nigra pars reticulata and rostroventral striatum in drug response/withdrawal, with 'upstream' regions of limbic cortex yet to be assessed. Currently, we are using RNAi and site-directed pharmacological methods to test the hypothesis that MPDZ and GIRK3 influence drug response/withdrawal via regulation of particular neurotransmitter receptors (e.g., serotonin-2C and opioid receptors).

Recent Publications

Ehlers CL, Walter NAR, Dick D, Buck KJ, Crabbe JC (2010). A comparison of selected quantitative trait loci associated with alcohol use phenotypes in humans and mouse models.  Addiction Biology (Jan issue), in press.

Kozell LB, Walter NAR, Milner LC, Wickman K, Buck KJ (2009). Mapping a barbiturate withdrawal locus to a 0.44 Mb interval and analysis of a novel null mutant identifies a role for Kcnj9 (GIRK3) in withdrawal from pentobarbital, zolpidem and ethanol. Journal of Neuroscience 29:11662.

Chen G, Reilly M, Kozell L, Hitzemann R, Buck KJ (2009). Chronic alcohol withdrawal severity is associated with neuronal activation of limbic and basal ganglia circuitry in mice.  Alcohol 43:411.

Walter NAR, Bottonly D, Laderas T, Mooney M, Darakjian P, McWeeney S, Hitzemann R, Buck KJ (2009). A call to sequence; high-throughput sequencing of a region on mouse chromosome 1 in DBA/2J and C57BL/6J uncovers an abundance of cryptic SNPs.  BMC Genomics 10:379.

Chen G, Kozell LB, Hitzemann R, Buck KJ (2008). Involvement of the limbic basal ganglia in ethanol withdrawal confulsivity in mice is influenced by a chronosome 4 locus. Journal of Neuroscience 28:9840.

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

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.

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.

Education

• B.S.   (1984)  Univ Minnesota
• Ph.D.  (1990)  Univ Colorado
• Postdoctoral fellow  (1994) Vollum Institute

Positions

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

Non-Academic Interests