Graduate Studies Faculty

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Major Areas

• Pharmacogenetics; tolerance and dependence; gene mapping

Summary of Current Research

I have developed mouse pharmacogenetic models for sensitivity to and dependence on ethanol by selectively breeding lines of mice resistant, or susceptible, to the severity of withdrawal from ethanol dependence. With my collaborators I am analyzing the neurobiological mechanisms underlying the large differences between the Withdrawal Seizure-Prone and -Resistant lines.  These studies are concentrated on the neuropharmacological mechanisms leading to alcohol withdrawal convulsions, on their differential susceptibility to other drugs of abuse, and on developing a more comprehensive set of behavioral assays characterizing withdrawal severity.
Other approaches include studies of multiple inbred and recombinant strains of mice examining the basis for genetic correlations between susceptibilities to different drugs of abuse. These studies are exploring the specificity of genetic influences across different environments, including multiple laboratories. They are also intended to elucidate gene-environment interactions. Strain patterns of sensitivity sometimes indicate the important influence of single genes on drug responses.  Using statistical techniques for mapping Quantitative Trait Loci (QTLs), we are identifying and mapping specific major and minor genes of importance.  We are beginning to identify candidate genes for particular QTLs, and are developing congenic strains by genotypic (marker-based) selection for certain QTLs of pleiotropic importance.  We are also developing a new line selectively bred for binge Drinking in the Dark as a part of the Integrative Neuroscience Initiative on Alcoholism (INIA-West) consortium.

Recent Publications

Rhodes, J.S., Ford, M.M., Yu, C.H., Brown, L.L., Finn, D.A., Garland, Jr., T., Crabbe, J.C. (2007)  Mouse inbred strain differences in ethanol drinking to intoxication. Genes Brain Behav 6:1-8.

Finn, D.A., Snelling, C., Fretwell, A.M., Tanchuck, M.A., Underwood, L., Cole, M., Crabbe, J.C., Roberts, A.J. (2007) Increased drinking during withdrawal from intermittent ethanol exposure is blocked by the CRF receptor antagonist D-Phe-CRF(12-41). Alcoholism: Clin. Exper. Res. 31:939-949.

Metten, P., Buck, K.J., Merrill, C.M., Roberts, A.J., Yu, C.-H., Crabbe, J.C. (2007) Use of a novel mouse genotype to model acute benzodiazepine withdrawal. Behav. Genetics 37:160-170.

Ponder, C.A., Kliethermes, C.L., Drew, M., Muller, M., Das, K., Risbrough, V.B., Crabbe, J.C., Gilliam, T.C., Palmer, A.A. (2007) Conditioned fear and innate anxiety have common genetic mechanisms that comprise aspects of emotionality. Genes Brain Behav. 6:736-749.

Crabbe, J.C., Cameron, A.J., Munn, E., Bunning, M, Wahlsten, D. (2008) Overview of mouse assays on ethanol intoxication. Curr. Protocols in Neurosci. 9.26.1-9.26.19, January, 2008.

Milner, L.C., Crabbe, J.C. (2008) Three murine anxiety models: results from multiple inbred strains comparisons. Genes Brain Behav. 7:496-505.

Beckley, E.H., Fretwell, A.M., Tanchuck, M.A., Gililland, K.R., Crabbe, J.C., Finn, D.A. (200x) Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice. Neuropsychopharmacol., in press.

Reilly, M.T., Milner, L.C., Shirley, R.L., Crabbe, J.C., Buck, K.J. (200x) 5-HT2C and GABAB receptors influence handling-induced convulsion severity in chromosome 4 congenic and DBA/2J background strain mice. Brain Res., in press.

Yoneyama, N., Crabbe, J.C., Murillo, A., Finn, D.A. (200x) Voluntary ethanol consumption in 22 inbred mouse strains. Alcohol, in press.

Mulligan, M.K., Ponomarev, I., Boehm, S.L. II, Owen, J.A., Levin, P.S., Blednov, Y.A., Crabbe, J.C., Bergeson, S.E. (200x) Alcohol trait and transcriptional genomic analysis of C57BL/6 substrains. Genes Brain Behav., in press.

Crabbe, J.C., Metten, P., Rhodes, J.S., Yu, C.H., Brown, L.L., Phillips, T.J., Finn, D.A. (200x) A line of mice selected for drinking in the dark to intoxication. Biol. Psychiatry, in press pending revision.

Philibin, S.D., Cameron, A.J., Metten, P., Crabbe, J.C. (200x) Motor impairment: a new ethanol withdrawal phenotype in mice.  Behav. Pharmacol., in press.

Belknap, J.K., Metten, P., Beckley, E.H., Crabbe, J.C. (200x) Genetic codetermination of drug abuse liability: multivariate analyses of mouse inbred strain responses to ethanol, morphine, diazepam, and pentobarbital. Trends in Pharmacological Sciences, in press.

Education

• B.A. (1968) Stanford University
• M.A. (1972) University of Colorado
• Ph.D. (1973) University of Colorado
  

Previous  Positions

• Research Fellow, Organon International BV, Oss, the Netherlands
• Lecturer, University of California