Kristen Keefe
Professor of Pharmacology and Toxicology
Title: Professor of Pharmacology and Toxicology
Email address: K.Keefe@utah.edu
Education and Training:
- B.S. 1984, Case Western Reserve University
- M.S. 1989, University of Pittsburgh
- Ph.D. 1992, University of Pittsburgh
- Post-doctoral fellow 1992-1995, NIMH
Research Interests:
My laboratory is interested in the structure and function of the basal ganglia, a group of subcortical nuclei in the brain involved in the control of movement and cognition. The importance of the basal ganglia for normal behavior is highlighted by the profound deficits observed in patients with Parkinson's disease, Huntington's disease, schizophrenia, and drug addiction -- diseases that are associated with dysfunction in the basal ganglia.
Our work determines the influence of both endogenous and exogenous chemicals on the function of neurons in the basal ganglia in an attempt to better understand 1) the role that glutamate (via NMDA receptors) and monoamines (dopamine and serotonin) play in regulating the activity of basal ganglia nuclei, 2) the mechanisms by which drugs of abuse that affect the basal ganglia exert their adverse effects, and 3) the mechanisms by which the function of the basal ganglia can be beneficially altered by drugs to better treat sequelae associated with dysfunction in these nuclei.
We use numerous techniques to examine the effects of both endogenous and exogenous drugs on basal ganglia function.
These techniques include: 1) In vivo microdialysis in the brain of awake animals to examine changes in the release of amino acid, monoamine, and neuropeptide neurotransmitters. 2) In situ hybridization histochemistry to measure changes in the levels of messenger RNAs in brain neurons to examine short- and long-term changes in gene expression in neurons of the basal ganglia. 3) Immunohistochemistry to examine changes in protein expression in defined basal ganglia neurons and nuclei. 4) In vitro, whole-cell patch-clamp electrophysiology (in collaboration with Dr. Karen Wilcox (Pharm/Tox)) to examine NMDA receptor-mediated currents and their regulation by dopamine in striatal efferent neurons. 5) Behavioral analyses (in collaboration with Dr. Raymond Kesner (Psychology) to determine the long-term consequences of altered basal ganglia function on organismal behavior.
Coupling these techniques, we can begin to understand how neurotransmitters and drugs acutely affect the function of basal ganglia neurons and the neuroadaptive changes that occur in response to neural injury in the basal ganglia and exposure to therapeutic and abused drugs.
The Keefe laboratory in the Department of Pharmacology and Toxicology is learning how drugs of abuse come to elicit powerful control over behavior by studying how such drugs affect molecules, such as activity-regulated cytoskeletal-associated protein ("Arc", in red), involved in modifying connections between cells (in green) in the brain."
Keefe Laboratory:
The Keefe laboratory in the Department of Pharmacology and Toxicology is learning how drugs of abuse come to elicit powerful control over behavior by studying how such drugs affect molecules, such as activity-regulated cytoskeletal-associated protein ("Arc", in red), involved in modifying connections between cells (in green) in the brain."
Selected Publications:
- Riedy, M.D., Kesner, R.P., Hanson, G.R., and Keefe K.A. Discriminative stimulus- vs. conditioned reinforcer-induced reinstatement of drug-seeking behavior and arc mRNA expression in dorsolateral striatum. The Basal Ganglia IX: Advances in Behavioral Biology. H. J. Groenewegen. New York, Springer. 58: 269-284, 2009.
- Hanson, J.E., Birdsall, E., Seferian, K.S., Crosby, M.A., Keefe, K.A., Gibb, J.W., Hanson, G.R., and Fleckenstein, A.E. Methamphetamine-induced dopaminergic deficits and refractoriness to subsequent treatment. European Journal of Pharmacology, 607(1-3): 68-73, 2009.
- Smeal, R.M, Keefe, K.A., and Wilcox, K.S. Differences in excitatory transmission between thalamic and cortical afferent pathways to single spiny efferent neurons of dorsal striatum. European Journal of Neuroscience, 28(10): 2041-2052, 2008.
- Daberkow, D.P., Riedy, M.D., Kesner, R.P., and Keefe, K.A. Effect of methamphetamine neurotoxicity on learning-induced arc mRNA expression in identified striatal efferent neurons. Neurotoxicity Research, 14(4): 307-315, 2008.
- Daberkow, D.P., Riedy, M.D., Kesner, R.P., and Keefe, K.A. Arc mRNA induction in striatal efferent neurons associated with response learning. European Journal of Neuroscience, 26, 228-241, 2007.
- Smeal, R.M., Gaspar, R.C., Keefe, K.A., Wilcox, K.S. A rat brain slice preparation for characterizing both thalamostriatal and corticostriatal afferents. Journal of Neuroscience Methods, 159, 224-235, 2007.
- Horner, K.A., Westwood, S.C., Hanson, G.R., and Keefe, K.A. Multiple, high doses of methamphetamine increase the number of preproneuropeptide Y mRNA-expressing neurons in the striatum of rat via a dopamine D1 receptor-dependent mechanism. Journal of Pharmacology and Experimental Therapeutics, 319: 414-421, 2006.
- Horner, K.A. and Keefe, K.A. Regulation of psychostimulant-induced preprodynorphin, c-fos, and zif/268 messenger RNA expression in the rat dorsal striatum by mu opioid receptor blockade. European Journal of Pharmacology, 532, 61-73, 2006.
Kristen's Students
- Matt Riedy, 2009, Post-doctoral fellow, laboratory of Dr. Gary Aston-Jones, Medical University of South Carolina.
- David P. Daberkow, 2006, Post-doctoral fellow, laboratory of Dr. Paul Garris, Illinois State University at Normal.
- David E. Chapman, 2003, Medical Science Liaison, Medical Affairs, UCB Pharma, Inc
- David A. Adams, 2001, Clinical Research Scientist, Eli Lilly and Company
- Amy C. Adams, 2000, Raising tomorrow’s scientists — Caroline and Ava.
- Anindita Ganguly, 2000, Senior Scientist, Research and Development, Acorda Therapeutics, Hawthorne, NY
Kristen's Post-Docs
- Kristen Ashley Horner, 2002-2006, Assistant Professor (Tenure Track), Dept. of Basic Medical Sciences, Mercer University School of Medicine, GA.
- Roy Maldine Smeal, 2003-2007, Research Assistant Professor, Depts. of Pharmacology and Toxicology and Bioengineering, University of Utah.
