KRISTEN A. KEEFE
|Professor of Pharmacology and Toxicology
Brain and Behavior
Neurobiology of Disease
Pharmacology of neurological and neuropsychiatric disorders, including drug abuse and addiction. Normal and pathological functions of the basal ganglia
My laboratory is interested in the functional neuroanatomy of the basal ganglia, a group of subcortical nuclei in the brain involved in the control of movement and cognition, including habit formation and procedural learning. 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 produce long-term alterations in basal ganglia function, 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 basal ganglia function including: 1) in vivo microdialysis; 2) in situ hybridization histochemistry; 3) immunohistochemistry; 4) in vitro, whole-cell patch-clamp electrophysiology; 5) behavioral analyses.
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.
Pastuzyn, E.P., Chapman, D.E., Wilcox, K.S., and Keefe, K.A. (2011) Altered Arc-regulated striatal learning in rats pretreated with a neurotoxic regimen of methamphetamine. Neuropsychopharmacology, Nov 9. doi: 10.1038/npp.2011.265. [Epub ahead of print].
Son, J-H., Latimer, C., and Keefe, K.A. (2011) Impaired formation of stimulus-response, but not action-outcome, associations in rats with methamphetamine-induced neurotoxicity. Neuropsychopharmacology, Nov;36(12):2441-2451.
Riedy, M.D., Kesner, R.P., Hanson, G.R., and Keefe K.A. (2009) 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.
Smeal, R.M, Keefe, K.A., and Wilcox, K.S. (2008) 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.
Daberkow, D.P., Riedy, M.D., Kesner, R.P., and Keefe, K.A. (2008) Effect of methamphetamine neurotoxicity on learning-induced arc mRNA expression in identified striatal efferent neurons. Neurotoxicity Research, 14(4):307-315.
Daberkow, D.P., Riedy, M.D., Kesner, R.P., and Keefe, K.A. (2007) Arc mRNA induction in striatal efferent neurons associated with response learning. European Journal of Neuroscience, 26:228-241.
Horner, K. A., and Keefe, K. A. (2006) 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.
Daberkow, D. P., Kesner, R. P., and Keefe, K. A. (2005) Relation of methamphetamine-induced monoamine loss to basal ganglia-dependent learning. Pharmacology, Biochemistry, and Behavior, 81:198-204.
Chapman, D. E., Keefe, K. A., and Wilcox, K. S. (2003) Evidence for functionally distinct synaptic NMDA receptors in ventromedial versus dorsolateral striatum. Journal of Neurophysiology, 89:69-80.
Adams, D. H., Hanson, G. R., and Keefe, K. A. (2003) Distinct effects of methamphetamine and cocaine on preprodynorphin messenger RNA in rat striatal patch and matrix. The Journal of Neurochemistry, 84:87-93.
Johnson-Davis, K. L., Hanson, G. R., and Keefe, K. A. (2002) Long-term post-synaptic consequences of methamphetamine on preprotachykinin mRNA expression. The Journal of Neurochemistry, 82:1472-1479.
Ganguly, A., and Keefe, K. A. (2001) Unilateral dopamine depletion increases expression of the NR2A subunit of the NMDA receptor in enkephalin-positive and enkephalin-negative striatal neurons. Neuroscience, 103:405-412.
Chapman, D. E., Hanson, G. R., Kesner, R. P., and Keefe, K. A. (2001) Long-term changes in basal ganglia function after a neurotoxic regimen of methamphetamine. The Journal of Pharmacology and Experimental Therapeutics 296:520-527.
Hanson, G. R., and Keefe, K. A. (1999) Dopamine D-1 regulation of caudate neurotensin mRNA in the presence or absence of the nigrostriatal dopamine pathway. Molecular Brain Research 66:111-121.
Keefe, K. A., and Ganguly, A. (1998) Effects of NMDA receptor antagonists on D1 dopamine receptor-mediated changes in striatal immediate early gene expression: Evidence for involvement of pharmacologically distinct NMDA receptors? Developmental Neuroscience 20:216-228.
Keefe, K. A., and Adams, A. C. (1998) Differential effects of NMDA receptor blockade on eticlopride-induced immediate early gene expression in the medial and lateral striatum. JPET 287:1076-1083.