Professor of Pharmacology and Toxicology
Neuroscience, Neurological and Neurophychiatric Disorders Basal Ganglia, Neurobiology
Molecular Biology Program
Biological Chemistry Program
B.S. Case Western Reserve University
Ph.D. University of Pittsburgh
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.
References (Selected Publications)
- Tandon S, Keefe KA, Taha SA. (2017) Mu opioid receptor signaling in the nucleus accumbens shell increases responsiveness of satiety-modulated lateral hypothalamus neurons. European Journal of Neuroscience, 45(11):1418-1430.
- Sheth, C, Furlong, TM, Keefe, KA, Taha, SA (2017) The lateral hypothalamus to lateral habenual projection, but not the ventral pallidum to lateral habenula projection, regulates voluntary ethanol consumption. Behavioral Brain Research, 328:195-208.
- Tandon S, Keefe KA, Taha SA (2017) Excitation of lateral habenula neurons as a neural mechanism underlying ethanol-induced conditioned taste aversion. Journal of Physiology, 595(4):1393-1412.
- Keefe, K.A. and Horner, K.A.@ Neurotransmitter Regulation of Striatal Gene Expression (Chapter 30). In Handbook of Basal Ganglia Structure and Function 2e (H. Steiner and K.Y. Tseng, Eds.), Elsevier, Inc., 2017.
- Sheth, C, Furlong, TM, Keefe, KA, Taha, SA (2016) Lesions of the rostromedial tegmental nucleus increase voluntary ethanol consumption and accelerate extinction of ethanol-induced conditioned-taste aversion. Psychopharmacology (Berl), 233(21-22):3737-3749.
- Kesner, R.P., Kirk, R.A., Clark, J.K., Keefe, K. (2016) Naloxone injections into CA3 disrupt pattern completion associated with relapse from cocaine seeking. Hippocampus, 26(7), 892-898.
- Furlong, T.M., Leavitt, L.S., Keefe, K.A., Son, J-H. (2016) Methamphetamine-, d-amphetamine-, and p-chloroamphetamine-induced neurotoxicity differentially effect impulsive responding on the stop-signal task in rats. Neurotoxicity Research, 29(4): 569-582.
- Fricks-Gleason, A.N., German, C.L., Hoonakker, A.J., Friend, D.M., Ganesh, K.K., Carver, A.S., Hanson, G.R., Fleckenstein, A.E., Keefe, K.A. (2016) An acute, epitope-specific modification in the dopamine transporter associated with methamphetamine-induced neurotoxicity. Synapse, 70(4), 139-146. *Cover Article*
- Garris, P.A. and Keefe, K.A. Voltammetric Analysis of Loss and Gain of Dopamine Function (Chapter 13). In Compendium of In Vivo Monitoring in Real-Time Molecular Neuroscience Volume 1: Fundamentals and Applications (G.S. Wilson and A.C. Michael, Eds.), World Scientific Publishing Co., 2015.
- Robinson, J.D., Howard, C.D., Pastuzyn, E.D., Byers, D.L., Keefe K.A., Garris P.A. (2014) Methamphetamine-induced neurotoxicity disrupts pharmacologically evoked dopamine transients in the dorsomedial and dorsolateral striatum. Neurotoxicity Research, 226(2):152-167.
- Pastuzyn, E.D., Keefe, K.A. (2014) Changes in neural circuitry regulating response-reversal learning and Arc-mediated consolidation of learning in rats with methamphetamine-induced partial monoamine loss. Neuropsychopharmacology, 39(4):963-72.
- Howard, C.D., Pastuzyn, E.P., Barker-Haliski, M.L., Garris, P.A., Keefe, K.A. (2013) Phasic-like stimulation of the medial forebrain bundle augments striatal gene expression despite methamphetamine-induced partial dopamine denervation. The Journal of Neurochemistry, 125(4):555-565.
- Howard, C.D., Keefe, K.A., Daberkow, D.P., Ramsson, E., Garris, P.A. (2013) Methamphetamine-induced neurotoxicity disrupts naturally occurring phasic dopamine transient activity in the striatum of freely moving rats. European Journal of Neuroscience, 38(1):2078-2088.
- Barker-Haliski, M.L., Oldenberger, K., Keefe, K.A. (2012) Impaired Arc/Arg 3.1 mRNA expression in striatal efferent neurons following partial monoamine loss induced by methamphetamine. The Journal of Neurochemistry, 123(5): 845-855.
- Pastuzyn, E.D. and Keefe, K.A. (2012) Altered Arc-regulated striatal learning in rats pretreated with a neurotoxic regimen of methamphetamine. Neuropsychopharmacology, Mar;37(4):885-95.
- 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, 36(12): 2441-51.
- Howard, C.D., Keefe, K.A., Garris, P.A., and Daberkow, D.P. (2011) Methamphetamine-induced neurotoxicity decreases phasic, but not tonic, dopaminergic signaling in the rat striatum. The Journal of Neurochemistry, 118(4):668-676.
- Keefe, K.A. and Horner, K.A. (2010) Neurotransmitter Regulation of Basal Ganglia Gene Expression (Chapter 27). In Handbook of Basal Ganglia Structure and Function, a Decade of Progress (H. Steiner and K.Y. Tseng, Eds.), Elsevier, Inc., pp 461-490.
- 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. Neurotox. Res., 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. Eur. J. Neurosci., 26, 228-241.
- Daberkow, D.P., Kesner, R.P., and Keefe, K.A. (2005) Relation of methamphetamine-induced monoamine loss to basal ganglia-dependent learning. Pharmacol, Biochem, Behav, 81, 198-204.
- 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. J Neurochem, 84, 87-93.
- Ganguly, A., and Keefe, K.A. (2001) Unilateral dopamine depletion increases expression of the 2A subunit of the N-methyl-D-aspartate receptor in enkephalin-positive and enkephalin-negative neurons. Neuroscience. 103(2):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. J. Pharmacol. and Exper. Ther, 296, 520-527.