About

Kristen A. Keefe is a distinguished professor and chair of the Department of Pharmacology and Toxicology at the University of Utah College of Pharmacy. Her research focuses on pharmacology and toxicology, contributing to the understanding of neurobiology and related fields. She is actively involved in mentoring students and supporting research programs such as IDEAS, which emphasizes neuroscience and neuroimmunology. Her leadership and research efforts are integral to advancing knowledge in these areas, fostering a collaborative environment for scientific discovery and education.

Research topics

• Medicine
• Computer Science
• Psychology
• Pharmacology
• Internal medicine
• Medical education
• Engineering
• Family medicine
• Endocrinology
• Pedagogy
• Developmental psychology
• Neuroscience
• Chemistry

Selected publications

• ASSESSMENT OF CELL-TYPE-SPECIFIC EXCITATORY SYNAPTIC STRENGTH IN THE DORSOLATERAL STRIATUM OF GOAL-DIRECTED AND HABITUAL COCAINE-SEEKING BEHAVIOR

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-08

  preprintOpen accessSenior authorCorresponding

  Abstract With repeated exposure to addictive drugs, there is a shift from drug abuse to drug addiction that is mediated by the transition from goal-directed to habitual control. It is well known that the development of habitual control over behavior relies upon cell-type-specific synaptic changes in both D1 and D2 medium spiny neurons (MSNs) in dorsal striatum. Specifically, habitual behavior is mediated by increased synaptic strength in D2 MSNs in dorsolateral striatum (DLS), suggesting similar cell-type-specific synaptic changes may underlie the development of habitual cocaine-seeking behavior. However, cell-type-specific synaptic changes have not been evaluated in DLS in this context. Therefore, we trained rats to self-administer cocaine in a cocaine self-administration paradigm that allows for differentiation of goal-directed vs. habitual cocaine-seeking behavior. Moreover, we used a viral vector under a D2-specific promoter to fluorescently label D2 MSNs with eYFP in DLS. Evoked excitatory postsynaptic currents (EPSCs) were used to determine AMPA:NMDA receptor ratio and the rectification index. Surprisingly, we did not observe any significant differences in these measures in DLS of cocaine-seeking rats, regardless of whether cocaine seeking was under habitual control. Interestingly, preliminary observations revealed significant changes in the paired pulse ratio (PPR), suggesting that presynaptic mechanisms may be involved in the development of habitual control over cocaine seeking. Overall, however, these results suggest there are no changes in postsynaptic strength of D2 MSNs in the DLS of rats with an extended history of cocaine self-administration and regardless of whether the cocaine seeking is under goal-directed or habitual control. Significance Statement The study of drug abuse and drug addiction represents a critical area of research with significant public health implications. Importantly, the underlying neurobiology of the transition between drug abuse and drug addiction is not well understood and insights to this transition may aid in the development of novel treatment options. Behaviorally, the shift from goal-directed to habitual control is thought to underly this transition. Much is known about the neurobiology of goal-directed and habitual behavior, however the transition in the context of drug-seeking is not well defined. We observed no significant differences in measures of synaptic strength, suggesting such postsynaptic neuroplasticity in the dorsolateral striatum is not involved in this transition.

  PublisherOA PDFDOI

• Review for "Pan‐striatal reduction in the expression of the astrocytic dopamine transporter precedes the development of dorsolateral striatum dopamine‐dependent incentive heroin seeking habits"

  2024-03-17

  peer-review1st authorCorresponding
  PublisherDOI

• Glutamate dynamics in the dorsolateral striatum of rats with goal-directed and habitual cocaine-seeking behavior

  Frontiers in Molecular Neuroscience · 2023-05-11

  articleOpen accessSenior authorCorresponding

  The shift from drug abuse to addiction is considered to arise from the transition between goal-directed and habitual control over drug behavior. Habitual responding for appetitive and skill-based behaviors is mediated by potentiated glutamate signaling in the dorsolateral striatum (DLS), but the state of the DLS glutamate system in the context of habitual drug-behavior remains undefined. Evidence from the nucleus accumbens of cocaine-experienced rats suggests that decreased transporter-mediated glutamate clearance and enhanced synaptic glutamate release contribute to the potentiated glutamate signaling that underlies the enduring vulnerability to relapse. Preliminary evidence from the dorsal striatum of cocaine-experienced rats suggests that this region exhibits similar alterations to glutamate clearance and release, but it is not known whether these glutamate dynamics are associated with goal-directed or habitual control over cocaine-seeking behavior. Therefore, we trained rats to self-administer cocaine in a chained cocaine-seeking and -taking paradigm, which yielded goal-directed, intermediate, and habitual cocaine-seeking rats. We then assessed glutamate clearance and release dynamics in the DLS of these rats using two different methods: synaptic transporter current (STC) recordings of patch-clamped astrocytes and the intensity-based glutamate sensing fluorescent reporter (iGluSnFr). While we observed a decreased rate of glutamate clearance in STCs evoked with single-pulse stimulation in cocaine-experienced rats, we did not observe any cocaine-induced differences in glutamate clearance rates from STCs evoked with high frequency stimulation (HFS) or iGluSnFr responses evoked with either double-pulse stimulation or HFS. Furthermore, GLT-1 protein expression in the DLS was unchanged in cocaine-experienced rats, regardless of their mode of control over cocaine-seeking behavior. Lastly, there were no differences in metrics of glutamate release between cocaine-experienced rats and yoked-saline controls in either assay. Together, these results suggest that glutamate clearance and release dynamics in the DLS are largely unaltered by a history of cocaine self-administration on this established cocaine seeking-taking paradigm, regardless of whether the control over the cocaine seeking behavior was habitual or goal directed.

  PublisherOA PDFDOI

• Review for "Pan‐striatal reduction in the expression of the astrocytic dopamine transporter precedes the development of dorsolateral striatum dopamine‐dependent incentive heroin seeking habits"

  2023-10-20

  peer-review1st authorCorresponding
  PublisherDOI

• Models of Methamphetamine-Induced Neurotoxicity

  2022-01-01

  book-chapterSenior authorCorresponding
  PublisherDOI

• Effects of methamphetamine-induced neurotoxicity on striatal long-term potentiation

  Psychopharmacology · 2022-01-01 · 6 citations

  articleOpen accessSenior authorCorresponding

  RATIONALE: Methamphetamine (METH) exposure is associated with damage to central monoamine systems, particularly dopamine signaling. Rodent models of such damage have revealed a decrease in the amplitude of phasic dopamine signals and significant striatal dysfunction, including changes in the molecular, system, and behavioral functions of the striatum. Dopamine signaling through D1 receptors promotes corticostriatal long-term potentiation (LTP), a critical substrate of these striatal functions. OBJECTIVES: Therefore, the purpose of this study was to determine if METH-induced dopamine neurotoxicity would impair D1 receptor-dependent striatal LTP in mice. METHODS: Mice were treated with a METH binge regimen (4 × 10 mg/kg d,l-methamphetamine, s.c.) that recapitulates all of the known METH-induced neurotoxic effects observed in humans, including dopamine toxicity. Three weeks later, acute brain slices containing either the dorsomedial striatum (DMS) or dorsolateral striatum (DLS) were prepared, and plasticity was assessed using white matter, high-frequency stimulation (HFS), and striatal extracellular electrophysiology. RESULTS: Under these conditions, LTP was induced in brain slices containing the DMS from saline-pretreated mice, but not mice with METH-induced neurotoxicity. Furthermore, the LTP observed in DMS slices from saline-pretreated mice was blocked by the dopamine D1 receptor antagonist SCH23390, indicating that this LTP is dopamine D1 receptor-dependent. Finally, acute in vivo treatment of METH-pretreated mice with bupropion (50 mg/kg, i.p.) promoted LTP in DMS slices. CONCLUSIONS: Together, these studies demonstrate that METH-induced neurotoxicity impairs dopamine D1 receptor-dependent LTP within the DMS and that the FDA-approved drug bupropion restores induction of striatal LTP in mice with METH-induced dopamine neurotoxicity.

  PublisherOA PDFDOI

• Consequences of Neurotoxin-Induced Dopamine Loss on Striatal Synaptic Plasticity

  2022-01-01

  book-chapterSenior authorCorresponding
  PublisherDOI

• The 5α-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder

  Journal of Clinical Investigation · 2021 · 21 citations

  • Medicine
  • Pharmacology
  • Internal medicine

  Opioid use disorder (OUD) has become a leading cause of death in the United States, yet current therapeutic strategies remain highly inadequate. To identify potential treatments for OUD, we screened a targeted selection of over 100 drugs using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. These findings were confirmed in rats; furthermore, finasteride reduced the physical signs associated with opioid withdrawal. In rat models of neuropathic pain, finasteride did not alter the antinociceptive effect of opioids and reduced withdrawal-induced hyperalgesia. Steroidomic analyses of the brains of fish treated with finasteride revealed a significant increase in dehydroepiandrosterone sulfate (DHEAS). Treatment with precursors of DHEAS reduced opioid self-administration in zebrafish in a fashion akin to the effects of finasteride. These results highlight the importance of steroidogenic pathways as a rich source of therapeutic targets for OUD and point to the potential of finasteride as a new treatment option for this disorder.

  PublisherOA PDFDOI

• Models of Methamphetamine-Induced Neurotoxicity

  2021-01-01 · 1 citations

  book-chapterSenior author
  PublisherDOI

• Consequences of Neurotoxin-Induced Dopamine Loss on Striatal Synaptic Plasticity

  2021-01-01

  book-chapterSenior author
  PublisherDOI

Recent grants

• NIH Grant F31MH009972

  NIH · $23k

• NIH Grant R01DA009407

  NIH · $3.1M · 2010

• Long-term consequences of methamphetamine toxicity

  NIH · $1.7M · 2008–2014

• NIH Grant R29NS035579

  NIH · $307k · 2002

• NIH Grant R01NS041673

  NIH · $1.4M · 2008

Frequent coauthors

• Glen R. Hanson

  University of Utah

  17 shared

• Donald Küfe

  Dana-Farber Cancer Institute

  10 shared

• Anne S. Gibson

  University of Tennessee at Knoxville

  10 shared

• Michael J. Zigmond

  University of Pittsburgh

  10 shared

• Miyako Abe

  Spanish Oncology Genitourinary Group

  9 shared

• Elizabeth D. Abercrombie

  Rutgers, The State University of New Jersey

  8 shared

• Teri M. Furlong

  UNSW Sydney

  8 shared

• Amy C. Adams

  University of Utah

  6 shared

Labs

• IDEAS Research ProgramPI

  Focus on neuroscience, pharmacology and toxicology, focusing on drug efficacy and safety

Awards & honors

• University of Utah Graduate Student and Postdoctoral Scholar…
• University of Utah Distinguished Teaching Award (2017)
• College of Pharmacy Teacher of the Year (2024)
• College of Pharmacy Second Professional Year Teacher of the…