About

Annette E. Fleckenstein, MS, PhD, is a faculty member at the Spencer Fox Eccles School of Medicine. She holds a Bachelor of Science degree from Western Michigan University, a Master of Science from Western Michigan University, and a PhD from Michigan State University. She completed postdoctoral fellowships at the National Institutes of Health, National Institute on Drug Abuse - Addiction Research Center, and the University of Utah. Her research focuses on the neurochemical and behavioral effects of drugs of abuse, including methamphetamine, nicotine, and synthetic cathinones, with particular attention to dopaminergic systems, neurotoxicity, and neurochemical alterations associated with substance use. Her work has contributed to understanding the neurobiological mechanisms underlying drug addiction and neurotoxicity, as well as the pharmacological targets involved in these processes.

Research topics

• Pharmacology
• Chemistry
• Biochemistry
• Internal medicine
• Medicine
• Endocrinology
• Biology
• Philosophy
• Psychology
• Psychoanalysis

Selected publications

• Trail Making Test performance in early abstinence from methamphetamine: human evidence for a drug-associated Parkinsonian-like phenotype

  Frontiers in Psychiatry · 2026-03-23

  articleOpen access

  Introduction: Methamphetamine misuse is associated with elevated rates of Parkinson's disease (PD), and both conditions degrade fronto-striatal circuitry, primarily demonstrated in animal and post-mortem human studies. Despite this, few clinical studies have examined overlapping presentation, or whether long-term methamphetamine users exhibit a Parkinsonian-like phenotype. To examine whether recently abstinent individuals with methamphetamine use disorder (MUD) show Parkinsonian-like cognitive inflexibility, and whether these deficits vary by sex or patterns of use. Methods: Forty-nine individuals with MUD (26 males, 23 females) were recruited from a 30-day residential treatment program and compared with thirty controls (16 males, 14 females). Cognitive flexibility was assessed using the Trail Making Task (TMT), a task sensitive to fronto-striatal deficits in PD. Between-group differences were tested with a two-way between-groups MANCOVA, within-group sex effects with a two-way within-group MANCOVA, and linear regression evaluated the influence of sex and drug intake patterns on PD-like presentation. Results: Both sexes in the methamphetamine group showed significant TMT deficits relative to controls, consistent with PD populations. Age of first use, duration, and amount of methamphetamine used did not impact performance. Intravenous use, however, was linked to more TMT errors in females but not males. Discussion: These findings support literature suggesting methamphetamine use resembles aspects of an early Parkinsonian-like phenotype. To our knowledge, this is among the first studies to show PD-like presentation in individuals with MUD, highlighting that women who inject methamphetamine may face disproportionate PD risk. As cognitive inflexibility can hinder treatment engagement, comprehensive interventions for MUD may need to address these deficits.

  PublisherOA PDFDOI

• Differential Effects of Neurotensin NTS1 and NTS2 Receptors on Locomotion

  Brain and Behavior · 2025-11-01

  articleOpen access

  INTRODUCTION: Neurotensin (NT) is an endogenous neuropeptide with diverse central and peripheral effects, particularly as related to modulation of central nervous system dopaminergic activity. For example, interactions between dopamine and NT have been associated with the motivation to use, and the motor consequences of drugs abuse, including nicotine. However, the relative contribution of the two subtypes of cell surface G-protein coupled NT receptors (NTS1 and NTS2) to dopamine-related drug-induced effects is unclear. METHODS: We investigated the locomotor behavior and exploratory drive of C57BL/6J mice deficient in either NTS1 (NTS1 -/-) or NTS2 (NTS2 -/-) compared to wild-type C57BL/6J (WT +/+) mice in an open-field. In addition, the effect of nicotine on locomotion and intra-session habituation to a novel open field was compared in each of these genetic strains. RESULTS: When compared to WT (+/+) mice, the results demonstrated less intra-session habituation across time (i.e., less accommodation (as assessed by distanced travelled, horizontal activity, and vertical activity) in mice deficient in the NTS1 receptor. In contrast, mice deficient in the NTS2 receptor accommodated more rapidly. Nicotine injection reduced all three parameters of locomotor activity in WT (+/+) and NTS1 (-/-) mice. In contrast to effects in both WT (+/+) and NTS1 (-/-) mice, NIC exposure had a negligible effect on TD in the NTS2 (-/-) mice. CONCLUSION: These results suggest opposing effects of the NTS1 and NTS2 receptor subtypes in modulating natural and nicotine-induced dopaminergic transmission and consequent locomotor behavior.

  PublisherOA PDFDOI

• In memoriam: Kenneth E. Moore

  Neuropsychopharmacology · 2024

  1st authorCorresponding
  • Psychoanalysis
  • Psychology
  • Philosophy
  PublisherOA PDFDOI

• Methcathinone decreases dopamine transporter function: Role of protein kinase C

  Journal of Neurochemistry · 2021 · 2 citations

  Senior authorCorresponding
  • Chemistry
  • Internal medicine
  • Endocrinology

  Abstract Methcathinone (MCAT) is a psychostimulant of abuse that can cause both persistent striatal dopaminergic and serotonergic, as well as hippocampal serotonergic, deficits. Evidence suggests that the rapid effects of stimulants that are structurally and mechanistically similar to MCAT on monoamine transporter function may contribute to the abuse liability and/or persistent monoaminergic deficits caused by these agents. Thus, effects of MCAT on 1) striatal dopamine (DA) transporter (DAT); and 2) striatal and hippocampal serotonin transporter (SERT) function, as determined in tissues from adult male rats, were assessed. As reported previously, a single administration of MCAT rapidly (within 1 hr) decreases striatal [ 3 H]DA uptake. Similarly, incubation of rat synaptosomes with MCAT at 37℃ (but not 4˚C) decreased striatal [ 3 H]DA uptake. Incubation with MCAT likewise decreased [ 3 H]5HT but not vesicular [ 3 H]DA uptake. MCAT incubation in vitro was without effect on [ 3 H]DA uptake in striatal synaptosomes prepared from MCAT‐treated rats. The decrease in [ 3 H]DA uptake caused by MCAT incubation: (a) reflected a decrease in V max , with minimal change in K m , and (b) was attenuated by co‐incubation with the cell‐permeable calcium chelator, N , N '‐[1,2‐ethanediylbis(oxy‐2,1‐phenylene)]bis[ N ‐[2‐[(acetyloxy)methoxy]‐2‐oxoethyl]‐1,1'‐bis[(acetyloxy)methyl] ester‐glycine (BAPTA‐AM), as well as the non‐selective protein kinase‐C (PKC) inhibitors bisindolylmaleimide‐1 (BIM‐1) and 2‐[1‐3(Aminopropyl)indol‐3‐yl]‐3(1‐methyl‐1H‐indol‐3‐yl)maleimide (or Bisindolylmaleimide VIII; Ro‐31‐7549). Taken together, these results suggest that in vitro MCAT incubation may model important aspects of MCAT administration in vivo, and that calcium and PKC contribute to the in vitro effects of MCAT on DAT. image

  PublisherDOI

• Methcathinone Rapidly Decreases Dopamine Transporter Function: Role of Calcium and Protein Kinase C

  The FASEB Journal · 2020

  Senior authorCorresponding
  • Chemistry
  • Pharmacology
  • Internal medicine

  Methcathinone (MCAT) is a synthetic cathinone that causes both persistent striatal dopaminergic as well as striatal and hippocampal serotonergic deficits. It has been demonstrated that the rapid effects of similar stimulants on dopamine (DA) transporter (DAT) function contribute to persistent monoaminergic deficits. Thus, the effect of MCAT on DAT was assessed. Results revealed that MCAT self‐administration (SA) decreased striatal [ 3 H]DA uptake, as assessed ex vivo in synaptosomes prepared from male rats 1 h after the final MCAT SA session. In vitro co‐incubation of synaptosomes with MCAT (1, 10, 100 μM) at 37°C likewise decreased striatal [ 3 H]DA uptake. There was no effect of in vitro co‐incubation with MCAT at 4°C, suggesting that decreases in [ 3 H]DA uptake are not due to residual drug. These effects were not limited to DAT as MCAT SA decreased hippocampal [ 3 H]serotonin uptake. Further, in vitro co‐incubation of synaptosomes with MCAT decreased both striatal and hippocampal [ 3 H]serotonin uptake. The in vitro effect on DAT function was attenuated by co‐incubation with the cell‐permeable calcium chelator, 1,2‐bis (2‐aminophenoxy) ethane‐N, N, N, N‐tetraacetic acid acetoxymethyl ester (BAPTA‐AM), as well as with the structurally related non‐specific protein kinase C (PKC) inhibitors bisindolylmaleimide I and Ro‐31‐7549. In contrast, this in vitro decrease in DAT function was not attenuated by co‐incubation with other non‐specific PKC inhibitors (NPC‐15437 and Go6976), nor with the PKC‐β inhibitor ruboxistaurin. Neither co‐incubation with the Ca 2+ /calmodulin‐dependent protein kinase II inhibitor, KN‐93, nor the glycogen synthase kinase 3β inhibitor, SB‐216763, attenuated the MCAT‐induced decrease in [ 3 H]DA uptake. Taken together, these results suggest that MCAT self‐administration and in vitro MCAT exposure have comparable effects to investigator administered MCAT on DAT and SERT function in the striatum and hippocampus; further, in vitro data suggest that the MCAT‐induced effect on DAT is dependent upon calcium and some, but not all, PKC isoforms. Support or Funding Information R01‐DA039145

  PublisherDOI

• 3,4-Methylenedioxypyrovalerone: Neuropharmacological Impact of a Designer Stimulant of Abuse on Monoamine Transporters

  Journal of Pharmacology and Experimental Therapeutics · 2020 · 6 citations

  Senior authorCorresponding
  • Pharmacology
  • Chemistry
  • Medicine
  PublisherOA PDFDOI

• Increased risk of diseases of the basal ganglia and cerebellum in patients with a history of attention-deficit/hyperactivity disorder

  Neuropsychopharmacology · 2018-09-11 · 64 citations

  articleOpen access
  PublisherOA PDFDOI

• Methylenedioxypryovalerone (MDPV) Rapidly Increases Dopamine Transporter and Vesicular Monoamine Transporter‐2 Function

  The FASEB Journal · 2018-04-01

  articleSenior author

  Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone designer drug primarily abused for its psychostimulant properties. Rapid dysregulation of central monoamine neurotransmitter transport into presynaptic terminals and synaptic vesicles are principal mechanisms of psychostimulant action, and contribute to the development of persistent monoaminergic deficits. Still, the impact of in vivo MDPV administration on the function of central monoamine transporters is not fully elucidated. Consequently, this study examined the response of the striatal dopamine transporter (DAT) and vesicular monoamine transporter‐2 (VMAT2) to a single MDPV exposure in adult male rats. A single in vivo MDPV administration rapidly (within 1 h) and reversibly (effect diminishes after 6 h) increased both DAT and VMAT2 function when assessed ex vivo in striatal synaptosomes and non‐membrane‐associated (presumably cytoplasmic) synaptic vesicles, respectively. MDPV treatment did not increase VMAT2 immunoreactivity within the cytoplasmic synaptic vesicle fraction, suggesting increased VMAT2 activity is unlikely due to intracellular trafficking increasing the number of available cytoplasmic VMAT2‐associated synaptic vesicles. In contrast to other psychostimulants, most notably methamphetamine and methylphenidate, MDPV acutely increases both DAT and VMAT2 function, and increased VMAT2 function is likely independent of vesicular trafficking‐mediated mechanisms. Together, these data suggest that MDPV has a unique and undescribed mechanism of action on striatal dopaminergic neurons. Support or Funding Information This work was supported by National Institutes of Health grants DA039145 and DA031883. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

  PublisherDOI

• Lack of Evidence for Methylenedioxypyrovalerone (MDPV)‐Induced Persistent Dopaminergic or Serotonergic Deficits: Comparison with Methamphetamine and Mephedrone

  The FASEB Journal · 2018-04-01

  articleSenior author

  β‐Ketoamphetamines such as methylenedioxypyrovalerone (MDPV) and mephedrone (MEPH) are synthetic cathinones with a structural similarity to methamphetamine (METH) that may account for some similarities in behavioral effects. However, the persistent effects of repeated high‐dose MDPV exposures on striatal dopaminergic and hippocampal serotonergic systems remain to be fully elucidated. Accordingly, the persistent effects of repeated high‐dose MPDV administrations were investigated. Results revealed that MDPV treatment did not alter striatal dopaminergic or hippocampal serotonergic systems as assessed 7 days later in synaptosomes prepared from treated rats. Further, MDPV did not alter hippocampal serotonin or 5‐hydroxyindoleacetic acid content at this time point. These data stand in contrast to our previous report that repeated high‐dose MEPH administrations cause persistent hippocampal serotonergic deficits. These data also stand in contrast to effects of repeated high‐dose METH administrations that include persistent striatal dopaminergic and hippocampal serotonergic deficits. Noteworthy, in these studies MDPV did not induce hyperthermia to the degree reported in previous studies of MEPH and METH. Further, the impact of MDPV on the dopamine transporter and vesicular monoamine transporter‐2 appears distinct from that of MEPH and METH. Taken together, these latter findings may contribute to the differential impact of MDPV, MEPH, and METH on dopaminergic and serotonergic systems. Support or Funding Information DA039145 and DA031883 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

  PublisherDOI

• Brain Slice Staining and Preparation for Three-Dimensional Super-Resolution Microscopy

  Methods in molecular biology · 2017-01-01 · 13 citations

  article
  PublisherDOI

Recent grants

• NIH Grant R29DA011389

  NIH · $523k · 2002

• Neurochemical and Behavioral Effects of Synthetic Cathinones

  NIH · $1.7M · 2016–2023

• NIH Grant K02DA019447

  NIH · $1.3M · 2016

• NIH Grant R01DA000869

  NIH · $5.4M · 2013

• NIH Grant R01DA011389

  NIH · $2.5M · 2014

Frequent coauthors

• Glen R. Hanson

  University of Utah

  117 shared

• Diana G. Wilkins

  University of Utah

  32 shared

• James W. Gibb

  27 shared

• Evan L. Riddle

  Biogen (United States)

  22 shared

• Paula L. Vieira‐Brock

  18 shared

• Lisa M. McFadden

  University of South Dakota

  18 shared

• Shannon M. Nielsen

  University of Utah

  16 shared

• Trent J. Volz

  University of Utah

  15 shared

Education

• B.S.

  Western Michigan University

• M.S.

  Western Michigan University

• Ph.D.

  Michigan State University

• Other

  National Institutes of Health, National Institute on Drug Abuse - Addiction Research Center