DOCSLIB.ORG

Mechanisms Underlying Differential Effectiveness of Memantine and Ketamine in Rapid Antidepressant Responses

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mechanisms Underlying Differential Effectiveness of Memantine and Ketamine in Rapid Antidepressant Responses Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses Erinn S. Gideons, Ege T. Kavalali, and Lisa M. Monteggia1 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111 Edited by Richard L. Huganir, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved May 1, 2014 (received for review December 22, 2013) Ketamine is an NMDA receptor (NMDAR) antagonist that elicits understanding of why ketamine, but not memantine, produces rapid antidepressant responses in patients with treatment-resis- a fast-acting antidepressant response has clinical implications and tant depression. However, ketamine can also produce psychoto- may provide novel information critical for the development of mimetic effects that limit its utility as an antidepressant, raising rapid antidepressant therapeutics based on NMDAR antagonism, the question of whether the clinically tolerated NMDAR antago- with fewer side effects. nist memantine possesses antidepressant properties. Despite its There is much interest in identifying the molecular mechanism similar potency to ketamine as an NMDAR antagonist, clinical data that underlies the rapid antidepressant response of ketamine. In re- suggest that memantine does not exert rapid antidepressant cent work, we demonstrated that the fast-acting antidepressant effect actions for reasons that are poorly understood. In this study, of ketamine requires deactivation of eukaryotic elongation factor 2 we recapitulate the ketamine and memantine clinical findings kinase (eEF2K) and subsequent desuppression of BDNF protein in mice, showing that ketamine, but not memantine, has antide- translation in the hippocampus (8, 9). We hypothesize that low-dose pressant-like effects in behavioral models. Using electrophysi- ketamine mediates its rapid antidepressant response by blockade of ology in cultured hippocampal neurons, we show that ketamine spontaneous glutamate release-mediated NMDAR activity. This and memantine effectively block NMDAR-mediated miniature 2+ + blockade, in turn, decreases calcium (Ca ) flow through the re- NEUROSCIENCE excitatory postsynaptic currents in the absence of Mg2 . However, 2+ ceptor, inhibiting eEF2K activity and resulting in decreased levels in physiological levels of extracellular Mg , we identified key of phosphorylated eukaryotic elongation factor 2 (eEF2) (10–12) functional differences between ketamine and memantine in their and desuppression of BDNF protein synthesis (8, 9, 13). In this ability to block NMDAR function at rest. This differential effect of study, we compared ketamine with memantine in their effective- ketamine and memantine extends to intracellular signaling cou- ness to block NMDAR activation during spontaneous neuro- pled to NMDAR at rest, in that memantine does not inhibit the transmission, subsequently inhibiting eEF2K and increasing BDNF phosphorylation of eukaryotic elongation factor 2 or augment protein translation. Our results reveal key differences between the subsequent expression of BDNF, which are critical determinants of effects of ketamine and memantine on resting NMDAR-mediated ketamine-mediated antidepressant efficacy. These results demon- neurotransmission and subsequent intracellular signaling pathways strate significant differences between the efficacies of ketamine that may explain the mechanistic differences between these two and memantine on NMDAR-mediated neurotransmission that have drugs in eliciting rapid antidepressant effects. impacts on downstream intracellular signaling, which we hypoth- esize is the trigger for rapid antidepressant responses. These data provide a novel framework on the necessary functional require- Significance ments of NMDAR-mediated neurotransmission as a critical deter- minant necessary to elicit rapid antidepressant responses. Ketamine is an NMDA receptor (NMDAR) antagonist that elicits rapid antidepressant responses in patients with treatment- eEF2 | spontaneous neurotransmission resistant depression. However, ketamine can also produce ad- verse side effects, which raised interest in whether the clini- etamine is a noncompetitive glutamate NMDA receptor cally tolerated NMDAR antagonist memantine can elicit similar K(NMDAR; also called GluN) antagonist that has been shown fast antidepressant action. Rather surprisingly, clinical data to mediate rapid antidepressant efficacy in patients with treatment- have shown that memantine does not trigger rapid antide- resistant major depression (1–3). The antidepressant effects of pressant effects for reasons that have yet to be elucidated. ketamine are fast-acting, with some patients reporting effects as Here, we reconstitute the ketamine and memantine clinical soon as 30 min to within a few hours following a single i.v. low- findings in animal models and, combined with the analysis dose injection of ketamine. However, ketamine can produce of synaptic function and subsequent intracellular signaling, adverse psychotomimetic effects, which may limit its use as an demonstrate significant differences between the efficacies antidepressant. Traditional antidepressant drugs target the mono- of ketamine and memantine on NMDAR-mediated neuro- amine system and typically require several weeks of treatment to transmission and downstream intracellular signaling. These mediate a therapeutic effect. There is an urgent need for rapid findings suggest a potential mechanism to explain the ear- antidepressant drugs, and the clinical data with ketamine suggest lier clinical observations. that blocking the NMDAR may be a viable therapeutic target. Author contributions: E.S.G., E.T.K., and L.M.M. designed research; E.S.G. performed re- Memantine is a noncompetitive NMDAR antagonist that has search; E.S.G., E.T.K., and L.M.M. analyzed data; and E.S.G., E.T.K., and L.M.M. wrote been approved by the US Food and Drug Administration for the the paper. treatment of Alzheimer’s disease. Memantine is a generally well- The authors declare no conflict of interest. tolerated drug that lacks the aversive effects (4) observed with This article is a PNAS Direct Submission. ketamine at therapeutic doses. However, attempts to test mem- 1To whom correspondence should be addressed. E-mail: lisa.monteggia@utsouthwestern. antine as an antidepressant in individuals with major depression edu. have yielded mixed results following long-term drug treatment, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. with no evidence of rapid antidepressant effects (5–7). A better 1073/pnas.1323920111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1323920111 PNAS Early Edition | 1of6 Downloaded by guest on October 1, 2021 Results Acute Memantine Treatment Does Not Trigger a Fast-Acting Antidepressant Response. We assessed whether memantine affects locomotor activity immediately following drug treatment. In all experiments, we included a ketamine group as a direct comparison, which has previously been shown to elicit an antidepressant re- sponse in mice 30 min after administration without effects on lo- comotor activity at this time point (8, 9, 14, 15). To examine a range of doses for the effects of this drug in vivo, we injected memantine at 20 mg/kg, a dose reported to have neuroprotective effects in rodents (16); 10 mg/kg, a dose that blocks morphine dependence (17); and 3 mg/kg, a dose that prevents estrogen- dependent tolerance to morphine. We found that a 3-, 10-, or 20-mg/kg dose of memantine did not have any effect on total lo- comotor activity in comparison to the saline-treated mice during the 60-min testing period (Fig. 1A, Inset). We examined the data in 5-min epochs and also did not find any significant differences between mice treated with memantine compared with saline (Fig. 1A). Ketamine caused an initial increase in locomotor activity during the first 10 min following drug administration; however, there were no significant differences in activity during the remaining 50 min of the test, specifically at the 30-min time point when antidepressant responses are measured (Fig. 1A). We next examined whether memantine produces rapid anti- depressant effects in the forced swim test (FST). In agreement with previous data, ketamine significantly reduced the im- mobility time at 30 min following injection, suggestive of an antidepressant response (8, 9) (Fig. 1B). In contrast, a single Fig. 1. Memantine (Mem) treatment does not cause a fast-acting antide- pressant effect. (A) Ketamine (Ket) causes a significant increase in locomotor injection of memantine at 3 or 10 mg/kg did not significantly activity at the 5- and 10-min intervals [two-way ANOVA interaction: F = alter immobility time in the FST at 30 min (Fig. 1B). Using 44,420 1.904, P = 0.0007; time: F11,420 = 25.87, P < 0.0001; treatment effects: F4,420 = separate cohorts of mice, we found that ketamine caused a sig- 2.784, P = 0.0264; Tukey’s post hoc analysis for Ket: 5 min vs. saline, *P = nificant decrease in immobility time at 8 or 24 h following acute 0.01; 10 min vs. saline, **P = 0.001 (n = 8 per group)]. (Inset) There were no administration in the FST that was not observed with either 3 or significant differences in the total number of beam breaks over 1 h. (B) Ket 10 mg/kg of memantine (Fig. 1B). Rather unexpectedly, mice treatment caused a significant decrease in immobility in the FST compared treated with 20 mg/kg of memantine had severe adverse effects with the saline control group at 30 min, 8 h, and 24 h following
Load more

Recommended publications
  • Directvote Election: Candidate Bios
    DirectVote Election: Candidate Bios Councilor Slot 2 Your Voting Status: Select 0 to 1 from below. Selected: 0 Vote For: Lisa Monteggia Lisa Monteggia Administrative Accomplishments: I have been involved in numerous administrative roles at UT Southwestern Medical Center, including Faculty Search Committees, membership in the Animal Resource Center advisory committee, Institutional Animal Care and Use Committee, Graduate Student Admissions committee, as well as the development of the Behavioral Core Facility. These opportunities have provided me with the skills and experience to deal with the needs and operations of basic science —in particular animal research— in a complex medical school campus. Degree, Institute, Year Earned: BS, University of Illinois-Urbana, 1989 MS, University of Illinois-Urbana, 1991 PhD, The Chicago Medical School, 1998 Postdoctoral fellow, Yale University, 1998-2000 Research Areas: My research interest is the molecular and cellular mechanisms underlying psychiatric disorders and neuropsychiatric treatment strategies. My laboratory studies two critical areas of translational brain research, mechanisms underlying antidepressant action and synaptic alterations that lead to the pathophysiology of the Rett syndrome. Our focus is on the role of synaptic plasticity mechanisms that may underlie these disorders and suggest potential targets for therapeutics. Current Position(s) at Your Current Institution: Ginny and John Eulich Professorship in Autism Spectrum Disorders, Professor of Neuroscience, UT Southwestern Medical
    [Show full text]
  • Essential Role of Brain-Derived Neurotrophic Factor in Adult Hippocampal Function
    Essential role of brain-derived neurotrophic factor in adult hippocampal function Lisa M. Monteggia*†, Michel Barrot*, Craig M. Powell*, Olivier Berton*, Victor Galanis*, Terry Gemelli*, Sven Meuth*, Andreas Nagy‡, Robert W. Greene*, and Eric J. Nestler* *Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9070; and ‡Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5 Edited by Floyd E. Bloom, The Scripps Research Institute, La Jolla, CA, and approved May 27, 2004 (received for review March 26, 2004) Brain-derived neurotrophic factor (BDNF) regulates neuronal de- specific enolase–tetracycline transcriptional activator (NSE– velopment and function. However, it has been difficult to discern tTA) line are on a BL6͞SJL ϫ ICR background, the TetOp-Cre its role in the adult brain in influencing complex behavior. Here, we are on an ICR background, and the floxed BDNF mice are on use a recently developed inducible knockout system to show that a BL6͞sv129 background. The NSE–tTA mice (14) and the deleting BDNF in broad forebrain regions of adult mice impairs TetOp-Cre mice (15, 16) were maintained as homozygotes then hippocampal-dependent learning and long-term potentiation. We crossed to generate the bigenic mice. The floxed LacZ reporter use the inducible nature of this system to show that the loss of mice (17) or floxed BDNF mice (13) were then crossed with the BDNF during earlier stages of development causes hyperactivity bigenic NSE–tTA͞TetOp-Cre mice to generate the inducible and more pronounced hippocampal-dependent learning deficits. KO mice. All experiments were performed on littermates de- We also demonstrate that the loss of forebrain BDNF attenuates rived from this mating paradigm to ensure analysis by matched the actions of desipramine, an antidepressant, in the forced swim controls.
    [Show full text]
  • LISA M. MONTEGGIA, Ph.D
    LISA M. MONTEGGIA, Ph.D. RANK/TITLE: Barlow Family Director of the Vanderbilt Brain Institute Professor, Department of Pharmacology Address: Vanderbilt University MRBIII, Suite 7140 465 21st Avenue South Nashville, TN 37240-7933 PH: (615) 936-5483 FX: (615) 6936-3613 EM: [email protected] EDUCATION: University of Illinois, Urbana, IL – B.S.- Microbiology – 1989 University of Illinois, Urbana, IL – M.S. – Biology – 1991 The Chicago Medical School, North Chicago, IL – Ph.D. – Neuroscience – 1999 (Dr. Marina Wolf, PI) POSTDOCTORAL TRAINING: 1998-2000 Department of Psychiatry (Dr. Eric Nestler, PI) Yale University, New Haven, CT OTHER TRAINING: 1991-1994 Associate Scientist, Department of Neuroscience, Abbott Laboratories, Abbott Park, IL 1994-1998 Scientist, Department of Neuroscience, Abbott Laboratories, Abbott Park, IL ACADEMIC APPOINTMENTS: 09/2000-10/2002 Research Assistant Professor, Department of Psychiatry, UT Southwestern, Dallas, TX 10/2002-09/2009 Assistant Professor, Department of Psychiatry, UT Southwestern, Dallas, TX 09/2009-09/2013 Associate Professor (tenure), Department of Psychiatry, UT Southwestern, Dallas, TX 06/2010-06/2018 Ginny and John Eulich Professorship in Autism Spectrum Disorders 09/2013-06/2018 Professor, Department of Neuroscience, UT Southwestern, Dallas, TX 07/2018- Director, Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 07/2018- Professor of Pharmacology, Vanderbilt University, Nashville, TN AWARDS/HONORS: 1985-1989 University of Illinois, Full Academic Tuition Scholarship 1991 Top 10% of Teaching Assistants for Excellence in Teaching, University of Illinois 1998-2000 NIH/NIDA Postdoctoral Training Grant, Yale University 2001 Young Investigator Award, NARSAD 2002 American College of Neuropsychopharmacology/Bristol-Myers Squibb Travel Award 2003 Developmental Neurobiology and Child Psychiatry, Otsuka Travel Award 2003 College on Problems on Drug Dependence, Center for Addictive Diseases Travel Award 2003 Young Investigator Award, NARSAD 2005 Daniel X.
    [Show full text]
  • Anxiety-Related Interventions in Rodent Defense Behaviors
    bioRxiv preprint doi: https://doi.org/10.1101/020701; this version posted November 18, 2015. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Anxiety-related interventions in rodent defense behaviors: systematic review and meta-analyses Authors Farhan Mohammad1, Joses Ho2, Chun Lei Lim, Jia Hern Woo, Dennis Jun Jie Poon2, Bhumika Lamba2 & Adam Claridge-Chang1, 2, 3, 4 Affiliations 1. Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore 138673 2. Institute for Molecular and Cell Biology, Agency for Science Technology and Research, Singapore 138673 3. Department of Physiology, National University of Singapore, Singapore 138673 4. Corresponding author: [email protected] Keywords anxiety, defense, behavior, rodent, stress, serotonin, meta-analysis 1 bioRxiv preprint doi: https://doi.org/10.1101/020701; this version posted November 18, 2015. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. ABSTRACT Background Assays measuring defense behavior in rodents, including the elevated plus maze, open field and light-dark box assays, have been widely used in preclinical models of anxiety to study the ability of therapeutic interventions to modulate the anxiety-like state. However, many important proposed anxiety-modulating factors, including genes, drugs and stressors have had paradoxical effects in these assays across different studies.
    [Show full text]
  • 9Th Annual Enhancing Neuroscience Diversity Through Undergraduate Research Education Experiences (ENDURE) Meeting
    9th Annual Enhancing Neuroscience Diversity through Undergraduate Research Education Experiences (ENDURE) Meeting October 19, 2019 | Chicago, IL The NIH Office of the Director and these NIH Institutes and Centers participate in the NIH Blueprint for Neuroscience Research: • NCATS • NIAAA • NIDCR • NINR • NCCIH • NIBIB • NIEHS • OBSSR • NEI • NICHD • NIMH • NIA • NIDA • NINDS TABLE OF CONTENTS ENDURE PROGRAM AND MEETING GOALS .................................................................................. 2 NOTICE OF INTENT TO RE-ISSUE BP-ENDURE FOA ...................................................................... 3 ENDURE MEETING AGENDA ........................................................................................................ 4 NIH BLUEPRINT WELCOME AND SPEAKER BIOGRAPHIES .......................................................... 5 ENDURE PROGRAM INFORMATION AND TRAINEE RESEARCH ABSTRACTS • BP-ENDURE AT HUNTER AND NYU ........................................................................................ 8 • BP-ENDURE AT ST. LOUIS: A NEUROSCIENCE PIPELINE ....................................................... 23 • BRAiN: BUILDING RESEARCH ACHIEVEMENT IN NEUROSCIENCE ......................................... 41 • BRIDGE TO THE PH.D. IN NEUROSCIENCE ............................................................................ 48 • ENHANCING NEUROSCIENCE DIVERSITY WITH TENNESSEE STATE UNIVERSITY – NEUROSCIENCE EDUCATION AND RESEARCH VANDERBILT EXPERIENCE (TSU-NERVE)...... 57 • NEUROSCIENCE RESEARCH OPPORTUNITIES TO
    [Show full text]
  • An in Vitro Characterization of the Raphe Nucleus and the Effects of Ssris on Synaptic Function
    AN IN VITRO CHARACTERIZATION OF THE RAPHE NUCLEUS AND THE EFFECTS OF SSRIS ON SYNAPTIC NEUROTRANSMISSION APPROVED BY SUPERVISORY COMMITTEE ________________________________________ Ilya Bezprozvanny, Ph.D. ________________________________________ Lisa Monteggia, Ph.D. ________________________________________ Joseph Albanesi, Ph.D ________________________________________ Melanie Cobb, Ph.D ________________________________________ Ege Kavalali, Ph.D Dedicated to my parents, Funke and Bashir Ashimi, my sister Laide and brother Idris, future husband Taofeek, and the rest of my family and friends for all their unconditional love and continued support. AN IN VITRO CHARACTERIZATION OF THE RAPHE NUCLEUS AND THE EFFECTS OF SSRIS ON SYNAPTIC NEUROTRANSMISSION By SUNBOLA SHEFIAT ASHIMI DISSERTATION Presented to the Faculty of the Graduate School of Biomedical Sciences The University of Texas Southwestern Medical Center at Dallas In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY The University of Texas Southwestern Medical Center at Dallas Dallas, Texas June 2010 Copyright by Sunbola Shefiat Ashimi, 2010 All Rights Reserved ACKNOWLEDGEMENTS I would like to thank Dr. Lisa Monteggia for her mentorship, support, and friendship over the past five years. I would also like to thank Dr. Ege Kavalali for his guidance and teaching me about the wonderful world of synaptic transmission. Regards to the past and present members of the Monteggia lab for their continued support, especially Erika Nelson, Megumi Adachi, and Waseem Akhtar for their training, scientific advice, and friendship. I want to thank Anita Autry for being such a wonderful and gracious friend to have taken this journey with. Also, I thank Melissa Mahgoub for her treasured friendship and for reminding me that there are still special people in the world.
    [Show full text]
  • LETTER Doi:10.1038/Nature10130
    LETTER doi:10.1038/nature10130 NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses Anita E. Autry1, Megumi Adachi1, Elena Nosyreva2, Elisa S. Na1, Maarten F. Los1, Peng-fei Cheng1, Ege T. Kavalali2 & Lisa M. Monteggia1 Clinical studies consistently demonstrate that a single sub-psycho- mimetic dose of ketamine, an ionotropic glutamatergic NMDAR a * * (N-methyl-D-aspartate receptor) antagonist, produces fast-acting 150 * * antidepressant responses in patients suffering from major depres- sive disorder, although the underlying mechanism is unclear1–3. Depressed patients report the alleviation of major depressive dis- 100 order symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks1–3, unlike Immobility (s) traditional antidepressants (serotonin re-uptake inhibitors), which 50 Vehicle take weeks to reach efficacy. This delay is a major drawback to Ketamine current therapies for major depressive disorder and faster-acting 3 antidepressants are needed, particularly for suicide-risk patients . 30 min 3 h 24 h 1 wk The ability of ketamine to produce rapidly acting, long-lasting anti- depressant responses in depressed patients provides a unique b * * opportunity to investigate underlying cellular mechanisms. Here 150 * we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived 100 neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) Immobility (s) kinase (also called CaMKIII), resulting in reduced eEF2 phosphor- 50 Vehicle ylation and de-suppression of translation of brain-derived neuro- CPP trophic factor.
    [Show full text]
  • Biographical Sketch Name
    OMB No. 0925-0001 and 0925-0002 (Rev. 03/2020 Approved Through 02/28/2023) BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: EGE T. KAVALALI eRA COMMONS USER NAME (credential, e.g., agency login): EKAVALALI POSITION TITLE: PROFESSOR EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) DEGREE Completion (if Date FIELD OF STUDY INSTITUTION AND LOCATION applicable) MM/YYYY Boğaziçi University, Istanbul, Turkey B.S. 1990 Electrical Engineering Rutgers University, New Brunswick, New Jersey Ph.D. 1995 Biomedical Engineering Stanford University School of Medicine, Stanford Postdoctoral 1995-1999 Molecular and Cellular California Fellowship Physiology A. Personal Statement My research interests are focused on the basic mechanisms that underlie the formation and function of synapses in the central nervous system in health and disease. Since its inception, our laboratory has uncovered several novel facets of synaptic transmission, synapse formation as well as synapse maturation in the CNS. The key contribution of our research is the demonstration that spontaneous and evoked neurotransmission processes are segregated both in their presynaptic origins and postsynaptic targets. Our work has identified spontaneous neurotransmission as an autonomous neuronal signaling pathway independent of action potential-evoked synaptic transmission. In the last decade, we used imaging and electrophysiological approaches as well as molecular tools to pursue this novel signaling mechanism on both sides of the synapse. We developed tools to visualize trafficking of multiple synaptic vesicle proteins simultaneously within individual synapses.
    [Show full text]
  • Anita E. Autry, Ph.D
    Anita E. Autry, Ph.D. Department of Molecular and Cellular Biology Email: [email protected] Harvard University Cell: 214-701-8761 16 Divinity Avenue, Biolabs 4023 Cambridge, MA 02138 SCHOLARLY PROFILE Neuroscience researcher using state of the art molecular tools to understand the functional neuroanatomy of circuits controlling behavior. RESEARCH EXPERIENCE 2011-present Postdoctoral Fellow, Harvard University, Department of Molecular and Cellular Biology Advisor: Catherine Dulac, Ph.D EDUCATION 2011 Ph.D. University of Texas Southwestern Medical Center at Dallas Neuroscience Graduate Program Advisor: Lisa Monteggia, Ph.D. 2005 B.A., B.S. University of South Carolina, Honors College Baccalaureus Degree CURRENT FUNDING 2016 K99/R00 Grantee Pathway to Independence Award K99 HD 085188 Sponsored by NICHD to research parental behavior 2015 NARSAD Young Investigator Brain and Behavior Research Foundation Received two years of funding to support research projects 2014 Fellow Ruth L. Kirschstein National Research Service Award F32 HD 078040 Sponsored by NICHD to research parental behavior PUBLICATIONS Selected Publications 1. Wu, Z., Autry, A.E., Bergan, J.F., Watabe-Uchida, M., Dulac, C.G. (2014). Galanin neurons in the medial preoptic area govern parental behavior. Nature, 509 (7500) 325-330. 2. Autry, A.E., Adachi, M., Nosyreva, E., Na, E., Los, M.F., Cheng, P., Kavalali, E.T., Monteggia, L.M. (2011). NMDA Receptor Blockade at Rest Desuppresses Protein Translation and Triggers Rapid Behavioural Antidepressant Responses. Nature, 475(7354) 91-5. 1 Additional Publications 3. Adachi, M.*, Autry, A.E.*, Maghoub, M., Suzuki, K., Monteggia, L.M. (2016). TrkB Signaling in Dorsal Raphe Nucleus is Essential for Antidepressant Efficacy and Normal Aggression Behavior.
    [Show full text]
  • Repeated Administration of Amphetamine Or Cocaine Does Not Alter AMPA Receptor Subunit Expression in the Rat Midbrain Wenxiao Lu, M.D., Lisa M
    Repeated Administration of Amphetamine or Cocaine Does Not Alter AMPA Receptor Subunit Expression in the Rat Midbrain Wenxiao Lu, M.D., Lisa M. Monteggia, Ph.D., and Marina E. Wolf, Ph.D. We previously reported that ventral tegmental area (VTA) withdrawal time. GluR1 immunolabeling was further dopamine neurons are supersensitive to AMPA when examined in rats killed 16–18 hrs or 24 hrs after a single recorded three days after discontinuing repeated injection of amphetamine or repeated injections of saline, amphetamine or cocaine administration. By increasing amphetamine (5 mg/kg ϫ 5 days) or cocaine (20 mg/kg ϫ 7 dopamine cell activity, this may contribute to the induction days). No significant differences were observed in any of behavioral sensitization. The goal of this study was to region. Finally, neither repeated amphetamine or cocaine determine if increased sensitivity to AMPA reflects administration significantly altered GluR1 mRNA levels as increased AMPA receptor expression in the midbrain. quantified by reverse transcriptase-polymerase chain reaction. Immunolabeling for GluR1, GluR2, GluR2/3, and GluR4 Our results suggest that enhanced responsiveness of VTA was quantified by immunohistochemistry with 35S-labeled dopamine neurons to AMPA after withdrawal from repeated secondary antibodies in VTA, substantia nigra, and a stimulant administration involves mechanisms more complex transitional area. First, rats were treated for five days with than increased expression of AMPA receptor subunits. saline or amphetamine (5 mg/kg) and killed three or 14 days [Neuropsychopharmacology 26:1–13, 2002] after the last injection. No significant changes in © 2001 American College of Neuropsychopharmacology. immunolabeling were observed for any subunit at either Published by Elsevier Science Inc.
    [Show full text]
  • Exploring Mechanisms of Depression-Related Behavior and Rapid Antidepressant Action
    MOLECULAR MECHANISMS UNDERLYING DEPRESSION-RELATED BEHAVIOR AND RAPID ANTIDEPRESSANT ACTION APPROVED BY SUPERVISORY COMMITTEE ________________________________________ Lisa Monteggia, Ph.D. ________________________________________ Kimberly Huber, Ph.D. ________________________________________ Ege Kavalali, Ph.D. ________________________________________ Carol Tamminga, M.D. Dedicated to my mom and dad Nick and Rita Autry, To my husband John Dixon, And to my family and friends For their unconditional love and support. EXPLORING MECHANISMS OF DEPRESSION-RELATED BEHAVIOR AND RAPID ANTIDEPRESSANT ACTION By ANITA ELLEN AUTRY DISSERTATION Presented to the Faculty of the Graduate School of Biomedical Sciences The University of Texas Southwestern Medical Center at Dallas In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY The University of Texas Southwestern Medical Center at Dallas Dallas, Texas April 2011 Copyright By ANITA ELLEN AUTRY, 2011 All rights reserved ACKNOWLEDGEMENTS I must first thank my mentor, Lisa Monteggia, Ph.D., for unwavering support, guidance, excellent mentorship, and being a role model both in and out of the laboratory. I would also like to thank Ege Kavalali, Ph.D. for teaching me neuroscience and for giving experimental advice as well as constructive criticism. I am also grateful to my thesis committee members Kimberly Huber, Ph.D., and Carol Tamminga, M.D., for insightful comments and direction over the years. I would like to thank Larry Reagan, Ph.D. for introducing me to research as well as past and present members of his lab, Claudia Grillo, Ph.D., Gerardo Piroli, Ph.D., and Leah Reznikov, Ph.D. I would like to thank Leslie Jones, Ph.D., for continuing advisement and support.
    [Show full text]
  • Synaptic Mechanisms Underlying Treatment of Depression and Bipolar Disorder Approved by Supervisory Committee
    SYNAPTIC MECHANISMS UNDERLYING TREATMENT OF DEPRESSION AND BIPOLAR DISORDER APPROVED BY SUPERVISORY COMMITTEE __________________________________________ Lisa Monteggia, Ph.D. __________________________________________ Mark Goldberg, M.D. __________________________________________ Ege Kavalali, Ph.D. __________________________________________ Adrian Rothenfluh, Ph.D. Dedicated to my parents, Heinrich and Jo Ann, my brothers Chris and Adam and their families, my grandfather Linwood, my dog Lina, my boyfriend Jerry, and the rest of my family and friends for their unending love and support. ii SYNAPTIC MECHANISMS UNDERLYING TREATMENT OF DEPRESSION AND BIPOLAR DISORDER by ERINN SOMMER GIDEONS DISSERTATION Presented to the Faculty of the Graduate School of Biomedical Sciences The University of Texas Southwestern Medical Center at Dallas In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY The University of Texas Southwestern Medical Center Dallas, Texas August 2016 iii Copyright by Erinn Sommer Gideons, 2016 All Rights Reserved iv ACKNOWLEDGEMENTS I would first like to thank my advisor Dr. Lisa Monteggia for her continual support, guidance, and patience during my time at UT-Southwestern. She has taught me how to be a successful scientist on many levels and is a true role model of a successful woman in science. I am extremely grateful for her mentorship and guidance. I would also like to thank Dr. Ege Kavalali not only for his experimental advice, but also for the many conversations about topics not dealing with science. I would not be an electrophysiologist without his influence. I want to think the current and past members of the Monteggia and Kavalali labs, especially Dr. Megumi Adachi, Dr. Anita Autry, and Pei-Yi Lin for taking me under their wings and teaching me about science and their continued friendship.
    [Show full text]