DOCSLIB.ORG

September, 2009

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

NIDA - Director's Report - September, 2009 NIDA Home > Publications > Director's Reports Director's Report to the National Advisory Council on Drug Abuse - September, 2009 Index Research Findings Multi-Division Research Basic Neurosciences Research Basic Behavioral Research Behavioral and Brain Development Research Clinical Neuroscience Research Epidemiology and Etiology Research Prevention Research Research on Behavioral and Combined Treatments for Drug Abuse Research on Pharmacotherapies for Drug Abuse Research on Medical Consequences of Drug Abuse and Co-Occurring Infections (HIV/AIDS, HCV) Services Research Clinical Trials Network Research International Research Intramural Research Program Activities Extramural Policy and Review Activities Congressional Affairs International Activities Meetings and Conferences Media and Education Activities Planned Meetings Publications Staff Highlights Grantee Honors https://archives.drugabuse.gov/DirReports/DirRep909/Default.html[11/17/16, 11:20:48 PM] NIDA - Director's Report - September, 2009 Archive Home | Accessibility | Privacy | FOIA (NIH) | Current NIDA Home Page The National Institute on Drug Abuse (NIDA) is part of the National Institutes of Health (NIH) , a component of the U.S. Department of Health and Human Services. Questions? _ See our Contact Information. https://archives.drugabuse.gov/DirReports/DirRep909/Default.html[11/17/16, 11:20:48 PM] NIDA - Director's Report - September, 2009 NIDA Home > Publications > Director's Reports > September, 2009 Index Director's Report to the National Advisory Council on Drug Abuse - September, 2009 Index Research Findings - Basic Neuroscience Research Research Findings Toll-Like Receptor-3 Activation in Human Neuronal Cells Induces Basic Neurosciences Interferon-λ Expression Research Basic Behavioral Research Interferon lambda (IFN-λ) belongs to the type III family of IFNs which when activated exerts antiviral, antitumor and immunoregulatory activities. Toll-like Behavioral and Brain receptors (TLRs) are a family of receptors that mediate innate immune Development Research responses to stimuli from pathogens and endogenous signals. It has been Clinical Neuroscience shown that agonists of TLR-3 can induce IFN-λ production in macrophages or Research plasmacytoid dendritic cells. Little is known about IFN-λ expression in human Epidemiology and Etiology neuronal cells and whether IFN-λ expression in human neuron relies on the TLR Research ligand activation. Human neuronal cells expressed endogenous IFN-λ1, but not IFNλ2/3, however upon activation of TLR-3 in neuronal cells all three Prevention Research structurally related cytokines were significantly induced. Activation of TLR-3 Research on Behavioral and also exhibited antiviral activity against pseudotyped HIV-1 infection of the Combined Treatments for neuronal cells. Human neuronal cells also expressed functional IFN-λ receptors Drug Abuse which when activated inhibited pseudotyped HIV-1 infection and induced Research on APOBEC 3G/3F, anti-HIV-1 cellular factors. This paper provides compelling Pharmacotherapies for Drug evidence that there is intracellular expression and regulation of IFN-λ in human Abuse neuronal cells, which may have a major role in the innate neuronal protection Research on Medical against viral infections in the CNS. Zhou L, Wang X, Wang YJ, Zhou Y, Hu S, Ye Consequences of Drug L, Hou W, Li H, Ho WZ. Activation of Toll-Like receptor-3 induces interferon-λ Abuse and Co-Occurring expression in human neuronal cells. Neuroscience. 2009 Mar 17;159(2):629- Infections (HIV/AIDS, HCV) 637. Services Research Chronic Cocaine Enhances Stress-Induced Potentiation of Clinical Trials Network Excitatory (Glutamatergic) Neurotransmission in Dopamine Research Neurons within the VTA International Research Intramural Research Current concepts suggest that stress-induced release of neuromodulators such as corticotropin-releasing factor (CRF) can drive drug-dependent behaviors. Program Activities Furthermore, prior drug exposure can enhance behavioral and neurochemical responses to stress. Previously, it had been shown that CRF can enhance Extramural Policy and NMDA-type glutamatergic transmission. This paper now shows that after Review Activities repeated cocaine exposure, the magnitude and duration of the CRF-induced potentiation of NMDA receptor-mediated neurotransmission is significantly Congressional Affairs increased within ventral tegmental area (VTA) dopamine neurons, a key locus of drug- and stress-induced neuroadaptation. Furthermore, although CRF itself International Activities does not enhance AMPA-type glutamatergic transmission, CRF did enhance AMPA receptor-mediated transmission in mice that were exposed to chronic Meetings and Conferences cocaine. Importantly, pharmacological experiments revealed that CRF receptor 1 and protein kinase A pathways were newly recruited after repeated cocaine Media and Education for the enhancement of CRF-induced NMDAR potentiation and the appearance Activities of AMPAR potentiation. Thus, enhanced CRF-induced potentiation of excitatory https://archives.drugabuse.gov/DirReports/DirRep909/DirectorReport1.html[11/17/16, 11:20:52 PM] NIDA - Director's Report - September, 2009 synaptic transmission onto VTA dopamine neurons after cocaine preexposure is Planned Meetings likely to produce an abnormal increase in dopamine release during stressful events and could augment activation of addictive behaviors in response to Publications stress. Hahn J, Hopf FW, Bonci A. Chronic cocaine enhances corticotropin- releasing factor-dependent potentiation of excitatory transmission in ventral Staff Highlights tegmental area dopamine neurons. J Neurosci. 2009 May 20;29(20):6535- 6544. Grantee Honors Impaired Synaptic Plasticity Following Chronic Cocaine Dr. Peter Kalivas and colleagues have been providing novel evidence that chronic drug abuse results in future deficits in the ability to generate synaptic plasticity (for review, see Kalivas PW. Nat Rev Neurosci. 2009 Aug;10(8):561- 572). In the present study, his group sought to determine whether withdrawal from repeated cocaine administration can alter the capacity of a subsequent cocaine injection to elicit morphological, biochemical, and physiological plasticity. Three weeks after termination of chronic daily cocaine or saline administration, the researchers filled neurons in the nucleus accumbens with the lipophilic dye, DiI. They observed a shift to larger diameter spines in the daily cocaine-pretreated rats. During the first 2 hours after an acute cocaine challenge, a bidirectional change in spine head diameter and increase in spine density was measured in the daily cocaine-pretreated animals. In contrast, no change in spine diameter or density was elicited by a cocaine challenge in daily saline animals during the first 2 hours after injection. However, spine density was elevated at 6 hours after a cocaine challenge in daily saline-pretreated animals. The time-dependent profile of proteins in the postsynaptic density subfraction of neurons elicited by a cocaine challenge in daily cocaine- pretreated subjects indicated that the changes in spine diameter and density were associated with a deteriorating actin cytoskeleton and a reduction in glutamate signaling-related proteins. Correspondingly, the amplitude of field potentials in accumbens evoked by stimulating prefrontal cortex was reduced for up to 6 hours after acute cocaine in daily cocaine-withdrawn animals. These data indicate that daily cocaine pretreatment dysregulates dendritic spine plasticity elicited by a subsequent cocaine injection. In humans, the altered drug experience caused by previous drug abuse may underlie diminishing behavioral control and contribute to a progressively deteriorating disorder. Shen H, Toda S, Moussawi K, Bouknight A, Zahm DS, Kalivas PW. Altered dendritic spine plasticity in cocaine-withdrawn rats. J Neurosci. 2009 Mar 4;29(9):2876-2884. Optical Fluorescent Tool Monitors Dopamine Release From Single Presynaptic Terminals Investigators at Columbia University have designed optical tracers of monoaminergic neuro-transmitters, or false fluorescent neurotransmitters, which are taken up by secretory vesicles (VMAT2) and released after stimulation as if they were native transmitters. This has allowed the researchers to examine transmitter accumulation and exocytosis from single presynaptic terminals in the striatum and to make observations relevant to stimulation-dependent synaptic plasticity. They found a relatively low percentage of vesicles fusing to the plasma membrane with each stimulus, and that the release of transmitter differed across separate terminals. That is, some terminals were more active than others; additionally, transmitter release from each terminal also depended on the frequency of stimulation. Further, when the presynaptic autoreceptors on neurons were blocked, release was inhibited from two-thirds of the terminals, which were the terminals that were least active. Thus, activity-dependent terminal heterogeneity is associated with receptor-mediated responses and underscores the presence of frequency- dependent coding that may determine how particular synapses are activated during important functions such as decision-making and learning. Gubernator https://archives.drugabuse.gov/DirReports/DirRep909/DirectorReport1.html[11/17/16, 11:20:52 PM] NIDA - Director's Report - September, 2009 NG, Zhang H, Staal RGW, Mosharov EV, Pereira DB, Yue M, Balsanek V, Vadola PA, Mukerjee B, Edwards RH, Sulzer D, Sames
Recommended publications
  • The Pharmacologist 2 0 0 6 December

    The Pharmacologist 2 0 0 6 December

    Vol. 48 Number 4 The Pharmacologist 2 0 0 6 December 2006 YEAR IN REVIEW The Presidential Torch is passed from James E. Experimental Biology 2006 in San Francisco Barrett to Elaine Sanders-Bush ASPET Members attend the 15th World Congress in China Young Scientists at EB 2006 ASPET Awards Winners at EB 2006 Inside this Issue: ASPET Election Online EB ’07 Program Grid Neuropharmacology Division Mixer at SFN 2006 New England Chapter Meeting Summary SEPS Meeting Summary and Abstracts MAPS Meeting Summary and Abstracts Call for Late-Breaking Abstracts for EB‘07 A Publication of the American Society for 121 Pharmacology and Experimental Therapeutics - ASPET Volume 48 Number 4, 2006 The Pharmacologist is published and distributed by the American Society for Pharmacology and Experimental Therapeutics. The Editor PHARMACOLOGIST Suzie Thompson EDITORIAL ADVISORY BOARD Bryan F. Cox, Ph.D. News Ronald N. Hines, Ph.D. Terrence J. Monks, Ph.D. 2006 Year in Review page 123 COUNCIL . President Contributors for 2006 . page 124 Elaine Sanders-Bush, Ph.D. Election 2007 . President-Elect page 126 Kenneth P. Minneman, Ph.D. EB 2007 Program Grid . page 130 Past President James E. Barrett, Ph.D. Features Secretary/Treasurer Lynn Wecker, Ph.D. Secretary/Treasurer-Elect Journals . Annette E. Fleckenstein, Ph.D. page 132 Past Secretary/Treasurer Public Affairs & Government Relations . page 134 Patricia K. Sonsalla, Ph.D. Division News Councilors Bryan F. Cox, Ph.D. Division for Neuropharmacology . page 136 Ronald N. Hines, Ph.D. Centennial Update . Terrence J. Monks, Ph.D. page 137 Chair, Board of Publications Trustees Members in the News .
  • A Role for Sigma Receptors in Stimulant Self Administration and Addiction

    A Role for Sigma Receptors in Stimulant Self Administration and Addiction

    Pharmaceuticals 2011, 4, 880-914; doi:10.3390/ph4060880 OPEN ACCESS pharmaceuticals ISSN 1424-8247 www.mdpi.com/journal/pharmaceuticals Review A Role for Sigma Receptors in Stimulant Self Administration and Addiction Jonathan L. Katz *, Tsung-Ping Su, Takato Hiranita, Teruo Hayashi, Gianluigi Tanda, Theresa Kopajtic and Shang-Yi Tsai Psychobiology and Cellular Pathobiology Sections, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, 21224, USA * Author to whom correspondence should be addressed; E-Mail: [email protected]. Received: 16 May 2011; in revised form: 11 June 2011 / Accepted: 13 June 2011 / Published: 17 June 2011 Abstract: Sigma1 receptors (σ1Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ1Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that σR antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by σR antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of σR agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the σR agonists were blocked by σR antagonists. Additionally, σR agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs.
  • Download Product Insert (PDF)

    Download Product Insert (PDF)

    PRODUCT INFORMATION 1-Palmitoyl-2-oleoyl-sn-glycero-3-PC Item No. 15102 CAS Registry No.: 26853-31-6 Formal Name: 1-palmitoyl-2-oleoyl-sn-glycero-3- O phosphatidylcholine Synonyms: 1-Palmitoyl-2-oleoyl-sn-glycero-3- O O Phosphocholine, 1,2-POPC O MF: C42H82NO8P FW: 760.1 O N+ Purity: ≥98% O P O Supplied as: A crystalline solid O- Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures 1-Palmitoyl-2-oleoyl-sn-glycero-3-PC (1,2-POPC) is supplied as a crystalline solid. A stock solution may be made by dissolving the 1,2-POPC in the solvent of choice, which should be purged with an inert gas. 1,2-POPC is soluble in the organic solvent ethanol at a concentration of approximately 25 mg/ml. Description 1,2-POPC is a phospholipid containing 16:0 and 18:1 fatty acids at the sn-1 and sn-2 positions, respectively. It belongs to a class of phospholipids that are a major component of biological membranes.1,2 This compound can be used for liposome production in order to study the properties of lipid bilayers. References 1. Moreno, M.J., Estronca, L.M.B.B., and Vaz, W.L.C. Translocation of phospholipids and dithionite permeability in liquid-ordered and liquid-disordered membranes. Biophys. J. 91, 873-881 (2006). 2. Heberle, F.A. and Feigenson, G.W. Phase separation in lipid membranes. Cold Spring Harb. Perspect. Biol. 3(4), 1-13 (2011).
  • 2018 Ibangs Meeting: the 20Th Annual Genes, Brain & Behavior Meeting

    2018 Ibangs Meeting: the 20Th Annual Genes, Brain & Behavior Meeting

    5/25/2018 Program for Thursday, May 17th 2018 IBANGS MEETING: THE 20TH ANNUAL GENES, BRAIN & BEHAVIOR MEETING WELCOME PROGRAM INDEXES PROGRAM FOR THURSDAY, MAY 17TH Days: next day all days View: session overview talk overview 08:30-16:00 Session FV: Pre-IBANGS Satellite Meeting, Functional Validation for Neurogenetics Location: Phillips Hall in the Siebens building room 1-11. The Siebens building is located at the Downtown Mayo Clinic Campus (not the Mayo Civic Center). Description:The transformative nature of next generation sequencing has changed how neuroscientists approach genomic sequence variation. Highly multiplexed molecular testing is providing an expanded level of information from which to make informed phenotypic predictions. The importance of this is reflected in the unprecedented expansion of genomic testing to determine the basis of neurologic conditions. Genomic testing results in many instances provide a definitive basis of a neurologic condition. However, in almost a high proportion of cases, the genomic sequencing results are confounded by the ambiguity of variants with uncertain clinical significance. Herein lies the key with which institutions will lead in the area of genomic medicine. There exists a critical need to provide a mechanism by which uncertain findings can be functionally characterized and translated into clinically actionable results. It is within thisr ealm that academic societies such as IBANGS can have a substantial and informative role on the future of clinical research and practice. This symposium will introduce the challenges and opportunities that exist in the field of human clinical neurogenetics and follow this with presentations of active work in the field of functional genetic finding validation for neurogenetics with a look to the future of genomic neurogenetics.
  • (4,5)-Bisphosphate Destabilizes the Membrane of Giant Unilamellar Vesicles

    (4,5)-Bisphosphate Destabilizes the Membrane of Giant Unilamellar Vesicles

    5112 Biophysical Journal Volume 96 June 2009 5112–5121 Profilin Interaction with Phosphatidylinositol (4,5)-Bisphosphate Destabilizes the Membrane of Giant Unilamellar Vesicles Kannan Krishnan,† Oliver Holub,‡ Enrico Gratton,‡ Andrew H. A. Clayton,§ Stephen Cody,§ and Pierre D. J. Moens†* †Centre for Bioactive Discovery in Health and Ageing, School of Science and Technology, University of New England, Armidale, Australia; ‡Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California, Irvine, California; and §Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia ABSTRACT Profilin, a small cytoskeletal protein, and phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] have been implicated in cellular events that alter the cell morphology, such as endocytosis, cell motility, and formation of the cleavage furrow during cytokinesis. Profilin has been shown to interact with PI(4,5)P2, but the role of this interaction is still poorly understood. Using giant unilamellar vesicles (GUVs) as a simple model of the cell membrane, we investigated the interaction between profilin and PI(4,5)P2. A number and brightness analysis demonstrated that in the absence of profilin, molar ratios of PI(4,5)P2 above 4% result in lipid demixing and cluster formations. Furthermore, adding profilin to GUVs made with 1% PI(4,5)P2 leads to the forma- tion of clusters of both profilin and PI(4,5)P2. However, due to the self-quenching of the dipyrrometheneboron difluoride-labeled PI(4,5)P2, we were unable to determine the size of these clusters. Finally, we show that the formation of these clusters results in the destabilization and deformation of the GUV membrane.
  • Cholesterol in Condensed and Fluid Phosphatidylcholine Monolayers Studied by Epifluorescence Microscopy

    Cholesterol in Condensed and Fluid Phosphatidylcholine Monolayers Studied by Epifluorescence Microscopy

    Biophysical Journal Volume 72 June 1997 2569-2580 2569 Cholesterol in Condensed and Fluid Phosphatidylcholine Monolayers Studied by Epifluorescence Microscopy Lynn-Ann D. Worthman,* Kaushik Nag,* Philip J. Davis,* and Kevin M. W. Keough*# *Department of Biochemistry and #Discipline of Pediatrics, Memorial University of Newfoundland, St. John's, Newfoundland Al B 3X9, Canada ABSTRACT Epifluorescence microscopy was used to investigate the effect of cholesterol on monolayers of dipalmi- toylphosphatidylcholine (DPPC) and 1 -palmitoyl-2-oleoyl phosphatidylcholine (POPC) at 21 ± 20C using 1 mol% 1 -palmitoyl- 2-{1 2-[(7-nitro-2-1, 3-benzoxadizole-4-yl)amino]dodecanoyl}phosphatidylcholine (NBD-PC) as a fluorophore. Up to 30 mol% cholesterol in DPPC monolayers decreased the amounts of probe-excluded liquid-condensed (LC) phase at all surface pressures (ir), but did not effect the monolayers of POPC, which remained in the liquid-expanded (LE) phase at all 7r. At low (2-5 mN/m), 10 mol% or more cholesterol in DPPC induced a lateral phase separation into dark probe-excluded and light probe-rich regions. In POPC monolayers, phase separation was observed at low IT when .40 mol% or more cholesterol was present. The lateral phase separation observed with increased cholesterol concentrations in these lipid monolayers may be a result of the segregation of cholesterol-rich domains in ordered fluid phases that preferentially exclude the fluorescent probe. With increasing 7r, monolayers could be transformed from a heterogeneous dark and light appearance into a homogeneous fluorescent phase, in a manner that was dependent on ir and cholesterol content. The packing density of the acyl chains may be a determinant in the interaction of cholesterol with phosphatidylcholine (PC), because the transformations in monolayer surface texture were observed in phospholipid (PL)/sterol mixtures having similar molecular areas.
  • Neuropharmacology and Toxicology of Novel Amphetamine-Type Stimulants

    Neuropharmacology and Toxicology of Novel Amphetamine-Type Stimulants

    Neuropharmacology and toxicology of novel amphetamine-type stimulants Bjørnar den Hollander Institute of Biomedicine, Pharmacology University of Helsinki Academic Dissertation To be presented, with the permission of the Medical Faculty of the University of Helsinki, for public examination in lecture hall 2, Biomedicum Helsinki 1, Haartmaninkatu 8, on January 16th 2015 at 10 am. Helsinki 2015 Supervisors Thesis committee Esa R. Korpi, MD, PhD Eero Castrén, MD, PhD Institute of Biomedicine, Pharmacology Neuroscience Center Faculty of Medicine University of Helsinki P.O. Box 63 (Haartmaninkatu 8) P.O. Box 56 (Viikinkaari 4) 00014 University of Helsinki, Finland 00014 University of Helsinki, Finland Esko Kankuri, MD, PhD Sari Lauri, PhD Institute of Biomedicine, Pharmacology Neuroscience Center and Faculty of Medicine Department of Biosciences/ Physiology P.O. Box 63 (Haartmaninkatu 8) University of Helsinki 00014 University of Helsinki, Finland P.O.Box 65 (Viikinkaari 1) 00014 University of Helsinki, Finland Reviewers Dissertation opponent Atso Raasmaja, Professor, PhD Prof David Nutt DM FRCP FRCPsych Division of Pharmacology and FMedSci Pharmacotherapy Edmond J. Safra Chair of Faculty of Pharmacy Neuropsychopharmacology P. O. Box 56 (Viikinkaari 5E) Division of Brain Sciences 00014 University of Helsinki, Finland Dept of Medicine Imperial College London Petri J. Vainio, MD, PhD Burlington Danes Building Pharmacology, Drug Development and Hammersmith Hospital Therapeutics Du Cane Road Institute of Biomedicine London W12 0NN, United Kingdom Faculty of Medicine Kiinamyllynkatu 10 C 20014 University of Turku, Finland The cover layout is done by Anita Tienhaara. The cover photo is by Edd Westmacott and shows a close-up of ecstasy tablets, photographed in Amsterdam in 2004.
  • Chiral Supramolecular Architecture of Stable Transmembrane Pores

    Chiral Supramolecular Architecture of Stable Transmembrane Pores

    www.nature.com/scientificreports OPEN Chiral supramolecular architecture of stable transmembrane pores formed by an α-helical antibiotic peptide in the presence of lyso- lipids Erik Strandberg1, David Bentz2, Parvesh Wadhwani1 & Anne S. Ulrich1,2* The amphipathic α-helical antimicrobial peptide MSI-103 (aka KIA21) can form stable transmembrane pores when the bilayer takes on a positive spontaneous curvature, e.g. by the addition of lyso-lipids. Solid-state 31P- and 15N-NMR demonstrated an enrichment of lyso-lipids in these toroidal wormholes. Anionic lyso-lipids provided additional stabilization by electrostatic interactions with the cationic peptides. The remaining lipid matrix did not afect the nature of the pore, as peptides maintained the same orientation independent of lipid charge, and a change in membrane thickness did not considerably afect their tilt angle. Under optimized conditions (i.e. in the presence of lyso-lipids and appropriate bilayer thickness), stable and well-aligned pores could be obtained for solid-state 2H-NMR analysis. These data revealed for the frst time the complete 3D alignment of this representative amphiphilic peptide in fuid membranes, which is compatible with either monomeric helices as constituents, or left- handed supercoiled dimers as building blocks from which the overall toroidal wormhole is assembled. Membrane-active antimicrobial peptides (AMPs) can kill microorganisms by permeabilizing the cell mem- brane. They are attracting much attention as potential new antibiotics against the increasingly common multidrug-resistant bacterial strains1–4. While it is clear that these peptides can target a wide range of microorgan- isms, the molecular mechanisms of membrane permeabilization are not yet fully characterized.

  • Effects of Antidepressants on the Conformation of Phospholipid Headgroups Studied by Solid-State NMR

    MAGNETIC RESONANCE IN CHEMISTRY Magn. Reson. Chem. 2004; 42: 105–114 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrc.1327 Effects of antidepressants on the conformation of phospholipid headgroups studied by solid-state NMR Jose S. Santos,1† Dong-Kuk Lee1,2 and Ayyalusamy Ramamoorthy1,2,3∗ 1 Biophysics Research Division, University of Michigan, Ann Arbor, Michigan 48109-1055, USA 2 Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA 3 Macromolecular Science and Engineering, University of Michigan, Ann Arbor, Michigan 48109-1055, USA Received 10 June 2003; Revised 25 August 2003; Accepted 1 September 2003 The effect of tricyclic antidepressants (TCA) on phospholipid bilayer structure and dynamics was studied to provide insight into the mechanism of TCA-induced intracellular accumulation of lipids (known as lipidosis). Specifically we asked if the lipid–TCA interaction was TCA or lipid specific and if such physical interactions could contribute to lipidosis. These interactions were probed in multilamellar vesicles and mechanically oriented bilayers of mixed phosphatidylcholine–phosphatidylglycerol (PC–PG) phospholipids using 31Pand14N solid-state NMR techniques. Changes in bilayer architecture in the presence of TCAs were observed to be dependent on the TCA’s effective charge and steric constraints. The results further show that desipramine and imipramine evoke distinguishable changes on the membrane surface, particularly on the headgroup order, conformation and dynamics of phospholipids. Desipramine increases the disorder of the choline site at the phosphatidylcholine headgroup while leaving the conformation and dynamics of the phosphate region largely unchanged. Incorporation of imipramine changes both lipid headgroup conformation and dynamics.
  • Diethylstilbestrol Modifies the Structure of Model Membranes And

    Diethylstilbestrol Modifies the Structure of Model Membranes And

    biomolecules Article DiethylstilbestrolArticle Modifies the Structure of Model Membranes Diethylstilbestrol Modifies the Structure of Model Membranes andand Is Is Localized Localized Close Close to the First Carbons of the Fatty Acyl Chains AlessioAlessio Ausili, Inés Inés Rodríguez-González, Rodríguez-González, Alejandro Torrecillas, JosJoséé A.A. TeruelTeruel andand JuanJuan C.C. GGómez-Fernándezómez-Fernández ** Departamento de Bioquímica y Biología Molecular “A”, Facultad de Veterinaria, Regional Campus of Departamento de Bioquímica y Biología Molecular “A”, Facultad de Veterinaria, Regional Campus of International Excellence “Campus Mare Nostrum”, Universidad de Murcia, Apartado de Correos 4021, International Excellence “Campus Mare Nostrum”, Universidad de Murcia, Apartado de Correos 4021, E-30080-Murcia, Spain; [email protected] (A.A.); [email protected] (I.R.-G.); [email protected] (A.T.); E-30080 Murcia, Spain; [email protected] (A.A.); [email protected] (I.R.-G.); [email protected] (A.T.); [email protected] (J.A.T.) [email protected] (J.A.T.) ** Correspondence: [email protected]; Tel.: +34 +34-868-884-766;-868-884-766; Fax: +34968364147 +34-968-364-147 Abstract:Abstract: TheThe synthetic synthetic estrogen estrogen diethylstilbestrol diethylstilbestrol (DES) (DES) is is used used to to treat treat metastatic metastatic carcinomas carcinomas and and prostateprostate cancer. cancer. We We studied studied its its interaction interaction with with membranes membranes and and its its localization to to understand its its mechanismmechanism of of action action and and side-effects. side-effects. We We used used differential differential scanning scanning calorimetry calorimetry (DSC) (DSC) showing showing that DESthat fluidized DES fluidized the membrane the membrane and has and poor has solubility poor solubility in DMPC in DMPC (1,2-dimyristoyl- (1,2-dimyristoyl-sn-glycero-3-phos-sn-glycero-3- phocholine)phosphocholine) in the influid the state.
  • CPDD 77Th Annual Meeting • Arizona Biltmore, Phoenix, Arizona

    CPDD 77Th Annual Meeting • Arizona Biltmore, Phoenix, Arizona

    CPDD 77th Annual Meeting • Arizona Biltmore, Phoenix, Arizona 1 2 EFFECT OF HEMISPHERIC DOMINANT VERSUS NON- SEX, DRUGS, AND VIOLENCE: AN ANALYSIS OF WOMEN IN DOMINANT INSULAR DAMAGE ON SMOKING BEHAVIORS. DRUG COURT. Amir Abdolahi1,2, Geoffrey Williams2, Curtis Benesch2, Henry Wang2, Eric Abenaa Acheampong2, Catherine W Striley3, David O Fakunle1, Linda Cottler3; Spitzer3, Bryan Scott3, Robert Block2, Edwin van Wijngaarden2; 1Philips 1Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Research, Briarcliff Manor, NY, 2University of Rochester, Rochester, NY, MD, 2University of Florida, Gainesville, FL, 3Epidemiology, University of 3Rochester General Health System, Rochester, NY Florida, Gainesville, FL Aims: Recent evidence suggests that damage to the insular cortex (IC), the cere- Aims: This analysis examines exposure to violence and substance use disorders bral cortex beneath the sylvian fissure, disrupts nicotine-induced cravings and is among women in drug court who are: current sex traders (CST), former sex associated with a greater likelihood of cessation relative to non-IC damage. The traders (FST), or women who have never traded sex. role hemispheric dominance may play in regulating these changes, however, has Methods: Data comes from 319 women recruited from a Municipal Drug Court not yet been explored. We hypothesized that current smokers with damage to System in the Midwest. Women were interviewed about sex trading, violence, their dominant IC would experience less withdrawal and cravings and be more and drug use. Women who traded sex in the past 4 months for drugs, alcohol, likely to quit than those with non-dominant IC damage. or other resources were classified as CST, while women who previously traded Methods: A total of 37 smokers with unilateral IC strokes (17 dominant and 20 sex but not in the past 4 months were classified as FST.
  • Discovery of E1r: a Novel Positive Allosteric Modulator of Sigma-1 Receptor

    Discovery of E1r: a Novel Positive Allosteric Modulator of Sigma-1 Receptor

    Edijs Vāvers DISCOVERY OF E1R: A NOVEL POSITIVE ALLOSTERIC MODULATOR OF SIGMA-1 RECEPTOR Doctoral Thesis for obtaining the degree of Doctor of Pharmacy Speciality − Pharmaceutical Pharmacology Scientific supervisor: Dr. pharm., Professor Maija Dambrova Riga, 2017 ANNOTATION Sigma-1 receptor (Sig1R) is a new drug target. Notably, the International Union of Basic and Clinical Pharmacology included Sig1R in its list of receptors only in 2013. It is believed that Sig1R ligands are potential novel drug candidates for the treatment of central and peripheral nervous system diseases. The aim of this thesis was to evaluate the pharmacological activity of novel Sig1R ligands and to search for their possible clinical applications. Methylphenylpiracetam (2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide) was synthesised in the Latvian Institute of Organic Synthesis. There are two chiral centres in the molecular structure of methylphenylpiracetam; therefore, it is possible to isolate four individual stereoisomers, which are denoted E1R, T1R, E1S and T1S. The activity of E1R was profiled using commercially available screening assays, which showed that the compound selectively modulates Sig1R activity but does not affect the other investigated neuronal receptors and ion channels. The following detailed in vitro studies, in which more selective Sig1R ligands were used, provided solid evidence that E1R is a positive allosteric modulator of Sig1R. It was found that the enantiomers with the R-configuration at the C-4 chiral centre in the 2-pyrrolidone ring (E1R and T1R) are more effective positive allosteric modulators of Sig1R than their optical antipodes. Since Sig1R agonists demonstrate neuroprotective properties and are effective in the treatment of cognitive disorders of various origins, the activity of E1R was tested in experimental models in vivo.