Problems of Drug Dependence 1997: Proceedings of the 59Th Annual Scientific Meeting the College on Problems of Drug Dependence, Inc

Total Page:16

File Type:pdf, Size:1020Kb

Problems of Drug Dependence 1997: Proceedings of the 59Th Annual Scientific Meeting the College on Problems of Drug Dependence, Inc National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Problems of Drug Dependence 1997: Proceedings of the 59th Annual Scientific Meeting The College on Problems of Drug Dependence, Inc. U.S. Department of Health and Human1 Services78 • National Institutes of Health BOARD OF DIRECTORS Steven G. Holtzman, Ph.D., President Scott E. Lukas, Ph.D. Linda A. Dykstra, Ph.D., President-elect Billy R. Martin, Ph.D. Robert L. Balster, Past-president A. Thomas McLellan, Ph.D. George E. Bigelow, Ph.D., Treasurer Roy W. Pickens, Ph.D. Richard Bonnie, L.L.B. Frank Porreca, Ph.D. Linda B. Cottler, Ph.D., M.P.H. Beny J. Primm, M.D. Harriet de Wit, Ph.D. Peter Reuter, Ph.D. Avram Goldstein, M.D. Sidney H. Schnoll, M.D., Ph.D. Dorothy Hatsukami, Ph.D. Charles R. Schuster, Ph.D. John Hughes, M.D. James E. Smith, Ph.D. M. Ross Johnson, Ph.D. Maxine L. Stitzer, Ph.D. Michael J. Kuhar, Ph.D. Alice M. Young, Ph.D. EXECUTIVE OFFICER Martin W. Adler, Ph.D. SCIENTIFIC PROGRAM COMMITTEE Thomas R. Kosten, Chair Martin W. Adler James Anthony Maureen Bronson Kathryn A. Cunningham Ellen B. Geller M. Ross Johnson Reese T. Jones Mary J. Kreek Sidney H. Schnoll Charles R. Schuster Maxine L. Stitzer George R. Uhl i TABLE OF CONTENTS PLENARY SESSION In Memoriam: Sydney Archer, Ph.D. - January 23, 1926 - August 22, 1997 J. M. Bidlack 1 The National Institute on Drug Abuse: A. I. Leshner 3 Introduction of the Nathan B. Eddy Memorial Award Recipient W. L. Dewey 9 Nathan B. Eddy Award Lecture M. W. Adler 11 SYMPOSIUM IV Opioids and Neuropeptides in Immune Function and Host Defenses Against Retroviruses T. Eisenstein and J. Madden, Chairpersons 23 SYMPOSIUM V The Effects of Prenatal Cocaine Exposure on CNS Development S. Mackler, Choir 27 SYMPOSIUM VI Drugs of Abuse, Impulsivity and Risk Taking H. de Wit and Gene Heyman, Chairpersons 30 SYMPOSIUM VII Recent Progress in Transporter Research M. Kuhar and J. Justice, Chairpersons 33 SYMPOSIUM VIII Drug Dependence and the Genome T. Kosten, Chair 36 SYMPOSIUM IX Current HIV and Drug Abuse Prevention Research Findings and Future Directions S. Coyle and R. Needle, Chairpersons 39 SYMPOSIUM X Approaches to the Molecular Genetics of Drug Abuse George Uhl, Chair 40 SYMPOSIUM XI Ethical Laboratory Research with Humans: The Devil is in the Details M. Fischman and C.-E. Johanson, Chairpersons 41 SYMPOSIUM XIII Novel Applications of Human Drug Discrimination of Understanding Effects C. Rush and J. Kamien, Chairpersons 45 ii SYMPOSIUM XIV PTSD and Substance Abuse: Nosology, Epidemiology, Genetics and Neurobiology N. Breslau and R. Price, Chairpersons 48 SYMPOSIUM XV HIV in the Brain B. Hoffer, Choir 52 SYMPOSIUM XVI Combined Cocaine and Opioid Abuse: From Neurobiology to the Clinic S. S. Negus and 1. Rowlett, Chairpersons 55 WORKSHOPS Making Audiences AMAZED, Not GLAZED: Techniques for Improving Presentations R. Eisenberg and F. George, Chairpersons 58 Food, Sex and Drug Incentives: Implications of a Common Substrate for Development of Anti-Craving Medications F. Vocci, A. R. Childress, Chairpersons 59 Fighting Back - Community Interventions to Reduce Drug Abuse R. S. Schottenfeld and C. Winick, Chairpersons 61 ORAL COMMUNICATIONS I Nicotine: Laboratory and Clinical Studies 64 ORAL COMMUNICATIONS II Marijuana: Clinical Studies 68 ORAL COMMUNICATIONS III Benzodiazepines 72 ORAL COMMUNICATIONS IV Medicinal Chemistry: Cocaine and Opioids 76 ORAL COMMUNICATIONS V Neurobiology of Stimulants 81 ORAL COMMUNICATIONS VI Analgesia 85 ORAL COMMUNICATIONS VII Treatment for Opioid Dependence 8 9 ORAL COMMUNICATIONS VIII Cannahinoids: Chemistry, Receptors and Behavior 93 ORAL COMMUNICATIONS IX Treatment for Stimulant Addictions 96 iii ORAL COMMUNICATIONS X HIV/AIDS: Risk Behaviors 101 ORAL COMMUNICATIONS XI Effects of Stimulants in Human Subjects 104 ORAL COMMUNICATIONS XII Opioids: Behavioral Studies 107 ORAL COMMUNICATIONS XIII Effects on the Immune System 112 ORAL COMMUNICATIONS XIV Alcohol 118 ORAL COMMUNICATIONS XV Perinatal Substance Abuse 122 ORAL COMMUNICATIONS XVI Opioid Receptors and Signal Transduction 126 ORAL COMMUNICATIONS XVII Psychiatric Comorbidity in Drug Abusers 129 ORAL COMMUNICATIONS XVIII Drug Use in Pregnancy 133 POSTER SESSION I 137 Treatment of Cocaine Dependence Imaging Nicotine Opioids: Chemistry, Molecular Biology, Physiology and Behavior Benzodiazepines and Barbiturates HIV/AIDS: Risk Prevention POSTER SESSION II 187 HIV/AIDS: Risk Reduction, Testing, Treatment, CNS Effects Drug Effects on Immune Function and Health Cardiovascular Effects of Cocaine Cocaine: Behavior Pharmacokinetics: Drug Testing Analgesia PCP, NMDA and Sigma Receptors; Inhalants Marijuana, Cannabinoids iv POSTER SESSIONS III 241 Alcohol Family Risk Factors Adolescents Comorbidity of Substance Abuse and Psychiatric Disorders Drugs and Crime Employment Research Design and Analysis Dopamine and Serotonin Caffeine POSTER SESSIONS IV 288 Amphetamines Cocaine: Motor Effects Treatment for Opiate Dependence Polydrug Abuse Drug Abuse in Women Substance Abuse in Pregnancy LATE ABSTRACTS 344 ANNUAL REPORTS BIOLOGICAL EVALUATION OF COMPOUNDS FOR THEIR PHYSICAL DEPENDENCE POTENTIAL AND ABUSE LIABILITY. XXI. DRUG EVALUATION COMMITTEE OF THE COLLEGE ON PROBLEMS OF DRUG DEPENDENCE (1997) A. E. Jacobson, Biological Coordinator, Drug Evaluation Committee, CPDD 346 DEPENDENCE STUDIES OF NEW COMPOUNDS IN THE RHESUS MONKEY, RAT AND MOUSE (1997) M. D. Aceto, E. R. Bowman, L. S. Harris, and E. L. May 363 EVALUATION OF NEW COMPOUNDS FOR OPIOID ACTIVITY (1997) J. H. Woods, F. Medzihradsky, C. B. Smith, R. R. Butelman, and G. Winger 408 PROGRESS REPORT FROM THE TESTING PROGRAM FOR STIMULANT AND DEPRESSANT DRUGS (1996) C. P. France, L. R. Gerak, J. K. Rowlett, W. L. Woolverlon, G. Winger, and J. H. Woods 429 STANDARD BINDING AND FUNCTIONAL ASSAYS RELATED TO MEDICATIONS DEVELOPMENT DIVISION TESTING FOR POTENTIAL COCAINE AND OPIATE NARCOTIC TREATMENT MEDICATIONS L. Toll, I. P. Berzetei-Gurske, W. E. Polgar, S. R. Brandt, I. D. Adapa, L. Rodriguez, R. W. Schwartz, D. Haggart, A. O’Brien, A. White, J. M. Kennedy, K. Craymer, L. Farrington, and J. S. Auh 440 AUTHOR INDEX 467 SUBJECT INDEX 483 v IN MEMORIAM SYDNEY ARCHER January 23, 1917 - August 22, 1997 Dr. Sydney Archer, a Research Professor and former Dean of Science at Rensselaer Polylechnic Institute, died from a stroke on August 22, 1996 in Albany, New York. Syd, as he was known to his numerous colleagues and friends, was a Charter Fellow and former member of the Board of Directors of the Committee (now College) on Problems of Drug Dependence. He was an active participant in CPDD meetings for more man four decades. Syd was born in Brooklyn on January 23, 1917. He received his B.S. in Chemistry from the University of Wisconsin in 1937. After completing his Ph.D. in Organic Chemistry at Pennsylvania State University in 1940, he was a postdoctoral fellow at Northwestern University and the University of Chicago. In 1943, Syd started his career at Sterling-Winthrop Research Institute as a Research Chemist. He became Director of the Chemistry Division in 1964, and from 1968 to 1973. Syd was Vice President and Associate Director of Research at Sterling- Winthrop. Syd synthesized hundreds of opioids during his tenure at Sterling-Winthrop, including pentazocine and 1 cyclazocine. He was the first to demonstrate that the substitution of a N-cyclopropylmethyl group for the N-methyl group in the benzomorphan series resulted in compounds displaying antagonist properties. Syd was instrumental in introducing partial agonists into the opioid field, compounds with both agonist and antagonist properties. In 1968, he was the recipient of the Medicinal Chemistry Award from the American Chemical Society. While at working at Sterling-Winthrop, Syd was also an Adjunct Professor at Rensselaer Polytechnic Institute, teaching medicinal chemistry in the evenings. His lectures on medicinal chemistry were also well known by his many colleagues, particularly. those that saved on NIDA Study Sections with him. Syd’s enthusiasm for chemistry and its applications was boundless and contagious. Upon retiring from Sterling-Winthrop in 1973. Syd launched a second career, as a Research Professor of Medicinal Chemistry at Rensselaer Polytechnic lnstitute in Troy, New York. He was Dean of the School of Science from 1980 to 1985. Syd played a central role in the creation of the New York State Capital District Center for Drug Abuse Research and Treatment. Holding more man 100 patents. Syd was named Inventor of the Year by the Eastern New York Patent Law Association in 1978. For the past two decades, most of his research in the drug abuse field focused on novel approaches for designing new drugs to treat heroin, cocaine, and alcohol abuse. Also, Syd synthesized a number of fluorescent opioids. He made key contributions in identifying opioid receptors on immune cells, and on microglia, the brain’s macrophages, that can become infected with HIV-1. Syd was continuing to synthesize new compounds up to the time of his death. Syd will be remembered for his inspiration, boundless enthusiasm, and optimistic outlook. He always focused on the future and had an endless supply of new ideas and energy. Also, Syd will be remembered for knowing the best restaurants in the world and for his strong appreciation of classical music. Syd was an extremely supportive colleague, and I was privileged to collaborate with him for a number of years. Syd is survived by his wife. Therese, and his three children, David, Eve, and Daniel. Prepared by: J. M. Bidlack Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 2 DRUG ABUSE AND ADDICTION: RESEARCH PROGRESS AND FUTURE PROSPECTS A. I. Leshner National Institute on Drug Abuse, National Institutes of Health, Rockville, MD I am extremely happy to be here again this year--to have the opportunity to meet face-to-face with so many of the talented scientists who are moving the drug abuse and addiction research field forward and to hear about the great science that you have been doing over the past year.
Recommended publications
  • Antinociceptive Effects of Monoamine Reuptake Inhibitors in Assays of Pain-Stimulated and Pain-Depressed Behaviors
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2012 Antinociceptive Effects of Monoamine Reuptake Inhibitors in Assays of Pain-Stimulated and Pain-Depressed Behaviors Marisa Rosenberg Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Medical Pharmacology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/2715 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. ANTINOCICEPTIVE EFFECTS OF MONOAMINE REUPTAKE INHIBITORS IN ASSAYS OF PAIN-STIMULATED AND PAIN-DEPRESSED BEHAVIOR A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University By Marisa B. Rosenberg Bachelor of Science, Temple University, 2008 Advisor: Sidney Stevens Negus, Ph.D. Professor, Department of Pharmacology/Toxicology Virginia Commonwealth University Richmond, VA May, 2012 Acknowledgement First and foremost, I’d like to thank my advisor Dr. Steven Negus, whose unwavering support, guidance and patience throughout my graduate career has helped me become the scientist I am today. His dedication to education, learning and the scientific process has instilled in me a quest for knowledge that I will continue to pursue in life. His thoroughness, attention to detail and understanding of pharmacology has been exemplary to a young person like me just starting out in the field of science. I’d also like to thank all of my committee members (Drs.
    [Show full text]
  • 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 .
    [Show full text]
  • Ketamine As a Novel Treatment for Major Depressive Disorder and Bipolar Depression: a Systematic Review and Quantitative Meta-Analysis☆
    General Hospital Psychiatry 37 (2015) 178–184 Contents lists available at ScienceDirect General Hospital Psychiatry journal homepage: http://www.ghpjournal.com Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative meta-analysis☆ Ellen E. Lee, M.D., Megan P. Della Selva, M.D., Anson Liu, M.D., Seth Himelhoch, M.D., M.P.H. ⁎ Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD article info abstract Article history: Objective: Given the significant disability, morbidity and mortality associated with depression, the promising Received 9 September 2014 recent trials of ketamine highlight a novel intervention. A meta-analysis was conducted to assess the efficacy Revised 29 December 2014 of ketamine in comparison with placebo for the reduction of depressive symptoms in patients who meet criteria Accepted 8 January 2015 for a major depressive episode. Method: Two electronic databases were searched in September 2013 for English-language studies that were ran- Keywords: domized placebo-controlled trials of ketamine treatment for patients with major depressive disorder or bipolar Ketamine Depression depression and utilized a standardized rating scale. Studies including participants receiving electroconvulsive ther- Therapy apy and adolescent/child participants were excluded. Five studies were included in the quantitative meta-analysis. Meta-analysis Results: The quantitative meta-analysis showed that ketamine significantly reduced depressive symptoms. The overall effect size at day 1 was large and statistically significant with an overall standardized mean difference of 1.01 (95% confidence interval 0.69–1.34) (Pb.001), with the effects sustained at 7 days postinfusion. The heteroge- neity of the studies was low and not statistically significant, and the funnel plot showed no publication bias.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2017/0020892 A1 Thompson Et Al
    US 20170020892A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0020892 A1 Thompson et al. (43) Pub. Date: Jan. 26, 2017 (54) USE OF NEGATIVE MODULATORS OF Related U.S. Application Data GABA RECEPTORS CONTAINING ALPHAS SUBUNITS AS FAST ACTING (60) Provisional application No. 61/972,446, filed on Mar. ANTDEPRESSANTS 31, 2014. (71) Applicant: University of Maryland, Baltimore, Publication Classification Baltimore, MD (US) (51) Int. Cl. A 6LX 3/557 (2006.01) (72) Inventors: Scott Thompson, Baltimore, MD (US); A6II 3/53 (2006.01) Mark D. Kvarta, Ellicott City, MD A6II 45/06 (2006.01) (US); Adam Van Dyke, Baltimore, MD (52) U.S. Cl. (US) CPC ........... A61 K3I/55.17 (2013.01); A61K 45/06 (2013.01); A61 K3I/53 (2013.01) (73) Assignee: University of Maryland, Baltimore, Baltimore, MD (US) (57) ABSTRACT Embodiments of the disclosure include methods and com (21) Appl. No.: 15/300,984 positions related to treatment of one or more medical conditions with one or more negative modulators of GABA (22) PCT Filed: Mar. 31, 2015 receptors. In specific embodiments, depression and/or Sui cidability is treated or ameliorated or prevented with one or (86) PCT No.: PCT/US2O15/023667 more negative modulators of GABA receptors, such as a S 371 (c)(1), partial inverse agonist of a GABA receptor comprising an (2) Date: Sep. 30, 2016 alpha5 subunit. Patent Application Publication Jan. 26, 2017. Sheet 1 of 12 US 2017/002O892 A1 ×1/ /|\ Patent Application Publication Jan. 26, 2017. Sheet 3 of 12 US 2017/002O892 A1 & Patent Application Publication Jan.
    [Show full text]
  • INTERNATIONAL COLLABORATIVE EXERCISES (ICE) Summary Report
    INTERNATIONAL QUALITY ASSURANCE PROGRAMME (IQAP) INTERNATIONAL COLLABORATIVE EXERCISES (ICE) Summary Report SEIZED MATERIALS 2016/1 INTERNATIONAL QUALITY ASSURANCE PROGRAMME (IQAP) INTERNATIONAL COLLABORATIVE EXERCISES (ICE) Table of contents Sample 1 Analysis Page 6 Identified substances Page 6 Statement of findings Page 11 Identification methods Page 20 False positives Page 26 Z-Scores Page 27 Sample 2 Analysis Page 31 Identified substances Page 31 Statement of findings Page 36 Identification methods Page 46 False positives Page 52 Z-Scores Page 53 Sample 3 Analysis Page 56 Identified substances Page 56 Statement of findings Page 61 Identification methods Page 70 False positives Page 76 Z-Scores Page 77 Sample 4 Analysis Page 80 Identified substances Page 80 Statement of findings Page 82 Identification methods Page 88 False positives Page 94 Z-Scores Page 95 Test Samples Information Samples Comments on samples Sample 1 SM-1 was prepared from a seizure containing 50.5 % (w/w) Cocaine base. The test sample also contained caffeine and levamisole. Benzoylecgonine and cinnamoyl cocaine were also detected as minor components. Sample 2 SM-2 was prepared from a seizure containing 13.8 % (w/w) MDMA. The test sample also contained lactose. Sample 3 SM-3 was prepared from a seizure containing 5.5 % (w/w) Amfetamine base. The test sample also contained caffeine and creatine. Sample 4 SM-4 wss a blank test sample prepared from plant material and contained no substances from the ICE menu Samples Substances Concentrations Comments on substances Sample 1 Caffeine - Quantification not required Cocaine 50.5 % Sample 2 3,4-Methylenedioxymetamfetamine (MDMA) 13.8 % Lactose - Quantification not required Sample 3 Amfetamine 5.5 % Caffeine - Quantification not required Sample 4 [blank sample] 2 2016/1-SM Copyright (c) 2016 UNODC Introduction An important element of the UNODC International Quality Assurance Programme (IQAP) is the implementation of the International Collaborative Exercises (ICE).
    [Show full text]
  • Studies on the Pharmacology of Conopharyngine, an Indole Alkaloid of the Voacanga Series
    Br. J. Pharmac. Chemother. (1967), 30, 173-185. STUDIES ON THE PHARMACOLOGY OF CONOPHARYNGINE, AN INDOLE ALKALOID OF THE VOACANGA SERIES BY P. R. CARROLL AND G. A. STARMER From the Department of Pharmacology, University of Sydney, New South Wales, Australia (Received January 17, 1967) Conopharyngine, the major alkaloid present in the leaves of Tabernaemontana (Conopharyngia) pachysiphon var. cumminsi (Stapf) H. Huber was isolated and identified by Thomas & Starmer (1963). The same alkaloid has also been found in the stem bark of a Nigerian variety of the same species by Patel & Poisson (1966) and in the stem bark of Conopharyngia durissima by Renner, Prins & Stoll (1959). Conopharyn- gine is an indole alkaloid of the voacanga type, being 18-carbomethoxy-12,13- dimethoxyibogamine (Fig. 1) and is thus closely related to voacangine and coronaridine. Me.0OC Fig. 1. Conopharyngine (18-carbomethoxy-12,13-dimethoxyibogamine). Some confusion exists in that an alkaloid with an entirely different structure, but also named conopharyngine, was isolated from a cultivated variety of Conopharyngia pachysiphon by Dickel, Lucas & Macphillamy (1959). This compound was shown to be the 3-D-9-glucoside of 55-20a-amino-3 8-hydroxypregnene, and was reported to possess marked hypotensive properties. The presence of steroid alkaloids in the Tabernaemontaneae was hitherto unknown and it was suggested by Raffauf & Flagler (1960) and Bisset (1961) that the plant material was open to further botanical confir- mation. The roots of the conopharyngia species are used in West Africa to treat fever (Kennedy, 1936), including that of malaria (Watt & Breyer-Brandwijk, 1962). The only report on the pharmacology of conopharyngine is that of Zetler (1964), who included it in a study of some of the effects of 23 natural and semi-synthetic alkaloids 174 P.
    [Show full text]
  • Dopamine Reuptake Transporter (DAT) “Inverse Agonism” E Anovel 66 2 67 3 Hypothesis to Explain the Enigmatic Pharmacology of Cocaine 68 4 * 69 5 Q5 David J
    NP5526_proof ■ 24 June 2014 ■ 1/22 Neuropharmacology xxx (2014) 1e22 55 Contents lists available at ScienceDirect 56 57 Neuropharmacology 58 59 60 journal homepage: www.elsevier.com/locate/neuropharm 61 62 63 64 65 1 Dopamine reuptake transporter (DAT) “inverse agonism” e Anovel 66 2 67 3 hypothesis to explain the enigmatic pharmacology of cocaine 68 4 * 69 5 Q5 David J. Heal , Jane Gosden, Sharon L. Smith 70 6 71 RenaSci Limited, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK 7 72 8 73 9 article info abstract 74 10 75 11 76 Article history: The long held view is cocaine's pharmacological effects are mediated by monoamine reuptake inhibition. 12 Available online xxx However, drugs with rapid brain penetration like sibutramine, bupropion, mazindol and tesofensine, 77 13 which are equal to or more potent than cocaine as dopamine reuptake inhibitors, produce no discernable 78 14 Keywords: subjective effects such as drug “highs” or euphoria in drug-experienced human volunteers. Moreover 79 15 Cocaine they are dysphoric and aversive when given at high doses. In vivo experiments in animals demonstrate 80 16 Dopamine reuptake inhibitor that cocaine's monoaminergic pharmacology is profoundly different from that of other prescribed 81 Dopamine releasing agent 17 monoamine reuptake inhibitors, with the exception of methylphenidate. These findings led us to 82 Dopamine transporter fi 18 Inverse agonist conclude that the highly unusual, stimulant pro le of cocaine and related compounds, eg methylphe- 83 19 DAT inverse agonist nidate, is not mediated by monoamine reuptake inhibition alone. 84 We describe the experimental findings which suggest cocaine serves as a negative allosteric 20 Novel mechanism 85 21 modulator to alter the function of the dopamine reuptake transporter (DAT) and reverse its direction of fi 86 22 transport.
    [Show full text]
  • 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.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,940,728 B2
    USOO894.0728B2 (12) UnitedO States Patent (10) Patent No.: US 8,940,728 B2 Mash et al. (45) Date of Patent: Jan. 27, 2015 (54) SUBSTITUTED NORIBOGAINE 5,152.994. A 10/1992 Lotsof 5,283,247 A 2f1994 Dwivedi et al. (71) Applicant: DemeRx, Inc., Miami, FL (US) 5,316,7595,290,784. A 3/19945/1994 Quetal.Rose et al. 5,382,657 A 1/1995 K. tal. (72) Inventors: Deborah C. Mash, Miami, FL (US); 5,426,112 A 6, 1995 ity a Richard D. Gless, Jr., Oakland, CA 5,552,406 A 9, 1996 Mendelson et al. (US); Robert M. Moriarty, Michiana 5,574,052 A 1 1/1996 Rose et al. Shores, IN (US) 5,578,645 A 11/1996 Askanazi et al. s 5,580,876 A 12/1996 Crain et al. 5,591,738 A 1, 1997 LotSof (73) Assignee: DemeRx, Inc., Miami, FL (US) 5,618,555 A 4/1997 Tokuda et al. - 5,703,101 A 12/1997 Rose et al. (*) Notice: Subject to any disclaimer, the term of this 5,726, 190 A 3, 1998 Rose et al. patent is extended or adjusted under 35 S.S.; A s 3. th. 1 U.S.C. 154(b)(b) bybV 144 davs.ayS 5,865.444.wwk A 2/1999 KempfetOSe et al. al. 5,925,634 A 7/1999 Olney (21) Appl. No.: 13/732,751 5,935,975 A 8/1999 Rose et al. 6,211,360 B1 4/2001 Glicket al. (22) Filed: Jan. 2, 2013 6,291.675 B1 9/2001 Coop et al.
    [Show full text]
  • “STOP” and “GO” Pathways for the Treatment of Alcohol Use Disorders
    UCSF UC San Francisco Previously Published Works Title Targeting the intracellular signaling "STOP" and "GO" pathways for the treatment of alcohol use disorders. Permalink https://escholarship.org/uc/item/6hd3x2cv Journal Psychopharmacology, 235(6) ISSN 0033-3158 Authors Ron, Dorit Berger, Anthony Publication Date 2018-06-01 DOI 10.1007/s00213-018-4882-z Peer reviewed eScholarship.org Powered by the California Digital Library University of California Psychopharmacology (2018) 235:1727–1743 https://doi.org/10.1007/s00213-018-4882-z REVIEW Targeting the intracellular signaling “STOP” and “GO” pathways for the treatment of alcohol use disorders Dorit Ron1 & Anthony Berger1 Received: 18 January 2018 /Accepted: 12 March 2018 /Published online: 14 April 2018 # The Author(s) 2018 Abstract In recent years, research has identified the molecular and neural substrates underlying the transition of moderate “social” con- sumption of alcohol to the characteristic alcohol use disorder (AUD) phenotypes including excessive and compulsive alcohol use which we define in the review as the GO signaling pathways. In addition, growing evidence points to the existence of molecular mechanisms that keep alcohol consumption in check and that confer resilience for the development of AUD which we define herein as the STOP signaling pathways. In this review, we focus on examples of the GO and the STOP intracellular signaling pathways and discuss our current knowledge of how manipulations of these pathways may be used for the treatment of AUD. Keywords Alcohol . Addiction . Signaling . Translation . Medication Development . Fyn . mTOR . BDNF . GDNF Introduction medications such as naltrexone, acamprosate, and disulfiram not only are beneficial but also suffer from efficacy and com- Alcohol use disorder (AUD) is a serious worldwide health prob- pliance issues (Wackernah et al.
    [Show full text]
  • GABA Receptors
    D Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews Review No.7 / 1-2011 GABA receptors Wolfgang Froestl , CNS & Chemistry Expert, AC Immune SA, PSE Building B - EPFL, CH-1015 Lausanne, Phone: +41 21 693 91 43, FAX: +41 21 693 91 20, E-mail: [email protected] GABA Activation of the GABA A receptor leads to an influx of chloride GABA ( -aminobutyric acid; Figure 1) is the most important and ions and to a hyperpolarization of the membrane. 16 subunits with γ most abundant inhibitory neurotransmitter in the mammalian molecular weights between 50 and 65 kD have been identified brain 1,2 , where it was first discovered in 1950 3-5 . It is a small achiral so far, 6 subunits, 3 subunits, 3 subunits, and the , , α β γ δ ε θ molecule with molecular weight of 103 g/mol and high water solu - and subunits 8,9 . π bility. At 25°C one gram of water can dissolve 1.3 grams of GABA. 2 Such a hydrophilic molecule (log P = -2.13, PSA = 63.3 Å ) cannot In the meantime all GABA A receptor binding sites have been eluci - cross the blood brain barrier. It is produced in the brain by decarb- dated in great detail. The GABA site is located at the interface oxylation of L-glutamic acid by the enzyme glutamic acid decarb- between and subunits. Benzodiazepines interact with subunit α β oxylase (GAD, EC 4.1.1.15). It is a neutral amino acid with pK = combinations ( ) ( ) , which is the most abundant combi - 1 α1 2 β2 2 γ2 4.23 and pK = 10.43.
    [Show full text]
  • The Alkaloids: Chemistry and Biology
    CONTRIBUTORS Numbers in parentheses indicate the pages on which the authors’ contributions begin. B. EMMANUEL AKINSHOLA (135), Department of Pharmacology, College of Medicine, Howard University, Washington, DC 20059, eakinshola@ howard.edu NORMA E. ALEXANDER (293), NDA International, 46 Oxford Place, Staten Island, NY 10301, [email protected] SYED F. ALI (79, 135), Division of Neurotoxicology, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079, [email protected] KENNETH R. ALPER (1, 249), Departments of Psychiatry and Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, [email protected] MICHAEL H. BAUMANN (79), Clinical Psychopharmacology Section, Intra- mural Research Program, NIDA, National Institutes of Health, Baltimore, MD 21224, [email protected] DANA BEAL (249), Cures-not-Wars, 9 Bleecker Street, New York, NY 10012, [email protected] ZBIGNIEW K. BINIENDA (193), Division of Neurotoxicology, National Cen- ter for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079, [email protected] WAYNE D. BOWEN (173), Laboratory of Medicinal Chemistry, NIDDK, NIH, Building 8 B1-23, 8 Center Drive, MSC 0820, Bethesda, MD 20892, [email protected] FRANK R. ERVIN (155), Department of Psychiatry and Human Genetics, McGill University, Montreal, Quebec H3A 2T5, Canada, md18@musica. mcgill.ca JAMES W. FERNANDEZ (235), Department of Anthropology, University of Chicago, 1126 E. 59th Street, Chicago, IL 60637, jwfi@midway. uchicago.edu xi xii CONTRIBUTORS RENATE L. FERNANDEZ (235), Department of Anthropology, University of Chicago, 1126 E. 59th Street, Chicago, IL 60637, rlf2@midway. uchicago.edu GEERTE FRENKEN (283), INTASH, P.O.
    [Show full text]