Role of Mu-Opioid Receptors in the Behavioral Effects of the Antidepressant

Total Page:16

File Type:pdf, Size:1020Kb

Role of Mu-Opioid Receptors in the Behavioral Effects of the Antidepressant Role of Mu-Opioid Receptors in the Behavioral Effects of the Antidepressant Tianeptine Jaena Han Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2021 © 2021 Jaena Han All Rights Reserved Abstract Role of Mu-Opioid Receptors in the Behavioral Effects of the Antidepressant Tianeptine Jaena Han For over half a century, the monoamine hypothesis has been the dominant theoretical framework guiding depression research and drug development. This hypothesis posits that depression arises from a deficiency in the monoaminergic neurotransmitters serotonin, norepinephrine, and possibly dopamine, and that antidepressants function by increasing extracellular availability of these monoamines in the brain, especially at the synaptic level. It is clear however, that the monoamine hypothesis cannot fully explain either the pathophysiology of depression nor the mechanisms of antidepressant action. Tianeptine is an atypical antidepressant used in Europe to treat patients who respond poorly to selective serotonin reuptake inhibitors (SSRIs). The recent discovery that tianeptine is a mu opioid receptor (MOR) and delta opioid receptor (DOR) agonist has provided a potential avenue for expanding our understanding of antidepressant treatment beyond the monoamine hypothesis. This dissertation aims to understand the neural circuits underlying tianeptine’s antidepressant effects. We first characterized the acute and chronic effects of tianeptine on depressive-like and other opioid-related behaviors in mice, and used genetic and pharmacological models to test whether these behavioral effects are mediated by MOR and/or DOR. We found that acute tianeptine administration produced an antidepressant-like reduction in immobility time in the forced swim test, as well as classic opioid-like effects including analgesia, hypophagia, hyperactivity, and conditioned place preference. These behavioral responses to tianeptine are abolished in MOR knockout (KO) mice and in mice that have been pretreated with an MOR antagonist. By contrast, all responses to tianeptine remained intact in DOR KO mice. Remarkably, unlike other classic opiates such as morphine, chronic tianeptine treatment did not produce tolerance to tianeptine’s analgesic effect, nor naloxone-precipitated withdrawal. The acute behavioral effects of tianeptine (excluding analgesic effects, which were present at 15 minutes, but not 1 hour) were established to occur at 1 hour post-injection and to be largely absent by 3 hours post-injection. Chronically, tianeptine produced an antidepressant effect in corticosterone-treated mice, and prevented the development of restraint-stress-induced depression-like behavior, both in an MOR-dependent manner. Interestingly, tianeptine’s chronic antidepressant-like effects were evident in mice after as little as one week of treatment, rather than several weeks as might be expected for SSRIs. Using tissue-specific MOR knockouts, we further showed that MOR expression on GABAergic cells, specifically somatostatin-positive neurons, is necessary for the acute and chronic antidepressant-like responses to tianeptine. By contrast, tianeptine’s behavioral effects did not require the expression MORs on D1- and parvalbumin-expressing cells, nor the expression of ß-arrestin 2. These experiments also revealed a dissociation between the antidepressant-like phenotype and other opioid-like phenotypes resulting from acute tianeptine administration such as analgesia, conditioned place preference, and hyperlocomotion. Critically, we found that tianeptine’s mechanism of action is distinct from fluoxetine in three important aspects: 1) tianeptine requires MORs but not DORs for its chronic antidepressant-like effect, while fluoxetine is the opposite, 2) unlike fluoxetine, tianeptine does not promote hippocampal neurogenesis, and 3) tianeptine’s effects appear to persist even after serotonin depletion. Taken together, these results suggest a novel entry point for understanding what circuit dysregulations may occur in depression, as well as possible targets for the development of new classes of antidepressant drugs. Table of Contents List of Figures ................................................................................................................................ v Acknowledgments ...................................................................................................................... viii Dedication ..................................................................................................................................... xi Chapter 1: Introduction ............................................................................................................... 1 1.1 The Monoamine Hypothesis ..................................................................................................... 1 1.2 The Opioid System and Depression .......................................................................................... 2 1.2.1 History........................................................................................................................ 2 1.2.2 Endogenous Opioid System ....................................................................................... 4 1.2.3 Preclinical Evidence of Opioid Involvement in Depression ...................................... 7 1.2.4 Opioid Regulation of Mood in Humans..................................................................... 9 1.2.5 Clinical Use of Opioids as Antidepressants ............................................................. 12 1.3 Tianeptine ............................................................................................................................... 12 1.4 Cell Type and Brain Region Specificity ................................................................................. 16 1.4.1 GABA and Depression ............................................................................................ 16 1.4.2 Brain Regions of Interest ......................................................................................... 20 1.4.2.1 Hippocampus ............................................................................................ 20 1.4.2.2 Amygdala .................................................................................................. 23 1.4.2.3 Habenula ................................................................................................... 25 1.4.2.4 Ventral Tegmental Area ............................................................................ 26 1.4.2.5 Striatum ..................................................................................................... 27 1.4.2.6 Ventral Pallidum ....................................................................................... 28 i 1.4.2.7 Anterior Cingulate Cortex......................................................................... 29 Chapter 2: Materials and Methods ........................................................................................... 32 2.1 Mice ........................................................................................................................................ 32 2.2 Drugs ....................................................................................................................................... 33 2.3 BrdU and DCX Immunohistochemistry ................................................................................. 34 2.4 Chronic Varied Odor Restraint Stress..................................................................................... 35 2.5 Behavioral Testing .................................................................................................................. 36 2.5.1 Open Field Test ........................................................................................................ 36 2.5.2 Home Cage Feeding Test ........................................................................................ 36 2.5.3 Novelty Suppressed Feeding Test ............................................................................ 37 2.5.4 Forced Swim Test .................................................................................................... 37 2.5.5 Conditioned Place Preference Test .......................................................................... 38 2.5.6 Hot Plate Test ........................................................................................................... 38 2.5.7 Withdrawal Test ....................................................................................................... 39 2.5.8 Sucrose Preference Test ........................................................................................... 39 2.6 RNAscope ............................................................................................................................... 40 2.7 [3H]DAMGO Autoradiography .............................................................................................. 41 2.8 Cannulations ........................................................................................................................... 41 Chapter 3: Results....................................................................................................................... 43 3.1 Opioid Mechanisms for Tianeptine’s Behavioral Effects ....................................................... 43 3.1.1 The Acute Behavioral Effects of Tianeptine Require MORs, but not DORs
Recommended publications
  • Involvement of Catecholaminergic and Gabaaergic Mediations in the Anxiety-Related Behavior in Long-Term Powdered Diet-Fed Mice T
    Neurochemistry International 124 (2019) 1–9 Contents lists available at ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/neuint Involvement of catecholaminergic and GABAAergic mediations in the anxiety-related behavior in long-term powdered diet-fed mice T ∗ Fukie Yaoitaa, , Masahiro Tsuchiyab, Yuichiro Araic, Takeshi Tadanod, Koichi Tan-Noa a Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan b Department of Nursing, Tohoku Fukushi University, 1-8-1 Kunimi, Aoba-ku, Sendai, 981-8522, Japan c Tokyo Ariake University of Medical and Health Science, 2-9-1 Ariake, Koto-Ku, Tokyo, 135-0063, Japan d Complementary and Alternative Medicine Clinical Research and Development, Graduate School of Medicine Sciences, Kanazawa University, Kakumamachi, Kanazawa, 920-1192, Japan ARTICLE INFO ABSTRACT Keywords: Dietary habits are important factors which affect metabolic homeostasis and the development of emotion. We Atomoxetine have previously shown that long-term powdered diet feeding in mice increases spontaneous locomotor activity Methylphenidate and social interaction (SI) time. Moreover, that diet causes changes in the dopaminergic system, especially PD168077 increased dopamine turnover and decreased dopamine D4 receptor signals in the frontal cortex. Although the Anxiety-related behavior increased SI time indicates low anxiety, the elevated plus maze (EPM) test shows anxiety-related behavior and Low anxiety impulsive behavior. In this study, we investigated whether the powdered diet feeding causes changes in anxiety- Bicuculline Attention deficit/hyperactivity disorder related behavior. Mice fed a powdered diet for 17 weeks from weaning were compared with mice fed a standard diet (control).
    [Show full text]
  • Antidepressant Discontinuation Syndrome CHRISTOPHER H
    Antidepressant Discontinuation Syndrome CHRISTOPHER H. WARNER, MAJ, MC, USA, Winn Army Community Hospital, Fort Stewart, Georgia WILLIAM BOBO, LCDR, MC, USN, Uniformed Services University of the Health Sciences, Bethesda, Maryland CAROLYNN WARNER, MAJ, MC, USA, Winn Army Community Hospital, Fort Stewart, Georgia SARA REID, CPT, USAF, MC, Bolling Air Force Base, Washington, D.C. JAMES RACHAL, MAJ, USAF, MC, Ehrling Berquist Air Force Hospital, Offutt Air Force Base, Omaha, Nebraska Antidepressant discontinuation syndrome occurs in approximately 20 percent of patients after abrupt discontinuation of an antidepressant medication that was taken for at least six weeks. Typical symptoms of antidepressant discontinuation syndrome include flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, and hyperarousal. These symptoms usu- ally are mild, last one to two weeks, and are rapidly extinguished with reinstitution of antide- pressant medication. Antidepressant discontinuation syndrome is more likely with a longer duration of treatment and a shorter half-life of the treatment drug. A high index of suspicion should be maintained for the emergence of discontinuation symptoms, which should prompt close questioning regarding accidental or purposeful self-discontinuation of medication. Before antidepressants are prescribed, patient education should include warnings about the potential problems associated with abrupt discontinuation. Education about this common and likely underrecognized clinical phenomenon will help prevent future episodes
    [Show full text]
  • A Novel Atypical Antidepressant That May Provide New Insights Into the Biomolecular Basis of Depression
    Recent Patents on CNS Drug Discovery, 2006, 1, 29-41 29 Tianeptine: A Novel Atypical Antidepressant that May Provide New Insights into the Biomolecular Basis of Depression Christiaan B. Brink*, Brian H. Harvey and Linda Brand Division of Pharmacology, North-West University (PUK), Potchefstroom, 2520, South Africa Received: July 29, 2005; Accepted: September 05, 2005; Revised: September 12, 2005 Abstract: Tianeptine, an atypical antidepressant patented and developed by Servier, enhances the synaptic reuptake of serotonin, without affecting norepinephrine and dopamine uptake, while it lacks affinity for neurotransmitter receptors. This mechanism for an antidepressant is apparently paradoxical, since the currently employed antidepressants enhance serotonin by inhibiting its breakdown or by inhibiting monoaminergic reuptake. Although tianeptine has been shown to reduce central 5HT availability and to indirecty modulate central adrenergic and dopaminergic systems and to indirectly inhibit cholinergic hyperactivity, its antidepressant action is believed to be more directly related to central neuronal remodeling and restoration of neuronal plasticity. In reliable animal models of depression tianeptine has been shown to prevent neurodegeneration and decreases in hippocampal volume in response to chronic stress. These effects on neuroplasticity are suspected to involve the normalization of the hypothalamic-pituitary-adrenal axis and modulatory effects on excitatory amino acids and N-methyl-D-aspartate receptors. Together with a body of related studies, these data provide further support for the hypothesis that depression may involve dysregulation of pathways controlling cellular resilience and that treatment should be directed towards the reversal thereof. Importantly, tianeptine is not anxiogenic and has also been shown to be effective in treatment-resistant depression, which may lead the way to a major breakthrough in the treatment of depression.
    [Show full text]
  • A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies
    Neuropsychopharmacology (2016) 41, 1803–1812 © 2016 American College of Neuropsychopharmacology. All rights reserved 0893-133X/16 www.neuropsychopharmacology.org A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies ,1 1 2 3 4 Anke Post* , Trevor S Smart , Judith Krikke-Workel , Gerard R Dawson , Catherine J Harmer , 3,4 1 5 6 6 1 Michael Browning , Kimberley Jackson , Rishi Kakar , Richard Mohs , Michael Statnick , Keith Wafford , 1 6 6 Andrew McCarthy , Vanessa Barth and Jeffrey M Witkin 1 2 3 4 5 Lilly UK, Windlesham, Surrey, UK; Eli Lilly, Netherlands; P1vital Limited, Oxfordshire, UK; University of Oxford, Oxford, UK; Innovative Clinical 6 Research-SICR, Ft. Lauderdale, FL, USA; Neuroscience Research, Eli Lilly and Company, Indianapolis, IN, USA Nociceptin/Orphanin FQ (N/OFQ) is an endogenous ligand of the N/OFQ peptide (NOP) receptor, which is a G protein-coupled receptor in brain regions associated with mood disorders. We used a novel, potent, and selective orally bioavailable antagonist, LY2940094, to test the hypothesis that blockade of NOP receptors would induce antidepressant effects. In this study we demonstrate that targeting NOP receptors with LY2940094 translates to antidepressant-like effects in rodent models and, importantly, to antidepressant efficacy in patients with major depressive disorder (MDD). The proof-of-concept study (POC) was an 8-week, double-blind, placebo- controlled trial that evaluated LY2940094 as a novel oral medication for the treatment of patients with MDD. Once daily oral dosing of LY2940094 at 40 mg for 8 weeks vs placebo provided some evidence for an antidepressant effect based on the change from baseline to week 8 in the GRID-Hamilton Depression Rating Scale-17 item total score, although the predefined POC efficacy criterion (probability of ⩾ LY2940094 being better than placebo 88%) was not met (82.9%).
    [Show full text]
  • 1-(4-Amino-Cyclohexyl)
    (19) & (11) EP 1 598 339 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 211/04 (2006.01) C07D 211/06 (2006.01) 24.06.2009 Bulletin 2009/26 C07D 235/24 (2006.01) C07D 413/04 (2006.01) C07D 235/26 (2006.01) C07D 401/04 (2006.01) (2006.01) (2006.01) (21) Application number: 05014116.7 C07D 401/06 C07D 403/04 C07D 403/06 (2006.01) A61K 31/44 (2006.01) A61K 31/48 (2006.01) A61K 31/415 (2006.01) (22) Date of filing: 18.04.2002 A61K 31/445 (2006.01) A61P 25/04 (2006.01) (54) 1-(4-AMINO-CYCLOHEXYL)-1,3-DIHYDRO-2H-BENZIMIDAZOLE-2-ONE DERIVATIVES AND RELATED COMPOUNDS AS NOCICEPTIN ANALOGS AND ORL1 LIGANDS FOR THE TREATMENT OF PAIN 1-(4-AMINO-CYCLOHEXYL)-1,3-DIHYDRO-2H-BENZIMIDAZOLE-2-ON DERIVATE UND VERWANDTE VERBINDUNGEN ALS NOCICEPTIN ANALOGE UND ORL1 LIGANDEN ZUR BEHANDLUNG VON SCHMERZ DERIVÉS DE LA 1-(4-AMINO-CYCLOHEXYL)-1,3-DIHYDRO-2H-BENZIMIDAZOLE-2-ONE ET COMPOSÉS SIMILAIRES POUR L’UTILISATION COMME ANALOGUES DU NOCICEPTIN ET LIGANDES DU ORL1 POUR LE TRAITEMENT DE LA DOULEUR (84) Designated Contracting States: • Victory, Sam AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Oak Ridge, NC 27310 (US) MC NL PT SE TR • Whitehead, John Designated Extension States: Newtown, PA 18940 (US) AL LT LV MK RO SI (74) Representative: Maiwald, Walter (30) Priority: 18.04.2001 US 284666 P Maiwald Patentanwalts GmbH 18.04.2001 US 284667 P Elisenhof 18.04.2001 US 284668 P Elisenstrasse 3 18.04.2001 US 284669 P 80335 München (DE) (43) Date of publication of application: (56) References cited: 23.11.2005 Bulletin 2005/47 EP-A- 0 636 614 EP-A- 0 990 653 EP-A- 1 142 587 WO-A-00/06545 (62) Document number(s) of the earlier application(s) in WO-A-00/08013 WO-A-01/05770 accordance with Art.
    [Show full text]
  • Introduced by Wayne, 13
    LB617 LB617 2017 2017 LEGISLATURE OF NEBRASKA ONE HUNDRED FIFTH LEGISLATURE FIRST SESSION LEGISLATIVE BILL 617 Introduced by Wayne, 13. Read first time January 18, 2017 Committee: Agriculture 1 A BILL FOR AN ACT relating to agricultural promotion; to amend section 2 28-401, Reissue Revised Statutes of Nebraska, and section 2-5701, 3 Revised Statutes Cumulative Supplement, 2016; to adopt the 4 Industrial Hemp Act; to provide an exemption as prescribed; to 5 provide an operative date; and to repeal the original sections. 6 Be it enacted by the people of the State of Nebraska, -1- LB617 LB617 2017 2017 1 Section 1. Sections 1 to 14 of this act shall be known and may be 2 cited as the Industrial Hemp Act. 3 Sec. 2. (1) The purpose of the Industrial Hemp Act is to assist the 4 State of Nebraska in moving to the forefront of industrial hemp 5 production, development, and commercialization of hemp products in 6 agribusiness, alternative fuel production, and other business sectors, 7 both nationally and globally and to the greatest extent possible. These 8 purposes shall be accomplished, in part, through: 9 (a) The creation of the Industrial Hemp Commission; 10 (b) The industrial hemp research program overseen by the commission, 11 working in conjunction with the staff of selected Nebraska postsecondary 12 institution agricultural research programs, along with other research 13 partners. This research program shall include the planting, cultivation, 14 and analysis of industrial hemp demonstration plots by selected growers 15 that are licensed by the commission; and 16 (c) The pursuit of any federal permits or waivers necessary to allow 17 industrial hemp to be grown in Nebraska.
    [Show full text]
  • Enkephalin Degradation in Serum of Patients with Inflammatory Bowel Diseases
    Pharmacological Reports 71 (2019) 42–47 Contents lists available at ScienceDirect Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep Original article Enkephalin degradation in serum of patients with inflammatory bowel diseases a, a b Beata Wilenska *, Dagmara Tymecka , Marcin Włodarczyk , b c Aleksandra Sobolewska-Włodarczyk , Maria Wisniewska-Jarosinska , d e b a,d, Jolanta Dyniewicz , Árpád Somogyi , Jakub Fichna , Aleksandra Misicka * a Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Warszawa, Poland b Department of Biochemistry, Medical University of Lodz, Łódz, Poland c Department of Gastroenterology, Medical University of Lodz, Łódz, Poland d Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Science, Warszawa, Poland e Campus Chemical Instrumentation Centre (CCIC), The Ohio State University, Columbus, OH, USA A R T I C L E I N F O A B S T R A C T Article history: Background: Inflammatory bowel diseases (IBD) are a group of chronic and recurrent gastrointestinal Received 18 April 2018 disorders that are difficult to control. Recently, a new IBD therapy based on the targeting of the Received in revised form 10 June 2018 endogenous opioid system has been proposed. Consequently, due to the fact that endogenous Accepted 1 August 2018 enkephalins have an anti-inflammatory effect, we aimed at investigating the degradation of serum Available online 2 August 2018 enkephalin (Met- and Leu-enkephalin) in patients with IBD. Methods: Enkephalin degradation in serum of patients with IBD was characterized using mass Keywords: spectrometry methods. Calculated half-life (T1/2) of enkephalins were compared and correlated with the Inflammatory bowel diseases disease type and gender of the patients.
    [Show full text]
  • Supplementary Materials
    Supplementary Materials Hyporesponsivity to mu-opioid receptor agonism in the Wistar-Kyoto rat model of altered nociceptive responding associated with negative affective state Running title: Effects of mu-opioid receptor agonism in Wistar-Kyoto rats Mehnaz I Ferdousi1,3,4, Patricia Calcagno1,2,3,4, Morgane Clarke1,2,3,4, Sonali Aggarwal1,2,3,4, Connie Sanchez5, Karen L Smith5, David J Eyerman5, John P Kelly1,3,4, Michelle Roche2,3,4, David P Finn1,3,4,* 1Pharmacology and Therapeutics, 2Physiology, School of Medicine, 3Centre for Pain Research and 4Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland. 5Alkermes Inc., Waltham, Massachusetts, USA. *Corresponding author: Professor David P Finn, Pharmacology and Therapeutics, School of Medicine, Human Biology Building, National University of Ireland Galway, University Road, Galway, H91 W5P7, Ireland. Tel: +353 (0)91 495280 E-mail: [email protected] S.1. Supplementary methods S.1.1. Elevated plus maze test The elevated plus maze (EPM) test assessed the effects of drug treatment on anxiety-related behaviours in WKY and SD rats. The wooden arena, which was elevated 50 cm above the floor, consisted of central platform (10x10 cm) connecting four arms (50x10 cm each) in the shape of a “plus”. Two arms were enclosed by walls (30 cm high, 25 lux) and the other two arms were without any enclosure (60 lux). On the test day, 5 min after the HPT, rats were removed from the home cage, placed in the centre zone of the maze with their heads facing an open arm, and the behaviours were recorded for 5 min with a video camera positioned on top of the arena.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,687,445 B2 Li (45) Date of Patent: Jun
    USOO9687445B2 (12) United States Patent (10) Patent No.: US 9,687,445 B2 Li (45) Date of Patent: Jun. 27, 2017 (54) ORAL FILM CONTAINING OPIATE (56) References Cited ENTERC-RELEASE BEADS U.S. PATENT DOCUMENTS (75) Inventor: Michael Hsin Chwen Li, Warren, NJ 7,871,645 B2 1/2011 Hall et al. (US) 2010/0285.130 A1* 11/2010 Sanghvi ........................ 424/484 2011 0033541 A1 2/2011 Myers et al. 2011/0195989 A1* 8, 2011 Rudnic et al. ................ 514,282 (73) Assignee: LTS Lohmann Therapie-Systeme AG, Andernach (DE) FOREIGN PATENT DOCUMENTS CN 101703,777 A 2, 2001 (*) Notice: Subject to any disclaimer, the term of this DE 10 2006 O27 796 A1 12/2007 patent is extended or adjusted under 35 WO WOOO,32255 A1 6, 2000 U.S.C. 154(b) by 338 days. WO WO O1/378O8 A1 5, 2001 WO WO 2007 144080 A2 12/2007 (21) Appl. No.: 13/445,716 (Continued) OTHER PUBLICATIONS (22) Filed: Apr. 12, 2012 Pharmaceutics, edited by Cui Fude, the fifth edition, People's Medical Publishing House, Feb. 29, 2004, pp. 156-157. (65) Prior Publication Data Primary Examiner — Bethany Barham US 2013/0273.162 A1 Oct. 17, 2013 Assistant Examiner — Barbara Frazier (74) Attorney, Agent, or Firm — ProPat, L.L.C. (51) Int. Cl. (57) ABSTRACT A6 IK 9/00 (2006.01) A control release and abuse-resistant opiate drug delivery A6 IK 47/38 (2006.01) oral wafer or edible oral film dosage to treat pain and A6 IK 47/32 (2006.01) substance abuse is provided.
    [Show full text]
  • Auckland Uniservices Limited
    Auckland UniServices Limited Legally available, unclassified psychoactive substances and illegal drugs in New Zealand before and after the ban on BZP: a web‐ based survey of patterns of use FINAL REPORT OF FINDINGS June 2009 Janie Sheridan, PhD, BPharm, BA, FRPharmS, RegPharmNZ Rachael Butler, BA, PGDipPH Christine Y. Dong, BSc Hons, BCom Hons Joanne Barnes, PhD, BPharm, MRPharmS, RegPharmNZ, FLS The School of Pharmacy The University of Auckland New Zealand TABLE OF CONTENTS 1 Executive Summary ........................................................................................... 7 2 Introduction .................................................................................................... 11 2.1 Background .............................................................................................. 11 2.1.1 The legislative and regulatory background ................................ 11 2.1.2 The current study ........................................................................ 12 2.2 Study aims ................................................................................................ 12 2.3 Study methods ......................................................................................... 13 2.4 Ethics approval ......................................................................................... 13 2.5 Structure of this report ............................................................................ 13 3 Adverse effects associated with herbal substances used for recreational purposes: a literature review
    [Show full text]
  • Cannabinoid Transmission in the Prelimbic Cortex Bidirectionally
    15642 • The Journal of Neuroscience, September 25, 2013 • 33(39):15642–15651 Behavioral/Cognitive Cannabinoid Transmission in the Prelimbic Cortex Bidirectionally Controls Opiate Reward and Aversion Signaling through Dissociable Kappa Versus ␮-Opiate Receptor Dependent Mechanisms Tasha Ahmad,1 Nicole M. Lauzon,1 Xavier de Jaeger,1 and Steven R. Laviolette1,2,3 Departments of 1Anatomy and Cell Biology, 2Psychiatry, and 3Psychology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N5Y 5T8 Cannabinoid, dopamine (DA), and opiate receptor pathways play integrative roles in emotional learning, associative memory, and sensory perception. Modulation of cannabinoid CB1 receptor transmission within the medial prefrontal cortex (mPFC) regulates the emotional valence of both rewarding and aversive experiences. Furthermore, CB1 receptor substrates functionally interact with opiate- related motivational processing circuits, particularly in the context of reward-related learning and memory. Considerable evidence demonstrates functional interactions between CB1 and DA signaling pathways during the processing of motivationally salient informa- tion. However, the role of mPFC CB1 receptor transmission in the modulation of behavioral opiate-reward processing is not currently known. Using an unbiased conditioned place preference paradigm with rats, we examined the role of intra-mPFC CB1 transmission during opiate reward learning. We report that activation or inhibition of CB1 transmission within the prelimbic cortical (PLC) division of the mPFC bidirectionally regulates the motivational valence of opiates; whereas CB1 activation switched morphine reward signaling into an aversive stimulus, blockade of CB1 transmission potentiated the rewarding properties of normally sub-reward threshold conditioning doses of morphine. Both of these effects were dependent upon DA transmission as systemic blockade of DAergic transmission prevented CB1-dependent modulation of morphine reward and aversion behaviors.
    [Show full text]
  • Moves to Amend HF No. 2711 As Follows
    05/05/20 ​ REVISOR KLL/JK A20-0767​ 1.1 .................... moves to amend H.F. No. 2711 as follows:​ 1.2 Delete everything after the enacting clause and insert:​ 1.3 "ARTICLE 1​ 1.4 APPROPRIATIONS​ 1.5 Section 1. APPROPRIATIONS.​ 1.6 The sums shown in the column under "APPROPRIATIONS" are added to or reduce the​ 1.7 appropriations in Laws 2019, First Special Session chapter 5, to the agencies and for the​ 1.8 purposes specified in this article. The appropriations are from the general fund, or another​ 1.9 named fund, and are available for the fiscal year indicated for each purpose.​ 1.10 APPROPRIATIONS​ 1.11 Available for the Year​ 1.12 Ending June 30​ 1.13 2020​ 2021​ 1.14 Sec. 2. CORRECTIONS​ 1.15 Subdivision 1. Total Appropriation​ $​ 205,000​ $​ 5,545,000​ 1.16 The amounts that may be spent for each​ 1.17 purpose are specified in the following​ 1.18 subdivisions.​ 1.19 Subd. 2. Correctional Institutions​ -0-​ (2,545,000)​ 1.20 To account for overall bed impact savings of​ 1.21 reductions in the penalties for controlled​ 1.22 substances offenses involving the possession​ 1.23 of marijuana, investments in community​ 1.24 supervision, and increased penalties for sex​ 1.25 trafficking offenses, the fiscal year 2021​ Article 1 Sec. 2.​ 1​ 05/05/20 ​ REVISOR KLL/JK A20-0767​ 2.1 appropriation from Laws 2019, First Special​ 2.2 Session chapter 5, article 1, section 15,​ 2.3 subdivision 2, is reduced by $2,545,000.​ 2.4 Subd.
    [Show full text]