DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2005/0004105 A1 Leahy Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2005/0004105 A1 Leahy Et Al US 2005.0004105A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0004105 A1 Leahy et al. (43) Pub. Date: Jan. 6, 2005 (54) TREATMENT FOR AATTENTION-DEFICIT Related U.S. Application Data HYPERACTIVITY DISORDER (60) Provisional application No. 60/443,457, filed on Jan. 29, 2003. (76) Inventors: Emer Leahy, Bedford, NY (US); Berend Olivier, Lelytstad (NL) Publication Classification (51) Int. Cl." ....................... A61K 31/55; A61K 31/496; Correspondence Address: A61K 31/495 MORGAN & FINNEGAN, L.L.P. (52) U.S. Cl. ............... 514/218; 514/252.13; 514/255.03 3 WORLD FINANCIAL CENTER NEW YORK, NY 10281-2101 (US) (57) ABSTRACT (21) Appl. No.: 10/767,788 A method for treating Attention Deficit/Hyperactivity Dis order (ADHD) in humans using a 5-HT1A receptor agonist is (22) Filed: Jan. 29, 2004 provided. Patent Application Publication Jan. 6, 2005 Sheet 1 of 15 US 2005/0004105 A1 sc) s.CO SRg Cd 8 3. wO N <16 s s 3 Cd Co (%) 3.e3Suodsay unuxeW Patent Application Publication Jan. 6, 2005 Sheet 2 of 15 US 2005/0004105 A1 FIGURE 2 2A -O- Vehicle -a- Fiesinoxan.03mg 2B 100 -O- Vehicle -A- Flesinoxan.03mg 40 2O v-v- -v- v-ve v-v-v- SN alolo all-we-de- s1-0-1 de O Time Bin Patent Application Publication Jan. 6, 2005 Sheet 3 of 15 US 2005/0004105 A1 FIGURE 3 3A 100 90 80 9. 70 dt 60 -O- Vehicle E 50 -A- FlesinoxanPloei 0.1mg/kg S 40 S 30 20 10 O cNCO YOONOOC)- - - - -ttittittstittstycyyyy overe cacy) wild conlood V-C cort Time Bin 3B -O- Vehicle -a- Flesinoxan 0.1mg/kg Patent Application Publication Jan. 6, 2005 Sheet 4 of 15 US 2005/0004105 A1 FIGURE 4 0.010 O.CO<>5CD3 CD O·+= 0.010 Patent Application Publication Jan. 6, 2005 Sheet 5 of 15 US 2005/0004105 A1 O O O O O O O LO rt cy (uo) peewell edueSpelo Patent Application Publication Jan. 6, 2005 Sheet 6 of 15 US 2005/0004105 A1 6 A 8000 Flesinoxan (0.3 mg/kg) 7OOO Vehicle 6OOO 5000 4000 3000 2000 1000 Crn WT 6 B 3000 - Cm, Flesinoxan (0.3 mg/kg) - Cm, Vehicle 2500 -O- WT, Flesinoxan (0.3 mg/kg) 2000 O WT, Vehicle. 1500 Patent Application Publication Jan. 6, 2005 Sheet 7 of 15 US 2005/0004105 A1 -••-• 9ETRIQOIH • OyGº09GZOzG\0\9 O9 GZZ Patent Application Publication Jan. 6, 2005 Sheet 8 of 15 US 2005/0004105 A1 D 5 O O O O O O O O O O O O O O O O O O O L) O ) O D (y) CN CN w v (uo) peene LeOueSIO le).O. Patent Application Publication Jan. 6, 2005 Sheet 9 of 15 US 2005/0004105 A1 009'[98]v[3890-99'f7Izoº68960290)Z07'68960Z90/????dÅ?Ou09|| JºW\OG?uenbSueÐINSºuenDSJOUunS-JO Patent Application Publication Jan. 6, 2005 Sheet 10 of 15 US 2005/0004105 A1 | E9ºun61– 0097 0007 0099 0009 00CZ 000Z 009|| 000|| 009 (uo) peene LeOue)SIO |e).O. Patent Application Publication Jan. 6, 2005 Sheet 12 of 15 US 2005/0004105 A1 O V : O Cy) O cy LO CN O CN H9eun61 LO v O v D 008 00/ 009 OOZ 00|| SeSSOJO euoz Patent Application Publication US 2005/0004105 A1 I-I-T-I-IIae555,-155,5€SÕES-BEZI S3SSONOQuOZJOJ3|qe1V/AONV Patent Application Publication Jan. 6, 2005 Sheet 14 of 15 US 2005/0004105 A1 O) O) -Y4 -Y N N O) O) E E o a C a H 5 H 5 SC E SC E - G - G O O D C) > r E E - 55s is cy)LO O O O g CY)O O CN H O t CN O v o w D O5 O O3 Oas 3O 8 O O cy) CN CN v- v N SeSSOJO euoz Patent Application Publication Jan. 6, 2005 Sheet 15 of 15 US 2005/0004105 A1 FIGURE 7 7 A DPAT 0.1 mg/kg Vehicle Cm, DPAT 0.1 mg/kg - Cm, Vehicle -O- WT, DPAT 0.1 mg/kg -O WT, Vehicle 2 5 O O 5 10 15 20 25 30 35 40 US 2005/0004 105 A1 Jan. 6, 2005 TREATMENT FOR AATTENTION-DEFICT and ADHD associated hyperactivity-impulsivity: meth HYPERACTIVITY DISORDER ylphenidate, d-amphetamine, pemoline, and a mixture of amphetamine salts (Spender et al., Arch. Gen. Psychiatry, FIELD OF THE INVENTION 52:434-443, 1995). These drugs block uptake sites for catecholamines on presynaptic neurons or Stimulate the 0001. The present invention is directed to a novel method release of granular Stores of catecholamines. They are of treating Attention-Deficit/Hyperactivity Disorder metabolized and leave the body fairly rapidly, and have a (“ADHD"). therapeutic duration of action of 1 to 4 hours. The psycho Stimulants do not appear, however, to effect long-term BACKGROUND OF THE INVENTION changes in Social or academic skills (Pelham et al., J. Clin. Child Psychology, 27:190-205, 1998). Stimulants are gen 0002 Attention-Deficit/Hyperactivity Disorder (ADHD) erally started at a low dose and adjusted weekly. Common is a behavior disorder characterized by problems with con Stimulant Side effects include insomnia, decreased appetite, trol of attention and hyperactivity-impulsivity. The atten Stomachaches, headaches, and jitterineSS. PsychoStimulants tional difficulties and impulsivity associated with ADHD have been persuasively documented in laboratory investi also have the potential for abuse, because they are addictive. gations using cognitive tasks. Although these problems Thus, current methods of treating ADHD provide inadequate typically present together, one may be present without the treatment for Some patients and/or have side effects that limit other to qualify for a diagnosis (Am. Psychiatric ASSoc. their usefulness. Diagnostic and Statistical Manual of Mental Disorders, 4" 0007 Children who cannot tolerate psychostimulants Ed., Text Revision, 2000) (DSM-IV-TR). Generally, atten often use the atypical antidepressant bupropion (Buck, Pedi tion deficit or inattention becomes apparent when a child atr. Pharmacother. Vol. 8, No. 4, April, 2002). While bupro enters elementary School. A modified form of the disorder pion is not as effective as Stimulants, it may be used as an can persist into adulthood (Am. Psychiatric ASSoc. Diag adjunct to augment Stimulant treatment. nostic and Statistical Manual of Mental Disorders, 3" Ed., 0008) Effective pharmacotherapy for ADHD is compli 1987). With respect to the attention component, the child is cated by the presence of comorbid behavioral disorders, easily distracted by outside Stimuli, neglects finishing tasks, including aggression, impulse control disorders, and depres and has difficulty maintaining attention. Regarding the activ Sion, which may be relieved by compounds that do not ity component, the child is often fidgety, impulsive, and address the core behavioral Symptoms of inattentiveness and overactive. The symptoms of ADHD may be apparent as impulsivity/hyperactivity. young as preschoolers and are virtually always present prior to the age of 7 (Halperinet al., J. Am. Acad. Child Adoles 0009 Castellanos et al. concluded that ADHD is a geneti cent Psychiatry, 32:1038-1043, 1993). cally programmed disorder of brain development resulting from altered function of the frontal-striatal-pallidal-thalamo 0003) According to the DSM-IV-TR, diagnostic criteria cortical loops which regulate cognitive processes, attention, for Attention-Deficit/Hyperactivity Disorder relate to symp and motor output behaviors (Castellanos et al., Arch. Gen. toms associated with inattention and/or hyperactivity-impul Psychiatry, 53:607-616, 1996). Although the precise etiol sivity. Three subtypes of ADHD are diagnosed based on the ogy of ADHD is unknown, neurotransmitter deficits, genet predominant Symptoms presented. ics, and perinatal complications have been implicated. 0004. Many of the symptoms that are characteristic of 0010 Individuals with ADHD have been reported to have ADHD occur occasionally in normal children. Children with impairments in their ability to perceive intervals of time ADHD, however, exhibit these symptoms frequently, which (Conners & Levin, Psychopharmacol. Bulletin, 32(1):67-73, tends to interfere with the child's day to day functioning. 1996). Time perception is a useful measure of cognitive Such children are often challenged by academic under function, Sensitive to dopaminergic and cholinergic manipu achievement because of excitability and impaired interper lations in animals and humans. AS in all behavioral tasks, Sonal relationships. Several processes underlie good steady State performance in 0005 ADHD affects 2-6% of grade school children. a temporal task. These behavioral tasks include: attention, Pediatricians report that approximately 4% of their patients motivation, Short and long term memory, motor coordina have ADHD; however, in practice the diagnosis is made in tion, and instrumental learning. Scaling, discrimination, and children who meet Several, but not all of the diagnostic reproduction are the three main types of temporal tasks that criteria that is recommended in DMS-IV-TR (Wolraich et have been identified. In Scaling, Subjects must, for example, al., Pediatrics, 86(1):95-101, 1990). Boys are four times categorize a stimulus into a given set of categories (“that was more likely to have the disorder than girls and the disorder a long duration”) or verbally estimate the duration (“that was is found in all cultures (Ross & Ross, Hyperactivity, New a 4 S duration'). In discrimination, a comparison is made York, 1982). between two durations (“the Second stimulus was longer 0006 Psychomotor stimulants are the most common than the first'). Finally, in reproduction, a response is made treatment for ADHD. Safer & Krager (1988) reported that that bears Some relation with the stimulus (e.g. only 99% of the children with ADHD were treated with Stimu responses that are as long or longer than the Stimulus are lants, of which 93% were given methylphenidate hydrochlo correct).
Load more

Recommended publications
  • Mechanism of Action of Antidepressants and Mood Stabilizers
    79 MECHANISM OF ACTION OF ANTIDEPRESSANTS AND MOOD STABILIZERS ROBERT H. LENOX ALAN FRAZER Bipolar disorder (BPD), the province of mood stabilizers, the more recent understanding that antidepressants share has long been considered a recurrent disorder. For more this property in UPD have focused research on long-term than 50 years, lithium, the prototypal mood stabilizer, has events, such as alterations in gene expression and neuroplas- been known to be effective not only in acute mania but ticity, that may play a significant role in stabilizing the clini- also in the prophylaxis of recurrent episodes of mania and cal course of an illness. In our view, behavioral improvement depression. By contrast, the preponderance of past research and stabilization stem from the acute pharmacologic effects in depression has focused on the major depressive episode of antidepressants and mood stabilizers; thus, both the acute and its acute treatment. It is only relatively recently that and longer-term pharmacologic effects of both classes of investigators have begun to address the recurrent nature of drugs are emphasized in this chapter. unipolar disorder (UPD) and the prophylactic use of long- term antidepressant treatment. Thus, it is timely that we address in a single chapter the most promising research rele- vant to the pharmacodynamics of both mood stabilizers and MOOD STABILIZERS antidepressants. As we have outlined in Fig. 79.1, it is possible to charac- The term mood stabilizer within the clinical setting is com- terize both the course and treatment of bipolar and unipolar monly used to refer to a class of drugs that treat BPD.
    [Show full text]
  • 5-HT1A Receptor Agonist Affects Fear Conditioning Through Stimulations of the Postsynaptic 5-HT1A Receptors in the Title Hippocampus and Amygdala
    5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the Title hippocampus and amygdala Author(s) Li, XiaoBai; Inoue, Takeshi; Abekawa, Tomohiro; Weng, ShiMin; Nakagawa, Shin; Izumi, Takeshi; Koyama, Tsukasa European Journal of Pharmacology, 532(1-2), 74-80 Citation https://doi.org/10.1016/j.ejphar.2005.12.008 Issue Date 2006-02-17 Doc URL http://hdl.handle.net/2115/8408 Type article (author version) File Information EJP22907revisedFinal.pdf Instructions for use Hokkaido University Collection of Scholarly and Academic Papers : HUSCAP 5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the hippocampus and amygdala. XiaoBai Lia, b, Takeshi Inouea, Tomohiro Abekawaa, ShiMin Weng b, Shin Nakagawaa, Takeshi Izumia, Tsukasa Koyamaa a Department of Psychiatry, Neural Function, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo, 060-8638, Japan bShanghai Mental Health Center, 600, Wan Ping Nan Lu, Shanghai 200030, China Correspondence to: Takeshi Inoue, MD, PhD, Department of Psychiatry, Neural Function, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan. Tel: +81-11-706-5160; Fax: +81-11-706-5081; E-mail: [email protected] Abstract Evidence from preclinical and clinical studies has shown that 5-HT1A receptor agonists have anxiolytic actions. The anxiolytic actions of 5-HT1A receptor agonists have been tested by our previous studies using fear conditioning. However, little is known about the brain regions of anxiolytic actions of 5-HT1A receptor agonists in this paradigm. In the present study, we investigated the effects of bilateral microinjections of flesinoxan, a selective 5-HT1A receptor agonist, into the hippocampus, amygdala and medial prefrontal cortex on the expression of contextual conditioned freezing and the defecation induced by conditioned fear stress in rats.
    [Show full text]
  • Eptapirone | Medchemexpress
    Inhibitors Product Data Sheet Eptapirone • Agonists Cat. No.: HY-19946 CAS No.: 179756-58-2 Molecular Formula: C₁₆H₂₃N₇O₂ • Molecular Weight: 345.4 Screening Libraries Target: 5-HT Receptor Pathway: GPCR/G Protein; Neuronal Signaling Storage: Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month SOLVENT & SOLUBILITY In Vitro DMSO : 50 mg/mL (144.76 mM; Need ultrasonic) Mass Solvent 1 mg 5 mg 10 mg Concentration Preparing 1 mM 2.8952 mL 14.4760 mL 28.9519 mL Stock Solutions 5 mM 0.5790 mL 2.8952 mL 5.7904 mL 10 mM 0.2895 mL 1.4476 mL 2.8952 mL Please refer to the solubility information to select the appropriate solvent. In Vivo 1. Add each solvent one by one: 10% DMSO >> 40% PEG300 >> 5% Tween-80 >> 45% saline Solubility: ≥ 2.5 mg/mL (7.24 mM); Clear solution 2. Add each solvent one by one: 10% DMSO >> 90% (20% SBE-β-CD in saline) Solubility: ≥ 2.5 mg/mL (7.24 mM); Clear solution 3. Add each solvent one by one: 10% DMSO >> 90% corn oil Solubility: ≥ 2.5 mg/mL (7.24 mM); Clear solution BIOLOGICAL ACTIVITY Description Eptapirone (F11440) is a potent, selective, high efficacy 5-HT1A receptor agonist with marked anxiolytic and antidepressant potential. IC₅₀ & Target 5-HT1A Receptor In Vitro The affinity of Eptapirone (F11440) for 5-HT1Abinding sites (pKi, 8.33) was higher than that of buspirone (pKi , 7.50), and somewhat lower than that of flesinoxan (pKi , 8.91).In vivo, Eptapirone (F11440) was 4- to 20-fold more potent than Page 1 of 2 www.MedChemExpress.com flesinoxan, and 30- to 60-fold more potent than buspirone, in exerting 5-HT1A agonist activity at pre- and postsynaptic receptors in rats (measured by, for example, its ability to decrease hippocampal extracellular serotonin (5-HT) levels and to increase plasma corticosterone levels, respectively).
    [Show full text]
  • Increased Tonic Activation of Rat Forebrain 5-HT1A Receptors by Lithium Addition to Antidepressant Treatments
    Increased Tonic Activation of Rat Forebrain 5-HT1A Receptors by Lithium Addition to Antidepressant Treatments Nasser Haddjeri, Ph.D., Steven T. Szabo, B.Sc., Claude de Montigny, M.D., Ph.D., and Pierre Blier, M.D., Ph.D. The present study was undertaken to determine whether 21 days, a dose of 50 ␮g/kg of WAY 100635 was needed to lithium addition to long-term treatment with different increase significantly the firing activity of these neurons. classes of antidepressant drugs could induce a greater effect On the other hand, WAY 100635, at a dose of only 25 ␮g/ on the serotonin (5-HT) system than the drugs given alone. kg, increased significantly the firing rate of CA3 pyramidal Because 5-HT1A receptor activation hyperpolarizes and neurons in rats receiving both a long-term antidepressant inhibits the firing activity of CA3 pyramidal neurons in the treatment and a short-term lithium diet. It is concluded that dorsal hippocampus, the degree of disinhibition produced by the addition of lithium to antidepressant treatments the selective 5-HT1A receptor antagonist WAY 100635 was produced a greater disinhibition of dorsal hippocampus CA3 determined using in vivo extracellular recordings. In pyramidal neurons than any treatments given alone. The controls, as well as in rats receiving a lithium diet for 3 days, present results support the notion that the addition of the administration of WAY 100635 (25-100 ␮g/kg, IV) did not lithium to antidepressants may produce a therapeutic modify the firing activity of dorsal hippocampus CA3 pyramidal response in treatment-resistant depression by enhancing neurons.
    [Show full text]
  • Serotonin (5HT), Fluoxetine, Imipramine and Dopamine Target Distinct 5HT Receptor Signaling to Modulate Caenorhabditis Elegans Egg-Laying Behavior
    Copyright © 2005 by the Genetics Society of America DOI: 10.1534/genetics.104.032540 Serotonin (5HT), Fluoxetine, Imipramine and Dopamine Target Distinct 5HT Receptor Signaling to Modulate Caenorhabditis elegans Egg-Laying Behavior Catherine M. Dempsey, Scott M. Mackenzie, Andrew Gargus, Gabriela Blanco and Ji Ying Sze1 Department of Anatomy and Neurobiology, College of Medicine, University of California, Irvine, California 92697-4040 Manuscript received June 18, 2004 Accepted for publication November 22, 2004 ABSTRACT Drugs that target the serotonergic system are the most commonly prescribed therapeutic agents and are used for treatment of a wide range of behavioral and neurological disorders. However, the mechanism of the drug action remain a conjecture. Here, we dissect the genetic targets of serotonin (5HT), the selective 5HT reuptake inhibitor (SSRI) fluoxetine (Prozac), the tricyclic antidepressant imipramine, and dopamine. Using the well-established serotonergic response in C. elegans egg-laying behavior as a paradigm, we show that action of fluoxetine and imipramine at the 5HT reuptake transporter (SERT) and at 5HT receptors are separable mechanisms. Even mutants completely lacking 5HT or SERT can partially respond to fluoxetine and imipramine. Furthermore, distinct mechanisms for each drug can be recognized to mediate these responses. Deletion of SER-1, a 5HT1 receptor, abolishes the response to 5HT but has only a minor effect on the response to imipramine and no effect on the response to fluoxetine. In contrast, deletion of SER-4, a 5HT2 receptor, confers significant resistance to imipramine while leaving the responses to 5HT or fluoxetine intact. Further, fluoxetine can stimulate egg laying via the Gq protein EGL-30, independent of SER-1, SER-4, or 5HT.
    [Show full text]
  • Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DIX to the HTSUS—Continued
    20558 Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DEPARMENT OF THE TREASURY Services, U.S. Customs Service, 1301 TABLE 1.ÐPHARMACEUTICAL APPEN- Constitution Avenue NW, Washington, DIX TO THE HTSUSÐContinued Customs Service D.C. 20229 at (202) 927±1060. CAS No. Pharmaceutical [T.D. 95±33] Dated: April 14, 1995. 52±78±8 ..................... NORETHANDROLONE. A. W. Tennant, 52±86±8 ..................... HALOPERIDOL. Pharmaceutical Tables 1 and 3 of the Director, Office of Laboratories and Scientific 52±88±0 ..................... ATROPINE METHONITRATE. HTSUS 52±90±4 ..................... CYSTEINE. Services. 53±03±2 ..................... PREDNISONE. 53±06±5 ..................... CORTISONE. AGENCY: Customs Service, Department TABLE 1.ÐPHARMACEUTICAL 53±10±1 ..................... HYDROXYDIONE SODIUM SUCCI- of the Treasury. NATE. APPENDIX TO THE HTSUS 53±16±7 ..................... ESTRONE. ACTION: Listing of the products found in 53±18±9 ..................... BIETASERPINE. Table 1 and Table 3 of the CAS No. Pharmaceutical 53±19±0 ..................... MITOTANE. 53±31±6 ..................... MEDIBAZINE. Pharmaceutical Appendix to the N/A ............................. ACTAGARDIN. 53±33±8 ..................... PARAMETHASONE. Harmonized Tariff Schedule of the N/A ............................. ARDACIN. 53±34±9 ..................... FLUPREDNISOLONE. N/A ............................. BICIROMAB. 53±39±4 ..................... OXANDROLONE. United States of America in Chemical N/A ............................. CELUCLORAL. 53±43±0
    [Show full text]
  • PHARMACEUTICAL APPENDIX to the HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2008) (Rev
    Harmonized Tariff Schedule of the United States (2008) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2008) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. ABACAVIR 136470-78-5 ACIDUM GADOCOLETICUM 280776-87-6 ABAFUNGIN 129639-79-8 ACIDUM LIDADRONICUM 63132-38-7 ABAMECTIN 65195-55-3 ACIDUM SALCAPROZICUM 183990-46-7 ABANOQUIL 90402-40-7 ACIDUM SALCLOBUZICUM 387825-03-8 ABAPERIDONUM 183849-43-6 ACIFRAN 72420-38-3 ABARELIX 183552-38-7 ACIPIMOX 51037-30-0 ABATACEPTUM 332348-12-6 ACITAZANOLAST 114607-46-4 ABCIXIMAB 143653-53-6 ACITEMATE 101197-99-3 ABECARNIL 111841-85-1 ACITRETIN 55079-83-9 ABETIMUSUM 167362-48-3 ACIVICIN 42228-92-2 ABIRATERONE 154229-19-3 ACLANTATE 39633-62-0 ABITESARTAN 137882-98-5 ACLARUBICIN 57576-44-0 ABLUKAST 96566-25-5 ACLATONIUM NAPADISILATE 55077-30-0 ABRINEURINUM 178535-93-8 ACODAZOLE 79152-85-5 ABUNIDAZOLE 91017-58-2 ACOLBIFENUM 182167-02-8 ACADESINE 2627-69-2 ACONIAZIDE 13410-86-1 ACAMPROSATE
    [Show full text]
  • Impact of Depressogenic- and Antidepressant-Like
    Impact of depressogenic- and antidepressant-like challenges on monoamine system activities: in vivo electrophysiological characterization studies Chris A. Oosterhof Department of Cellular & Molecular Medicine University of Ottawa Thesis submitted in partial fulfillment of the requirements for the Doctor of Philosophy Degree in Neuroscience © Chris A. Oosterhof, Ottawa, Canada, 2016 Table of contents Table of contents ............................................................................................................. ii Acknowledgements ........................................................................................................ iv Statement of contributions .............................................................................................. v List of figures ................................................................................................................. vi List of tables .................................................................................................................. vii Glossary ........................................................................................................................ viii Abstract .......................................................................................................................... xi 1) Major depressive disorder ............................................................................................... 1 2) Monoamine systems.......................................................................................................
    [Show full text]
  • Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists As New Therapeutic Agents Adeline Etievant#, Cécile Bétry#, and Nasser Haddjeri*,1
    The Open Neuropsychopharmacology Journal, 2010, 3, 1-12 1 Open Access Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents Adeline Etievant#, Cécile Bétry#, and Nasser Haddjeri*,1 Laboratory of Neuropharmacology, Faculty of Pharmacy, University Lyon I, EAC CNRS 5006, 8 Avenue Rockefeller 69373 LYON Cedex 08 France Abstract: The therapeutic efficacy of current antipsychotic or antidepressant agents still present important drawbacks such as delayed onset of action and a high percentage of non-responders. Despite significant advancements in the devel- opment of new drugs with more acceptable side-effect profiles, patients with schizophrenia or major depression experi- ence substantial disability and burden of disease. The present review discusses the usefulness of partial dopamine D2/serotonin 5-HT1A receptors agonists in the treatment of schizophrenia, major depression and bipolar disorder as well as in Parkinson’s disease. Partial agonists can behave as modulators since their intrinsic activity or efficacy of a partial ago- nist depends on the target receptor population and the local concentrations of the natural neurotransmitter. Thus, these drugs may restore adequate neurotransmission while inducing less side effects. In schizophrenia, partial DA D2/5-HT1A receptor agonists (like aripiprazole or bifeprunox), by stabilizing DA system via a preferential reduction of phasic DA re- lease, reduce side effects i.e. extrapyramidal symptoms and improve cognition by acting on 5-HT1A receptors. Aripipra- zole appears also as a promising agent for the treatment of depression since it potentiates the effect of SSRIs in resistant treatment depression. Concerning bipolar disorders aripiprazole may have only a benefit effect in the treatment of manic episodes.
    [Show full text]
  • THE ROLE of the 5-HT Ta RECEPTOR in CENTRAL CARDIOVASCULAR REGULATION Printed By: Duphar B.V
    THE ROLE OF THE 5-HT tA RECEPTOR IN CENTRAL CARDIOVASCULAR REGULATION Printed by: Duphar B.V. C.J. van Houtenlaan 36 1381 CP Weesp The Netherlands Isbn 90-9004025-0 Cover design by F. W. Pompe. © G.H. Dreteler, Elst, 1991 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, photocopying. recording, or otherwise. without written permission from the publisher. THE ROLE OF THE S-HT1A RECEPTOR IN CENTRAL CARDIOVASCULAR REGULATION DE ROL VAN DE 5-HT1A RECEPTOR IN DE CENTRALE CARDIOVASCULAIRE REGULA TIE PROEFSCHRIFT TER VERKRIJGING VAN DE GRAAD VAN DOCTOR AAN DE ERASMUS UNIVERSITEIT ROTTERDAM OP GEZAG VAN DE RECTOR MAGNIFICUS PROF.DR. C.J. RIJNVOS EN VOLGENS BESLUIT VAN HET COLLEGE VAN DEKANEN DE OPENBARE VERDEDIGING ZAL PLAATSVINDEN OP WOENSDAG 27 MAART 1991 OM 15.45 UUR door GERRIE HENDRIKA DRETELER GEBOREN TE DELDEN PROMOTIECOMMISSIE PROMOTOR: PROF.DR. P.R. SAXENA OVERIGE LEDEN: PROF.DR. A.J. MAN IN 'T VELD PROF.DR. P.A. VAN ZWIETEN DR. J.F.M. SMITS CO-PROMOTOR: DR. W. WOUTERS The investigations described in this thesis have been performed at the Institute of Pharmacology, Erasmus University Rotterdam, the Department of Pharmacology. Duphar B.V., Weesp, The Netherlands and the Department of Pharmacology, Royal Free Hospital School of Medicine, London, U.K. The work was supported by Duphar B.V., Weesp. CONTENTS page CHAPTER I General introduction 1.1 Serotonin (5-HT) I l.l.l Localisation of 5-HT I 1.1.2 Function of 5-HT 2 1.2 5-HT receptors
    [Show full text]
  • Hormonal and Temperature Responses to the 5-HT1A Receptor Agonist Flesinoxan in Normal Volunteers
    Psychopharmacology (2002) 164:27–32 DOI 10.1007/s00213-002-1177-0 ORIGINAL INVESTIGATION William Pitchot · Jacques Wauthy · Michel Hansenne · Emmanuel Pinto · Sonia Fuchs · Jean Reggers · Jean-Jacques Legros · Marc Ansseau Hormonal and temperature responses to the 5-HT1A receptor agonist flesinoxan in normal volunteers Received: 22 October 2001 / Accepted: 18 June 2002 / Published online: 30 July 2002 Springer-Verlag 2002 Abstract Rationale: Flesinoxan is a highly potent and able to induce a release of some hormones such as growth selective 5-HT1A agonist and appears to be a potentially hormone (GH), prolactin (PRL), adrenocorticotropin interesting neuroendocrine serotonergic probe. Objec- (ACTH) or cortisol, and a decrease in body temperature. tives: We assessed hormonal (ACTH, cortisol, prolactin Studies with the 5-HT1A receptor partial agonist buspirone and growth hormone) and temperature responses to have reported a significant PRL release (Meltzer et al. flesinoxan in normal volunteers. Methods: In a double- 1983; Coccaro et al. 1990; Dinan et al. 1990; Anderson blind placebo-controlled study, single doses of 0.5 mg and and Cowen 1992; Bridge et al. 2001), but recent data have 1 mg were injected over 10 min into 12 healthy male shown the importance of dopaminergic effects of the drug volunteers at 1-week intervals. Temperature and hormon- in the induction of PRL release (Bridge et al. 2001). al responses were measured at times –30, 0, 15, 30, 60, Stimulation of the hypothalamo-pituitary-adrenal axis 90, and 120 min. Results: Flesinoxan induced a significant (HPA) by the 5-HT1A agonist ipsapirone has been and dose-dependent increase in adrenocorticotropic hor- demonstrated in several studies (Kahn et al.
    [Show full text]
  • Serotonergic Drugs and Masculine Sexual Behavior in Laboratory Rats and Men
    * 1995 Elsevier Science B. V. All rights reserved. The Pharmacology of Sexual Function and Dysfunction J. Bancroft, editor 235 Serotonergic drugs and masculine sexual behavior in laboratory rats and men S.M. Haensel1, D.L. Rowland2 and A.K. Slob1 Department of Endocrinology & Reproduction, Faculty of Medicine and Health Sciences, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. 2Department of Psychology, Valparaiso University, Valparaiso, IN 46383, USA. Introduction The neurotransmitter serotonin (5-HT) has been known for its involvement in sexual behavior since the late sixties [1]. By now, there is quite an extensive literature on the effects of serotonergic agents, especially the agonists, on sexual behavior of rats [reviews: 2-5]. In recent years we have studied the effects of serotonin agonists on sexual behaviors in rats. We investigated the effects of 8-OH-DPAT (a selective 5-HT1A receptor agonist) in male and female rats [6-8] and the effects of flesinoxan, also a selective 5-HT1A agonist [9] on masculine sexual behavior in male rats. In the human we studied the effects of clomipramine, a tricyclic antidepressant with selective serotonin reuptake inhibitor properties [10], in men with ejaculatory and erectile dysfunctions and in a group of control men without sexual dysfunction. In this paper we present recent [7-8] and new rat data, and hitherto unpublished human data. ANIMAL STUDIES General method Animals and laboratory conditions Albino Wistar rats were used, except the male rats in Exp. 2 and 3, which were Fr hybrids of two inbred Wistar strains (RxU). The animals were housed 2 to 3 to a cage, of the same sex and treatment.
    [Show full text]