Stereotypies in the Autism Spectrum Disorder: Can We Rely on an Ethological Model?
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TABLE 1 Studies of Antagonist Activity in Constitutively Active
TABLE 1 Studies of antagonist activity in constitutively active receptors systems shown to demonstrate inverse agonism for at least one ligand Targets are natural Gs and constitutively active mutants (CAM) of GPCRs. Of 380 antagonists, 85% of the ligands demonstrate inverse agonism. Receptor Neutral Antagonist Inverse Agonist Reference Human β2-adrenergic Dichloroisoproterenol, pindolol, labetolol, timolol, Chidiac et al., 1996; Azzi et alprenolol, propranolol, ICI 118,551, cyanopindolol al., 2001 Turkey erythrocyte β-adrenergic Propranolol, pindolol Gotze et al., 1994 Human β2-adrenergic (CAM) Propranolol Betaxolol, ICI 118,551, sotalol, timolol Samama et al., 1994; Stevens and Milligan, 1998 Human/guinea pig β1-adrenergic Atenolol, propranolol Mewes et al., 1993 Human β1-adrenergic Carvedilol CGP20712A, metoprolol, bisoprolol Engelhardt et al., 2001 Rat α2D-adrenergic Rauwolscine, yohimbine, WB 4101, idazoxan, Tian et al., 1994 phentolamine, Human α2A-adrenergic Napthazoline, Rauwolscine, idazoxan, altipamezole, levomedetomidine, Jansson et al., 1998; Pauwels MPV-2088 (–)RX811059, RX 831003 et al., 2002 Human α2C-adrenergic RX821002, yohimbine Cayla et al., 1999 Human α2D-adrenergic Prazosin McCune et al., 2000 Rat α2-adrenoceptor MK912 RX821002 Murrin et al., 2000 Porcine α2A adrenoceptor (CAM- Idazoxan Rauwolscine, yohimbine, RX821002, MK912, Wade et al., 2001 T373K) phentolamine Human α2A-adrenoceptor (CAM) Dexefaroxan, (+)RX811059, (–)RX811059, RS15385, yohimbine, Pauwels et al., 2000 atipamezole fluparoxan, WB 4101 Hamster α1B-adrenergic -
From Inverse Agonism to 'Paradoxical Pharmacology' Richard A
International Congress Series 1249 (2003) 27-37 From inverse agonism to 'Paradoxical Pharmacology' Richard A. Bond*, Kenda L.J. Evans, Zsirzsanna Callaerts-Vegh Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 521 Science and Research Bldg 2, 4800 Caltioun, Houston, TX 77204-5037, USA Received 16 April 2003; accepted 16 April 2003 Abstract The constitutive or spontaneous activity of G protein-coupled receptors (GPCRs) and compounds acting as inverse agonists is a recent but well-established phenomenon. Dozens of receptor subtypes for numerous neurotransmitters and hormones have been shown to posses this property. However, do to the apparently low percentage of receptors in the spontaneously active state, the physiologic relevance of these findings remains questionable. The possibility that the reciprocal nature of the effects of agonists and inverse agonists may extend to cellular signaling is discussed, and that this may account for the beneficial effects of certain p-adrenoceptor inverse agonists in the treatment of heart failure. © 2003 Elsevier Science B.V. All rights reserved. Keywords. Inverse agonism; GPCR; Paradoxical pharmacology 1. Brief history of inverse agonism at G protein-coupled receptors For approximately three-quarters of a century, ligands that interacted with G protein- coupled receptors (GPCRs) were classified either as agonists or antagonists. Receptors were thought to exist in a single quiescent state that could only induce cellular signaling upon agonist binding to the receptor to produce an activated state of the receptor. In this model, antagonists had no cellular signaling ability on their own, but did bind to the receptor and prevented agonists from being able to bind and activate the receptor. -
The Effect of 5-HT1A Receptor Antagonist on Reward-Based
The Journal of Physiological Sciences (2019) 69:1057–1069 https://doi.org/10.1007/s12576-019-00725-1 ORIGINAL PAPER The efect of 5‑HT1A receptor antagonist on reward‑based decision‑making Fumika Akizawa1 · Takashi Mizuhiki1,2 · Tsuyoshi Setogawa1,2 · Mai Takafuji1 · Munetaka Shidara1,2 Received: 5 July 2019 / Accepted: 27 October 2019 / Published online: 8 November 2019 © The Physiological Society of Japan and Springer Japan KK, part of Springer Nature 2019 Abstract When choosing the best action from several alternatives, we compare each value that depends on the balance between beneft and cost. Previous studies have shown that animals and humans with low brain serotonin (5-HT) level tend to choose smaller immediate reward. We used a decision-making schedule task to investigate whether 5-HT1A receptor is responsible for the decisions related to reward. In this task, the monkeys chose either of two diferent alternatives that were comprised of 1–4 drops of liquid reward (beneft) and 1–4 repeats of a color discrimination trial (workload cost), then executed the chosen schedule. By the administration of 5-HT1A antagonist, WAY100635, the choice tendency did not change, however, the sen- sitivity to the amount of reward in the schedule part was diminished. The 5-HT1A could have a role in maintaining reward value to keep track with the promised reward rather than modulating workload discounting of reward value. Keywords 5-HT1A · Value discounting · WAY100635 · Decision-making · Workload · Rhesus monkey Introduction comprises an iteration of simple color discriminations. The monkey can choose one of two diferent schedules to earn Whenever we choose an option from two or more alterna- promised reward. -
(12) Patent Application Publication (10) Pub. No.: US 2010/0221245 A1 Kunin (43) Pub
US 2010O221245A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0221245 A1 Kunin (43) Pub. Date: Sep. 2, 2010 (54) TOPICAL SKIN CARE COMPOSITION Publication Classification (51) Int. Cl. (76) Inventor: Audrey Kunin, Mission Hills, KS A 6LX 39/395 (2006.01) (US) A6II 3L/235 (2006.01) A638/16 (2006.01) Correspondence Address: (52) U.S. Cl. ......................... 424/133.1: 514/533: 514/12 HUSCH BLACKWELL SANDERS LLP (57) ABSTRACT 4801 Main Street, Suite 1000 - KANSAS CITY, MO 64112 (US) The present invention is directed to a topical skin care com position. The composition has the unique ability to treat acne without drying out the user's skin. In particular, the compo (21) Appl. No.: 12/395,251 sition includes a base, an antibacterial agent, at least one anti-inflammatory agent, and at least one antioxidant. The (22) Filed: Feb. 27, 2009 antibacterial agent may be benzoyl peroxide. US 2010/0221 245 A1 Sep. 2, 2010 TOPCAL SKIN CARE COMPOSITION stay of acne treatment since the 1950s. Skin irritation is the most common side effect of benzoyl peroxide and other anti BACKGROUND OF THE INVENTION biotic usage. Some treatments can be severe and can leave the 0001. The present invention generally relates to composi user's skin excessively dry. Excessive use of some acne prod tions and methods for producing topical skin care. Acne Vul ucts may cause redness, dryness of the face, and can actually garis, or acne, is a common skin disease that is prevalent in lead to more acne. Therefore, it would be beneficial to provide teenagers and young adults. -
Muscarinic Acetylcholine Receptor
mAChR Muscarinic acetylcholine receptor mAChRs (muscarinic acetylcholine receptors) are acetylcholine receptors that form G protein-receptor complexes in the cell membranes of certainneurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibersin the parasympathetic nervous system. mAChRs are named as such because they are more sensitive to muscarine than to nicotine. Their counterparts are nicotinic acetylcholine receptors (nAChRs), receptor ion channels that are also important in the autonomic nervous system. Many drugs and other substances (for example pilocarpineand scopolamine) manipulate these two distinct receptors by acting as selective agonists or antagonists. Acetylcholine (ACh) is a neurotransmitter found extensively in the brain and the autonomic ganglia. www.MedChemExpress.com 1 mAChR Inhibitors & Modulators (+)-Cevimeline hydrochloride hemihydrate (-)-Cevimeline hydrochloride hemihydrate Cat. No.: HY-76772A Cat. No.: HY-76772B Bioactivity: Cevimeline hydrochloride hemihydrate, a novel muscarinic Bioactivity: Cevimeline hydrochloride hemihydrate, a novel muscarinic receptor agonist, is a candidate therapeutic drug for receptor agonist, is a candidate therapeutic drug for xerostomia in Sjogren's syndrome. IC50 value: Target: mAChR xerostomia in Sjogren's syndrome. IC50 value: Target: mAChR The general pharmacol. properties of this drug on the The general pharmacol. properties of this drug on the gastrointestinal, urinary, and reproductive systems and other… gastrointestinal, urinary, and reproductive systems and other… Purity: >98% Purity: >98% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 1 mg, 5 mg 1 mg, 5 mg AC260584 Aclidinium Bromide Cat. No.: HY-100336 (LAS 34273; LAS-W 330) Cat. -
The Effect of Positive Reinforcement Training on an Adult Female Western Lowland Gorilla’S (Gorilla Gorilla Gorilla) Rate of Abnormal and Aggressive Behavior
ABC 2016, 3(2):78-87 Animal Behavior and Cognition DOI: 10.12966/abc.02.05.2016 ©Attribution 3.0 Unported (CC BY 3.0) The Effect of Positive Reinforcement Training on an Adult Female Western Lowland Gorilla’s (Gorilla gorilla gorilla) Rate of Abnormal and Aggressive Behavior Austin Leeds1,2, Roby Elsner3, & Kristen E. Lukas1,2 1Cleveland Metroparks Zoo 2Case Western Reserve University 3Audubon Zoo *Corresponding author (Email: [email protected]) Citation – Leeds, A., Elsner, R., & Lukas, K. E. (2016). The effect of positive reinforcement training on an adult female Western lowland gorilla’s (Gorilla gorilla gorilla) rate of abnormal and aggressive behavior. Animal Behavior and Cognition, 3(2), 78–87. doi: 10.12966/abc.02.05.2016 Abstract - Positive reinforcement training (PRT) has become a widely used tool in improving the ease with which husbandry and veterinary procedures are performed for animals under human care. PRT provides positive social interaction, cognitive stimulation, and choice, in addition to desensitization towards potentially stressful situations. As a result, PRT has been used as enrichment to decrease abnormal and aggressive behavior in various primate species, however, this has not been empirically tested in western lowland gorillas (Gorilla gorilla gorilla). This study used an ABA design to test the effect of PRT on the abnormal and aggressive behavior of an adult female gorilla both during and outside of interaction sessions. No change in behavior was observed during the PRT phase of this study. However, a decrease in ear covering and keeper-directed aggression were observed in the post-training period. Here we argue that the combination of both PRT and non-training interactions cumulatively provided social and cognitive stimuli resulting in the observed changes. -
How to Prevent the Malignant Progression of Bipolar Disorder Robert M
Braz J Psychiatry. 2020 Sep-Oct;42(5):552-557 doi:10.1590/1516-4446-2020-0874 Brazilian Psychiatric Association 00000000-0002-7316-1185 SPECIAL ARTICLE How to prevent the malignant progression of bipolar disorder Robert M. Post0000-0000-0000-0000 Bipolar Collaborative Network, School of Medicine, George Washington University, Washington, USA. There is increasing recognition that, in a high percentage of cases, bipolar disorder is a progressive illness. Multiple types of sensitization (or increased reactivity to repetition of the same stimulus) drive illness progression. One of the clearest is that of episode sensitization, where increased numbers of prior episodes are associated with: faster recurrences; more dysfunction; disability; social, educa- tional, and employment deficits; suicide; medical comorbidities; cognitive dysfunction; and an increased incidence of dementia in old age. Repetition of stressors and bouts of substance abuse can also result in sensitization. Each type of sensitization appears to have an epigenetic basis, such that preventing sensitization should minimize the accumulation of adverse epigenetic chemical marks on DNA, histones, and microRNA. New data emphasize the importance of early, consistent intervention after an initial manic episode. The cognitive dysfunction associated with a first episode improves only if there are no further episode recurrences during the next year. A randomized study has also shown that comprehensive multimodal prophylactic intervention for 2 years leads to improvements in illness course -
Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: a PET Study in Conscious Monkeys
Neuropsychopharmacology (2013) 38, 2666–2674 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 www.neuropsychopharmacology.org Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys 1 1 1 1 1 Shigeyuki Yamamoto , Hiroyuki Ohba , Shingo Nishiyama , Norihiro Harada , Takeharu Kakiuchi , 1 ,2 Hideo Tsukada and Edward F Domino* 1 2 Central Research Laboratory, Hamamatsu Photonics KK, Hamakita, Japan; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear. In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated. Five young monkeys 11 underwent four positron emission tomography measurements with [ C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzoni- 11 trile ([ C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a 11 dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [ C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later. The effect of ketamine on the serotonin 1A receptor (5-HT1A-R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [11C]DASB. No significant changes were observed in either 5-HT -R or DAT binding after ketamine infusion. Microdialysis analysis indicated that ketamine infusion transiently increased 1A serotonin levels in the extracellular fluid of the prefrontal cortex. -
The Role of Polyunsaturated Fatty Acids
biomedicines Review Mental Health in Childhood and Adolescence: The Role of Polyunsaturated Fatty Acids Paola Bozzatello, Cecilia Blua, Paola Rocca and Silvio Bellino * Department of Neuroscience, University of Turin, 10126 Turin, Italy; [email protected] (P.B.); [email protected] (C.B.); [email protected] (P.R.) * Correspondence: [email protected]; Tel.: +39-011-6634848; Fax: +39-011-673473 Abstract: There is increasing awareness of the importance of polyunsaturated fatty acids (PUFAs) for optimal brain development and function. In recent decades, researchers have confirmed the central role of PUFAs in a variety of patho-physiological processes. These agents modulate the mechanisms of brain cell signalling including the dopaminergic and serotonergic pathways. Therefore, nutri- tional insufficiencies of PUFAs may have adverse effects on brain development and developmental outcomes. The role of n-3 PUFAs has been studied in several psychiatric disorders in adulthood: schizophrenia, major depression, bipolar disorder, anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, eating disorders, substance use disorder, and borderline personality disorder. In contrast to the great number of studies conducted in adults, there are only limited data on the effects of n-3 PUFA supplementation in children and adolescents who suffer from mental disorders or show a high risk of developing psychiatric disorders. The aim of this review is to provide a complete and updated account of the available evidence of the impact of polyunsaturated fatty acids on develop- mental psychopathology in children and adolescents and the effect of fatty acid supplementation during developmental milestones, particularly in high-risk populations of children with minimal but Citation: Bozzatello, P.; Blua, C.; detectable signs or symptoms of mental disorders. -
Amanita Muscaria (Fly Agaric)
J R Coll Physicians Edinb 2018; 48: 85–91 | doi: 10.4997/JRCPE.2018.119 PAPER Amanita muscaria (fly agaric): from a shamanistic hallucinogen to the search for acetylcholine HistoryMR Lee1, E Dukan2, I Milne3 & Humanities The mushroom Amanita muscaria (fly agaric) is widely distributed Correspondence to: throughout continental Europe and the UK. Its common name suggests MR Lee Abstract that it had been used to kill flies, until superseded by arsenic. The bioactive 112 Polwarth Terrace compounds occurring in the mushroom remained a mystery for long Merchiston periods of time, but eventually four hallucinogens were isolated from the Edinburgh EH11 1NN fungus: muscarine, muscimol, muscazone and ibotenic acid. UK The shamans of Eastern Siberia used the mushroom as an inebriant and a hallucinogen. In 1912, Henry Dale suggested that muscarine (or a closely related substance) was the transmitter at the parasympathetic nerve endings, where it would produce lacrimation, salivation, sweating, bronchoconstriction and increased intestinal motility. He and Otto Loewi eventually isolated the transmitter and showed that it was not muscarine but acetylcholine. The receptor is now known variously as cholinergic or muscarinic. From this basic knowledge, drugs such as pilocarpine (cholinergic) and ipratropium (anticholinergic) have been shown to be of value in glaucoma and diseases of the lungs, respectively. Keywords acetylcholine, atropine, choline, Dale, hyoscine, ipratropium, Loewi, muscarine, pilocarpine, physostigmine Declaration of interests No conflicts of interest declared Introduction recorded by the Swedish-American ethnologist Waldemar Jochelson, who lived with the tribes in the early part of the Amanita muscaria is probably the most easily recognised 20th century. His version of the tale reads as follows: mushroom in the British Isles with its scarlet cap spotted 1 with conical white fl eecy scales. -
"GVS Assessment of Indacaterol/Glycopyrronium
> Return address PO Box 320, 1110 AH Diemen National Health Care Institute Care II To the Minister of Medical Care and Sports Cardiovascular & Pulmonary PO Box 20350 Willem Dudokhof 1 2500 EJ Den Haag 1112 ZA Diemen PO Box 320 1110 AH Diemen www.zorginstituutnederland.nl [email protected] 2020037637 T +31 (0)20 797 85 55 Contact Dr T.H.L. Tran T +31 (0)6-12001412 Date 24 September 2020 Subject Enerzair® Breezhaler® (indacaterol/glycopyrronium/mometasone) Our reference 2020037637 Dear Ms van Ark, In your letter of 7 September 2020 (CIBG-20-0910), you asked Zorginstituut Nederland to assess whether the product indacaterol acetate/glycopyrronium/mometasone furoate (Enerzair® Breezhaler®) can be included in the Medicine Reimbursement System (GVS). Enerzair® Breezhaler® is a combination preparation with three active ingredients: indacaterol as acetate, a long-acting beta2-adrenergic agonist; glycopyrronium bromide, a long-acting muscarine receptor agonist; and mometasone furoate, a synthetic corticosteroid. Enerzair® Breezhaler® is registered for as a maintenance treatment of asthma in adult patients not adequately controlledwith a maintenance combination of a long- acting beta2-agonist and a high dose of an inhaled corticosteroid who experienced one or more asthma exacerbations in the previous year. The dosage of Enerzair® Breezhaler® is one inhalation capsule to be inhaled once daily. The dosage in the capsules contains 150 micrograms of indacaterol (as acetate), combined with 63 micrograms of glycopyrronium bromide, which corresponds to 50 micrograms of glycopyrronium and 160 micrograms of mometasone furoate. Each dose delivered contains 114 micrograms of indacaterol, 58 micrograms of glycopyrronium bromide, which corresponds to 46 micrograms of glycopyrronium and 136 micrograms of mometasone furoate. -
The Clinical Presentation of Psychotic Disorders Bob Boland MD Slide 1
The Clinical Presentation of Psychotic Disorders Bob Boland MD Slide 1 Psychotic Disorders Slide 2 As with all the disorders, it is preferable to pick Archetype one “archetypal” disorder for the category of • Schizophrenia disorder, understand it well, and then know the others as they compare. For the psychotic disorders, the diagnosis we will concentrate on will be Schizophrenia. Slide 3 A good way to organize discussions of Phenomenology phenomenology is by using the same structure • The mental status exam as the mental status examination. – Appearance –Mood – Thought – Cognition – Judgment and Insight Clinical Presentation of Psychotic Disorders. Slide 4 Motor disturbances include disorders of Appearance mobility, activity and volition. Catatonic – Motor disturbances • Catatonia stupor is a state in which patients are •Stereotypy • Mannerisms immobile, mute, yet conscious. They exhibit – Behavioral problems •Hygiene waxy flexibility, or assumption of bizarre • Social functioning – “Soft signs” postures as most dramatic example. Catatonic excitement is uncontrolled and aimless motor activity. It is important to differentiate from substance-induced movement disorders, such as extrapyramidal symptoms and tardive dyskinesia. Slide 5 Disorders of behavior may involve Appearance deterioration of social functioning-- social • Behavioral Problems • Social functioning withdrawal, self neglect, neglect of • Other – Ex. Neuro soft signs environment (deterioration of housing, etc.), or socially inappropriate behaviors (talking to themselves in