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Mary-Anne Bellwood Mackay The use of adjuvant L-arginine in schizophrenia: A behavioural and neurochemical analysis by Mary-Anne Bellwood MacKay A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Psychopharmacology Department of Psychiatry University of Alberta © Mary-Anne Bellwood MacKay, 2016 ABSTRACT Schizophrenia is a complex neurodevelopmental illness that often requires a combination of treatments to adequately control its symptoms. Despite the availability of several neuroleptic medications on the market, many patients with schizophrenia remain symptomatic. Research has shifted emphasis towards impaired glutamate signaling as a major contributor to the illness. Drug targets specific to the glutamate-nitric oxide (NO) pathway may offer a promising new approach to treatment. The therapeutic effect of the amino acid L-arginine (Arg), the substrate for the NO-producing enzyme neuronal nitric oxide synthase (nNOS) was examined in this thesis. As an augmenting strategy, Arg was administered (at 6g per day) to patients with schizophrenia in an attempt to improve the efficacy of antipsychotic therapy. Responders to Arg therapy had a reduction in anxiety symptoms that were previously resistant to prescribed medication. The anxiolytic effect of Arg may be directly related to an increase in endogenous central NO production and the downstream induction of cyclic guanosine monophosphate (cGMP)-mediated signaling cascades. L-Arginine also proved to be a safe strategy in the treatment of schizophrenia and did not exacerbate any of the known side-effects that were already present as a result of ongoing antipsychotic therapy. This thesis also investigated genetic influences on glutamate N- methyl-D-aspartate (NMDA) receptor functioning and treatment response to Arg therapy. The Neuronal Period-Arylhydrocarbon Nuclear Translocator ii (ARNT)-Single-minded (PAS) domain containing 3 (NPAS3) gene codes for a protein that functions as a transcription factor. NPAS3 and its related variants may be important for the development of functional postsynaptic density (PSD-95) scaffolding proteins that directly link the NMDA receptor to the nNOS enzyme in the brain. Variants associated with NPAS3 and schizophrenia were examined to elucidate the integrity of the PSD-95 protein and used to predict the outcome of the effects of adjuvant Arg therapy. Two carriers of a NPAS3 variant who did not respond to Arg treatment may have had compromised NMDA receptor function related to altered neurodevelopmental processes that occurred during early brain development. Participants were also genotyped for the catechol-O- methyltransferase (COMT ) enzyme single nucleotide polymorphism (SNP) p.V158M to explore the relationship between this genetic marker and clinical outcomes. No significant gene-gene interaction between NPAS3 and COMT was determined that would influence treatment response to Arg therapy. Preclinical experiments were also included in this thesis to determine the behavioural and neurochemical mechanisms by which Arg was able to exert its therapeutic effect. Competing metabolic enzymes that utilize Arg as a substrate were investigated by measurement of related amino acids ornithine (Orn) and citrulline (Cit). The immediate potentiation of whole brain Cit levels following Arg administration suggested that NO is produced quickly and NOS enzymes require a much lower concentration of Arg than that of the arginase enzymes. iii This thesis was also able to confirm the utility of phencyclidine (PCP) as a comprehensive pharmacological model of psychosis and the ability of antipsychotic drugs to reduce PCP-induced hyperlocomotor activity. The administration of Arg alone in a rodent PCP model had no significant effect on hyperlocomotor activity (a behavioural measure of the positive symptoms of psychosis) and it also did not enhance the locomotor-reducing effects of antipsychotic drugs. These results were consistent with the clinical trial data where no significant changes in positive symptoms were also found when augmenting antipsychotic treatment with Arg. Although Arg therapy was unable to potentiate antipsychotic effects in schizophrenia, work presented in this thesis does support the use of Arg as a tolerable and effective strategy that may target intrinsic anxiety in treatment-refractory schizophrenia. iv PREFACE This thesis is an original work done by Mary-Anne Bellwood MacKay. The clinical research project which is part of this thesis received research ethics approval from the University of Alberta Research Ethics Board, Project Name “A RANDOMISED DOUBLE-BLIND CROSS-OVER, PLACEBO-CONTROLLED ADJUNCTIVE TREATMENT OF L-ARGININE ADDED TO TREATMENT AS USUAL (TAU) IN SCHIZOPHRENIA: AN EXPLORATORY THERAPEUTIC CLINICAL TRIAL PROTOCOL” REB approval No. MS3_Pro00002053 DECEMBER 14, 2007. v DEDICATION I would like to dedicate this thesis to my father Ronald George Buchanan MacKay vi ACKNOWLEGEMENTS I would like to express my appreciation for all of the support and encouragement I have received from a number of people throughout my studies. First of all, to my supervisor, Dr. Serdar Dursun, who has been a tremendous mentor and teacher to me. I can never thank him enough for his exceptional guidance as a clinical research scientist. I have been so fortunate to work along side him and could not have asked for a better supervisor. I would also like to thank the members of my supervisory committee. To Dr. Glen Baker, for his ongoing support throughout my project and for his excellent guidance in the writing of this thesis. Also, to Dr. John Lind, for his words of encouragement over the years and his infectious enthusiasm for statistical methods. Thanks as well to Drs. Satyabrata Kar and Harold Robertson for taking the time to review my thesis as external examiners. To Gail Rauw, for spending all of the time you did with me in the lab and patiently teaching me the analytical techniques relevant to my thesis. Thanks to all at the Neurochemical Research Unit for making me feel so welcome. To Andy Greenshaw, your support and perspective made the milestones of graduate school seem much less intimidating. Also, thanks to Drs. Diane Cox and Georgina Macintyre for allowing me to work with you in your laboratory. Thanks also to Drs. P.J. White and Cory Czarnecki and all of the psychiatrists and nurses at Alberta Hospital Edmonton as well as the Addictions and Mental Health Clinic in Edmonton who helped support my efforts in recruiting for my study. A heartfelt thank you to all of the dedicated individuals that participated in the study and who were willing to investigate L-Arginine treatment for their illness. Finally, I am forever grateful to my family for their love and support. To my mum, I could not have completed this thesis without you. Thank you for being so kind and good to us. To my brother, his genuine love of science has always been an inspiration to me. He is the smartest fellow I know. And finally, to my friends, Lynn and Terence, for teaching me about true determination and to never give up. vii TABLE OF CONTENTS CHAPTER 1 – GENERAL INTRODUCTION ............................................................. 1 1.1 FORWORD ........................................................................................................................... 2 1.2 SCHIZOPHRENIA .............................................................................................................. 3 1.2.1 Neurodevelopmental hypothesis ........................................................................ 3 1.2.2 Disease course ............................................................................................................ 4 1.2.3 Etiology .......................................................................................................................... 5 1.2.4 Genetic risk factors ................................................................................................... 5 1.2.5 Environmental risk factors .................................................................................... 6 1.2.6 Diagnosis ....................................................................................................................... 7 1.3 ANTIPSYCOTIC DRUG DEVELOPMENT ................................................................... 8 1.3.1 First-generation antipsychotic drugs ................................................................ 8 1.3.2 Second-generation antipsychotic drugs ........................................................... 9 1.3.3 Third-generation antipsychotic drugs aripiprazole and brexpiprazole ........................................................................................................................................ 11 1.4 GLUTAMATE .................................................................................................................... 11 1.4.1 Glutamate synthesis ............................................................................................... 11 1.4.2 Glutamate receptors .............................................................................................. 12 1.5 NMDA RECEPTOR COMPLEX .................................................................................... 15 1.6 NITRIC OXIDE ................................................................................................................. 18 1.7 DYSREGULATED GLUTAMATE IN SCHIZOPHRENIA ....................................... 19 viii 1.7.1 Glutamate hypofunction hypothesis ..............................................................
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