Advanced Neurotransmitters & Neuroglia

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1 Advanced Neurotransmitters & Neuroglia Otsuka Pharmaceutical Development & Commercialization, Inc Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD Lundbeck, LLC. February 2017 MRC2.CORP.D advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

2 This program was developed with the support of Otsuka Pharmaceutical Development & Commercialization, Inc. and Lundbeck, LLC. The speakers are either employees or paid contractors of Otsuka Pharmaceutical Development & Commercialization, Inc. 2 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

3 Table of Contents Neurotransmitter Receptor Subtypes Neurotransmitter Circuitry and Biosynthesis Functional Connectivity of Monoaminergic Neurotransmitters Morphology and Function of Neuroglia Neuroglia Cell Types 3

4 Neurotransmitters and Receptors* Neurotransmitter receptor subtypes Neurotransmitter Acetylcholine 1 Histamine 1 Dopamine 1 Noradrenaline 1,2 Serotonin 3 Glutamate 1,4 GABA 1 Receptor subtypes Cholinergic receptors: muscarinic receptors (M 1-5 subtypes), nicotinic receptors Histaminic receptors (H 1-3 subtypes) Dopaminergic receptors (D 1-5 subtypes) α-adrenergic receptors (α 1A, B, D, α 2A-C subtypes) β-adrenergic receptors (β 1-3 subtypes) 5-HT receptors (5-HT 1A-B, 5-HT 1D-F, 5-HT 2A-C, 5-HT 3-7 subtypes) Ionotropic receptors: non-nmda (AMPA, kainate), NMDA receptors Metabotropic receptors (mglurs) GABA A, GABA B, and GABA C receptors 5-HT, serotonin; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; D, dopamine; GABA, gamma-aminobutyric acid; H, histamine; M, muscarinic; mglurs, metabotropic glutamate receptors; NMDA, N-methyl-D-aspartate. *Common targets for drugs; will be discussed in further detail in disease-specific modules. 1. Stahl SM. Stahl s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th edition. Cambridge University Press; Quaglia W, et al. Expert Opin Ther Pat. 2011;21(4): Polter AM, et al. Front Mol Neurosci. 2011;4: Purves D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates;

5 Neurotransmitter: Acetylcholine Circuitry 1 Synthesis 2 Glucose Pyruvate Acetyl CoA Choline O CoA S C CH 3 CH 2 CH 2 N (CH 3 ) 3 Choline acetyltransferase Acetylcholine O CH 3 C O CH 2 CH 2 N (CH 3 ) 3 Receptors 1 Muscarinic receptors: (G protein-coupled) M1-Type: 1, 3, 5 M2-Type: 2, 4 Media septal nucleus in basal forebrain Image based on: Brichta L, et al; Acetyl CoA, acetyl coenzyme A; M1, muscarinic acetylcholine receptor M1; M2, muscarinic acetylcholine receptor M2. 1. Brichta L, et al. Trends Neurosci. 2013;36(9): Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; Neuronal nicotinic receptors: (Ligand-gated ion channels) Group II: α7 Group III-1: α2, α3, α4, α6 Group III-2: β2, β4 Group III-3: β3, α5 5

6 Neurotransmitter: Histamine 1 Circuitry Synthesis Histidine _ COO CH 2 CH NH 3 HN N Histidine decarboxylase Histamine CO 2 CH 2 CH 2 NH 3 HN N Receptors Histaminic receptors: (G protein-coupled) H1, H2, H3 Tuberomammillary nucleus of hypothalamus Image based on: Purves D, et al; H1, histamine receptor H1; H2, histamine receptor H2; H3, histamine receptor H3. 1. Purves D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates;

7 Neurotransmitter: Dopamine Circuitry 1 Tyrosine Synthesis 1 Dihydroxyphenylalanine (DOPA) OH O 2 COO _ CH 2 CH NH 3 Tyrosine hydroxylase COO _ CH 2 CH NH3 DOPA decarboxylase Dopamine CO 2 CH 2 CH 2 NH 3 OH Receptors 2 Substantia nigra and ventral tegmental area Dopamine receptors: (G protein-coupled) Image based on: Purves D, et al; D1, dopamine receptor 1; D2, dopamine receptor 2; D3, dopamine receptor 3; D4, dopamine receptor 4, D5, dopamine receptor Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; 2004; Brichta L, et al. Trends Neurosci. 2013;36(9): D1-like: D1, D5 D2-like: D2, D3, D4 7

8 Neurotransmitter: Norepinephrine Circuitry 1 Synthesis 1 CH 2 CH 2 NH 2 Dopamine Dopamine β-hydroxylase OH CH CH 2 NH 2 Norepinephrine Receptors 2 Locus coeruleus Adrenergic receptors: (G protein-coupled) α 1 A, α 1 B, α 1 D α 2 A, α 2 B, α 2 C β 1, β 2, β 3 Image based on: Purves D, et al; α 1 A, alpha-1a adrenergic receptor; α 1 B, alpha-1b adrenergic receptor; α 1 D, alpha-1d adrenergic receptor; α 2 A, alpha-2a adrenergic receptor; α 2 B, alpha-2b adrenergic receptor; α 2 C, alpha-2c adrenergic receptor; β 1, beta-1 adrenergic receptor β 2, beta-2 adrenergic receptor; β 3, beta-3 adrenergic receptor. 1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; 2004; 2. Brichta L, et al. Trends Neurosci. 2013;36(9):

9 Neurotransmitter: Serotonin Circuitry 1 Synthesis 1 COO _ Tryptophan CH 2 CH NH 3 5-Hydroxytryptophan Tryptophan-5- hydroxylase O 2 Aromatic L-amino acid decarboxylase Serotonin N N N CO 2 Receptors 2 CH 2 COO _ CH CH 2 CH 2 NH 3 NH 3 Raphe nuclei Image based on: Purves D, et al; HT1A, serotonin 1A receptor; 1B, serotonin 1B receptor; 1D, serotonin 1D receptor; 1E, serotonin 1E receptor; 1F, serotonin 1F receptor; 5- HT2A, serotonin 2A receptor; 2C, serotonin 2C receptor; 5-HT3, serotonin 3 receptor; 5-HT4, serotonin 4 receptor; 5-HT5, serotonin 5 receptor; 5-HT6, serotonin 6 receptor; 5-HT7, serotonin 7 receptor. 1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; 2004; 2. Brichta L, et al. Trends Neurosci. 2013;36(9): Serotonin receptors: G protein-coupled: 5-HT1A, 1B, 1D, 1E, 1F 5-HT2A, 2C 5-HT4, 5-HT5, 5-HT6, 5-HT7 Ligand-gated ion channel: 5-HT3 9

10 Neurotransmitter: Glutamate Circuitry 1 Synthesis 2 Glutamine _ COO O H 3 N CH CH 2 CH 2 C NH 2 Glutaminase Glutamate H 3 N _ COO CH CH 2 CH 2 COO _ Receptors 1,2 Metabotropic (mglur): (G protein-coupled) Group I: 1,5 Group II: 2,3 Group III: 4,6,7,8 Image based on: Brichta L, et al: Ionotropic: NMDA AMPA Kainate AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; mglur, metabotropic glutamate receptors; NMDA, N-methyl-D-aspartate. 1. Brichta L, et al. Trends Neurosci. 2013;36(9): ; 2. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates;

11 Neurotransmitter: GABA Circuitry 1 Synthesis 2 Glucose Glutamate H 3 N _ COO CH CH 2 CH 2 COO _ GABA H 3 N Glutamic acid decarboxylase pyridoxal phosphate CH 2 CH 2 CH 2 COO _ Receptors 2 GABA receptors: Ionotropic: GABA A, GABA C Metabotropic: GABA B Image based on: Carlsson A, et al; GABA A, gamma-aminobutyric acid type A receptor; GABA B, gamma-aminobutyric acid type B receptor; GABA C, gamma-aminobutyric acid type C receptor. 1. Carlsson A. Int Clin Psychopharmacol. 1995;10(Suppl 3):21-28; 2. Purves D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates;

12 Functional Connectivity Across Monoamine Systems 1 5-HT NE Postsynaptic neuron DA D 2 receptor α1 receptor α2 receptor 5-HT 1A receptor 5-HT 1B receptor GABAergic interneuron Reuptake transporter 5-HT, serotonin; 5-HT 1A, serotonin 1A receptor; 5-HT 1B, serotonin 1B receptor; α1, alpha-1 adrenergic receptor; α2, alpha-2 adrenergic receptor; D2, dopamine receptor 2; DA, dopamine; GABA, gamma-aminobutyric acid; NE, norepinephrine. 1. Blier P. Int J Neuropsychopharmacol. 2014;17(7): Image based on: Blier P;

13 Neuroglia 1 Glia = glue in Greek Glia cells of the central nervous system (CNS) are called neuroglia Neuroglia are different than neurons: Smaller than neurons Do not have axons, dendrites or conduct nerve impulses Outnumber neurons in brain ~3:1 ratio Essential in maintaining homeostasis within CNS: Assist in nervous system repair and maintenance Assist in development of nervous system, insulating neurons, and providing metabolic functions for neurons characteristics 1. Purves D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates;

14 Types of Neuroglia 1,2 Image from Designua , with contextual support provided by Purves Designua. Digital image RF website. Accessed 09 December Available at: 2. Purves D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates;

15 Summary Although there are similarities among neurotransmitter subtypes (eg monoamines, amino acids), substantial differences exist in each neurotransmitter s neuroanatomical expression and synthesis 1 4 Due to the functional connectivity of neurotransmitter systems, alterations in one system can impact the others 5 Neuroglia perform several key functions relating to the metabolic and physical support of neurons 6 1. Purves D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; Brichta L, et al. Trends Neurosci. 2013;36(9): McCarthy MM, et al. Trends Neurosci. 2002;25(6): Carlsson A. Int Clin Psychopharmacol. 1995;10 Suppl 3: Blier P. Int J Neuropsychopharmacol. 2014;17(7): Linser PJ. J Neurosci. 1985;5(9):

16 Advanced Neurotransmitters & Neuroglia Otsuka Pharmaceutical Development & Commercialization, Inc Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD Lundbeck, LLC. February 2017 MRC2.CORP.D advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

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