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CNS Neurotransmitters Dr. Joan Heller Brown BIOM 255 2012 1 Gross anatomy of the human brain 2 3 Anatomy of a neuron 4 Figure 1. 5 6 • Peripheral Nervous System (PNS) – Autonomic division : neuron to smooth muscle, cardiac muscle and gland – Somatic division : neuron to skeletal muscle • Central Nervous System ( CNS) – neuron to neuron 8 Sites of CNS drug action 9 10 Multiple sites of CNS drug action • • • • • • • Conduction Synthesis and storage Release and reuptake Degradation Receptors, pre-and post-synaptic Ion channels Second messengers 12 CNS neurotransmitters 13 Table 1. Classes of CNS Transmitters Neurotransmitter % of Synapses Brain Concentration Monoamines Catecholamines: DA, NE, EPI Indoleamines: serotonin (5-HT) 2-5 nmol/mg protein (low) Slow change in excitability (secs) GPCRs Acetylcholine (ACh) 5-10 nmol/mg protein (low) Slow change in excitability (secs) GPCRs μmol/mg protein (high) Rapid inhibition (msecs) Ion channels μmol/mg protein (high) Rapid excitation (msecs) Ion channels Amino acids Inhibitory: GABA, glycine Excitatory: Glutamate, aspartate 15-20 75-80 Function Primary Receptor Class 14 Table 1. Classes of CNS Transmitters Neurotransmitter % of Synapses Brain Concentration Monoamines Catecholamines: DA, NE, EPI Indoleamines: serotonin (5-HT) 2-5 nmol/mg protein (low) Slow change in excitability (secs) GPCRs Acetylcholine (ACh) 5-10 nmol/mg protein (low) Slow change in excitability (secs) GPCRs μmol/mg protein (high) Rapid inhibition (msecs) Ion channels μmol/mg protein (high) Rapid excitation (msecs) Ion channels Amino acids Inhibitory: GABA, glycine Excitatory: Glutamate, aspartate 15-20 75-80 Function Primary Receptor Class 16 Classes of Receptors • GPCR=7 transmembrane spanning = metabotropic • Ligand gated ion channel=ionotropic 17 Most neurotransmitters can activate multiple receptor subtypes and receptor classes 18 Table 2. Major Neurotransmitter Receptors in the CNS Neurotransmitter Receptor Subtypes G Protein-Coupled (G) vs. Ligand-Gated Ion Channel (LG) DA D1 D2 D3 D4 D5 G G G G G NE/EPI α1 α2 β1 β2 β3 G G G G G 5-HT 5-HT1A 5-HT1B 5-HT1D 5-HT2A 5-HT2B 5-HT2C 5-HT3 5-HT4 G G G G G G LG G ACh Muscarinic M1 Muscarinic M2 Muscarinic M3 Muscarinic M4 Nicotinic G G G G LG Glutamate NMDA AMPA Kainate Metabotropic LG LG LG G GABA A B LG G 19 20 Neurotransmitter regulation of ion channels affects membrane potential and action potential generation (firing) 21 22 Principles of CNS Drug action • Selectivity for the targeted pathway – – – – Receptor subtypes Allosteric sites on receptors Presynaptic and postsynaptic actions Partial/inverse agonist (activity dependent) • Plasticity reveals adaptive changes in drug response – Pharmacokinetic: drug metabolism – Pharmacodynamic: cellular Monoamine Neurotransmitters 24 Table 3. Localization of Monoamines in the Brain Neurotransmitter Cell Bodies Terminals Norepinephrine (NE) Locus coeruleus Lateral tegmental area Very widespread: cerebral cortex, thalamus, cerebellum, brainstem nuclei, spinal cord Basal forebrain, thalamus, hypothalamus, brainstem, spinal cord Epinephrine (EPI) Small, discrete nuclei in medulla Thalamus, brainstem, spinal cord Dopamine (DA) Substantia nigra (pars compacta) Ventral tegmental area Arcuate nucleus Striatum Limbic forebrain, cerebral cortex Median eminence Serotonin (5-HT) Raphe nuclei (median and dorsal), pons, medulla Very widespread: cerebral cortex, thalamus, cerebellum, brainstem nuclei, spinal cord Monoamine Biosynthesis Catecholamines Indoleamines 26 Important monoamine metabolites formed in the CNS • NE MAO, COMT MHPG (MOPEG) • DA MAO, COMT HVA • 5HT MAO 5HIAA Noradrenergic Pathways in the Brain Locus ceruleus to cortical and subcortical sites 28 Serotonergic Pathways in the Brain Midline raphe nuclei to cortical and subcortical areas 29 CNS functions regulated by NE • Arousal • Mood • Blood pressure control 30 CNS functions regulated by 5HT • Sleep • Mood • Sexual function • Appetite 31 Figure 15-1, G&G Monoamine Biosynthesis Catecholamines 33 34 35 Major Dopaminergic (DA) pathways • Nigrostriatal (substantia nigra to striatum) • Mesolimbic/mesocortical (ventral tegmental midbrain to n.accumbens, hippocampus, and cortex) • Tuberoinfundibular (arcuate nucleus of hypothalamus to median eminence then anterior pituitary) 36 CNS functions regulated by DA • Nigrostriatal (substantia nigra to striatum) – extrapyramidal motor control • Mesolimbic/mesocortical hippocampus, and cortex) (ventral tegmental to n.accumbens, – emotion – cognition • Tuberoinfundibular (arcuate nucleus of hypothalamus to median eminence then anterior pituitary) – prolactin release 37 Brain Amines and Disease States • Biogenic amine theory of depression • Dopaminergic theory of schizophrenia • Dopaminergic involvement in Parkinson’s disease 38 Brain Amines and Disease States • Biogenic amine theory of depression • Dopaminergic theory of schizophrenia • Dopaminergic involvement in Parkinson’s disease 40 Brain Amines and Disease States • Biogenic amine theory of depression • Dopaminergic theory of schizophrenia • Dopaminergic involvement in Parkinson’s disease 42 DA involvement in Parkinson’s disease (PD) • Pathology of disease: DA neurons in nigrostriatal pathway degenerate • Replacing DA is a therapeutic approach to treat PD • Parkinson like symptoms are side effects of DA receptor blockade with antipsychotic drugs • MPTP, a neurotoxin, destroys DA neurons and induces PD 45 ACh as a CNS neurotransmitter • Memory (ChEI in Alzheimers disease) – Basal forebrain to cortex/hippocampus (A) • Extrapyramidal motor responses (benztropine for Parkinsonian symptoms) – Striatum (B) • Vestibular control (scopolamine patch for motion sickness) 46 Cholinergic pathways in the CNS B A Nucleus basalis to cortex (A) and interneurons in striatum ( B) 47 48 49 Amino Acid Neurotransmitters • Inhibitory – GABA and Glycine – Hyperpolarize = don’t fire • Excitatory – Glutamate ( and Aspartate) – Depolarize = fire 50 GABA Synthesis COOH Glutamic acid decarboxylase (GAD) NH2 – CH – CH2 – CH2 - COOH Glutamate NH2 – CH2 – CH2 – CH2 - COOH GABA 51 52 53 Location and CNS functions of GABA • Nigrostriatal pathway – extrapyramidal motor responses • Interneurons throughout the brain – inhibit excitability, stabilize membrane potential, prevent repetitive firing 54 Synaptic effects of GABAA receptor activation Inhibitory transmitters (I) hyperpolarize the membrane. The IPSP stabilizes against excitatory (E) depolarization and action potential generation 55 The ionotropic GABAA receptor 56 Subunit composition of GABAA receptors • Five subunits, each with four transmembrane domains (like nAChR) • Most have two alpha (α),two beta (β), one gamma (γ) subunit • α1 β2 γ2 is predominant in mammalian brain but there are different combinations in specific brain regions 57 Modified from nAChR, G and G 2011 58 Pharmacology of the GABAA receptor 60 GABAA receptor pharmacology • There are two GABA binding sites per receptor. • Benzodiazepines and the newer hypnotic drugs bind to allosteric sites on the receptor to potentiate GABA mediated channel opening. • Babiturates act at a distinct allosteric site to also potentiate GABA inhibition. • These drugs act as CNS depressants • Picrotoxin blocks the GABA-gated chloride channel 62 64 GABAA receptor involvement in seizure disorders • Loss of GABA-ergic transmission contributes to excessive excitability and impulse spread in epilepsy. • Picrotoxin and bicuculline ( GABA receptor blocker) inhibit GABAA receptor function and are convulsants. • BDZs and barbiturates increase GABAA receptor function and are anticonvulsants. • Drugs that block GABA reuptake (GAT) and metabolism ( GABA-T) to increase available GABA are anticonvulsants 66 Glycine as an inhibitory CNS neurotransmitter • Major role is in the spinal cord • Glycine receptor is an ionotropic chloride channel analagous to the GABAA receptor. • Strychnine, a competitive antagonist of glycine, removes spinal inhibition to skeletal muscle and induces a violent motor response. The metabotropic GABAB receptor • These receptors are GPCRS • Largely presynaptic, inhibit transmitter release • Most important role is in the spinal cord • Baclofen, an agonist at this receptor, is a muscle relaxant 68 Glutamate as a CNS neurotransmitter 69 Glutamate • Neurotransmitter at 75-80% of CNS synapses • Synthesized within the brain from – Glucose (via KREBS cycle/α-ketoglutarate) – Glutamine (from glial cells) • Actions terminated by uptake through excitatory amino acid transporters (EAATs) in neurons and astrocytes Glutamate Synthesis Glutamine (from glia) COOH NH2 – CH – CH2 – CH2 - COOH Glutamate transaminases α-ketoglutarate 71 Figure 24. 72 Glutamate Receptor Subtypes Subunits GluR 1-4 GluA1-4 GluR 5-7, GluK1-3 KA1,2 GluK4-5 GluN1 NR1, GluN2A-D NR2A-2D GluN3A-B mGlu1 mGlu5 mGlu2 mGlu3 mGlu4 mGlu6-8 Ionotropic glutamate receptors: ligand gated sodium channels 74 Glutamate Figure 20A. 76 Pharmacology of NMDA receptors 77 NMDA receptor as a coincidence detector : requirement for membrane depolarization 78 NMDA receptor uses glycine as a co-agonist 79 NMDA receptor channel is blocked by phencyclidine (PCP) 80 NMDA receptor is Ca++ permeable 81 Calcium (Ca++) permeability of AMPA vs NMDA receptors • It is the GluR2 subunit that makes most AMPA receptors Ca++ impermeant • The GluR2 subunit contains one amino acid substitution : arginine (R) versus glutamine (Q) in all other GluRs 82 RNA editing of GluR subunits Properties of NMDA Receptor • Blocked at resting membrane potential (coincidence detector) • Requires glycine binding • Permeable to Ca++ as well as Na 84 NMDA receptors involvement in disease - seizure disorders - learning and memory - neuronal cell death 85 NMDA receptors in seizure disorders 86 87 NMDA receptors in long term potentiation 88 89 90 Figure 32. 91 NMDA receptors in excitotoxic cell death 92 Necrosis Apoptosis 93 End of CNS NT lecture slides 94 Extra stuff 95 Drugs acting on serotonergic neurons Drugs acting on noradrenergic neurons Drugs acting on serotonergic neurons