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Introduction to CNS pharmacology
By S.Bohlooli, PhD
School of Medicine, Ardabil University of Medical Sciences
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Ion channels & neurotransmitter receptors
Voltage gated channels Ligand gated channels
Ionotropic receptors Metabotropic receptors
Membrane delimited Diffusible second messenger
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Nicotinic acetylcholine receptor
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The synapse & synaptic potentials
Excitatory Excitatory post-synaptic potential (EPSP) Ionotropic receptor
Inhibitory Inhibitory post-synaptic potential (IPSP) Presynaptic inhibition
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Table 21-1. Some toxins used to characterize ion channels.
Channel Types Mode of Toxin Action Source
Voltage-gated
Sodium channels
Tetrodotoxin (TTX) Blocks channel from outside Puffer fish
Batrachotoxin (BTX) Slows inactivation, shifts activation Colombian frog
Potassium channels
Apamin Blocks "small Ca-activated" K channel Honeybee
Charybdotoxin Blocks "big Ca-activated" K channel Scorpion
Calcium channels
Omega conotoxin (-CTX-GVIA)
Blocks N-type channel Pacific cone snail
Agatoxin (-AGA-IVA) Blocks P-type channel Funnel web spider
Ligand-gated
Nicotinic ACh receptor
-Bungarotoxin Irreversible antagonist Marine snake
GABAA receptor
Picrotoxin Blocks channel South Pacific plant
Glycine receptor
Strychnine Competitive antagonist Indian plant
AMPA receptor
Philanthotoxin Blocks channel Wasp
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Site of drug action
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Identification of central neurotransmitters
More difficult for CNS Anatomic complexity Limitation of available techniques
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Criteria for neurotransmitter identification
Localization Microcytochemical immonocytochemical
Release Simulation of Brain slices Calcium dependency of release
Synaptic mimicry Microiontophoresis Physiological view Pharmacological view
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Cellular organization of the brain
Hierarchical systems Sensory perception, motor control Phasic information, delineated pathways Two types of neurons
Projection or relay Local circuit neurons
Limited number of transmitters Nonspecific or diffuse neuronal systems
Affecting global function of CNS Small number of neurons, projections to wide
area of CNS
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Central neurotransmitters Amino acids
Neutral amino acids Acidic amino acids
Acetylcholine Monoamines
Dopamine Norepinephrine 5-hydroxytryptamine
Peptides Nitric oxide endocananbiniods
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Table 21-2. Summary of neurotransmitter pharmacology in the central nervous system. (Many other central transmitters have been identified [see text].)
Transmitter Anatomy
Receptor Subtypes and
Preferred Agonists
Receptor Antagonists
Mechanisms
Acetylcholine
Cell bodies at all levels; long and short connections
Muscarinic (M1):
muscarine
Pirenzepine, atropine
Excitatory: in K+ conductance; ↑ IP3,
DAG
Muscarinic (M2):
muscarine, bethanechol
Atropine, methoctramine
Inhibitory: ↑ K+ conductance; cAMP
Motoneuron-Renshaw cell synapse
Nicotinic: nicotine
Dihydro--erythroidine, -bungarotoxin
Excitatory: ↑ cation conductance
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Dopamine Cell bodies at all levels; short, medium, and long connections
D1
Phenothiazines Inhibitory (?): cAMP
D2: bromocriptine
Phenothiazines, butyrophenones
Inhibitory (presynaptic): Ca2+; Inhibitory (postsynaptic): in K+
conductance, cAMP
GABA Supraspinal and spinal interneurons involved in pre- and postsynaptic inhibition
GABAA: muscimol
Bicuculline, picrotoxin
Inhibitory: Cl–conductance
GABAB: baclofen
2-OH saclofen Inhibitory (presynaptic): Ca2+ conductance; Inhibitory (postsynaptic): K+ conductance
Transmitter Anatomy Receptor Subtypes and Preferred Agonists
Receptor Antagonists
Mechanisms
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Glutamate Relay neurons at all levels and some interneurons
N-Methyl-D-aspartate (NMDA): NMDA
2-Amino-5-phosphonovalerate, dizocilpine
Excitatory: cation conductance, particularly Ca2+
AMPA: AMPA CNQX Excitatory: cation conductance
Kainate: kainic acid, domoic acid
Metabotropic: ACPD, quisqualate
MCPG Inhibitory (presynaptic): Ca2+ conductance cAMP; Excitatory: K+ conductance, IP3, DAG
Glycine Spinal interneurons and some brain stem interneurons
Taurine, -alanine Strychnine Inhibitory: Cl–conductance
Transmitter Anatomy Receptor Subtypes and Preferred Agonists
Receptor Antagonists
Mechanisms
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5-Hydroxytryptamine (serotonin)
Cell bodies in midbrain and pons project to all levels
5-HT1A: LSD
Metergoline, spiperone
Inhibitory: K+ conductance, cAMP
5-HT2A: LSD
Ketanserin Excitatory: K+ conductance, IP3,
DAG
5-HT3: 2-methyl-5-
HT
Ondansetron Excitatory: cation conductance
5-HT4
Excitatory: K+ conductance
Transmitter Anatomy Receptor Subtypes and Preferred Agonists
Receptor Antagonists
Mechanisms
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Norepinephrine Cell bodies in pons and brain stem project to all levels
1: phenylephrine
Prazosin Excitatory: K+ conductance, IP3, DAG
2: clonidine
Yohimbine Inhibitory (presynaptic): Ca2+ conductance; Inhibitory: K+ conductance, cAMP
1: isoproterenol,
dobutamine
Atenolol, practolol Excitatory: K+ conductance, cAMP
2: albuterol
Butoxamine Inhibitory: may involve in electrogenic sodium pump; cAMP
Transmitter Anatomy Receptor Subtypes and Preferred Agonists
Receptor Antagonists
Mechanisms
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Transmitter Anatomy Receptor Subtypes and Preferred Agonists
Receptor Antagonists
Mechanisms
Histamine Cells in ventral posterior hypothalamus
H1: 2(m-
fluorophenyl)-histamine
Mepyramine Excitatory: K+ conductance, IP3, DAG
H2: dimaprit
Ranitidine Excitatory: K+ conductance, cAMP
H3: R--methyl-
histamine
Thioperamide Inhibitory autoreceptors
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Transmitter Anatomy Receptor Subtypes and Preferred Agonists
Receptor Antagonists
Mechanisms
Opioid peptides Cell bodies at all levels; long and short connections
Mu: bendorphin Naloxone Inhibitory (presynaptic): Ca2+ conductance, cAMP
Delta: enkephalin Naloxone Inhibitory (postsynaptic): K+ conductance, cAMP
Kappa: dynorphin Naloxone
Tachykinins Primary sensory neurons, cell bodies at all levels; long and short connections
NK1: Substance P methylester, aprepitant
Aprepitant Excitatory: K+ conductance, IP3,
DAG
NK2
NK3
Endocannabinoids
Widely distributed CB1: Anandamide, 2-arachidonyglycerol
Rimonabant Inhibitory (presynaptic): Ca2+ conductance, cAMP
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Schematic diagram of a glutamate synapse