Introduction to CNS pharmacology By S.Bohlooli, PhD School of medicine, Ardabil University of Medical Sciences

Ion channels & neurotransmitter receptors  Voltage gated channels  Ligand gated channels  Ionotropic receptors  Metabotropic receptors Membrane delimited Diffusible second messenger

Ion channels

Metabotropic receptors

3D structure of Nicotine receptor

The synapse & synaptic potentials  Excitatory Excitatory post-synaptic potential (EPSP) Ionotropic receptor  Inhibitory Inhibitory post-synaptic potential (IPSP) Presynaptic inhibition

Channel TypesMode of Toxin ActionSource Voltage-gated Sodium channels Tetrodotoxin (TTX)Blocks channel from outsidePuffer fish Batrachotoxin (BTX)Slows inactivation, shifts activationColombian frog Potassium channels ApaminBlocks "small Ca-activated" K channelHoneybee CharybdotoxinBlocks "big Ca-activated" K channelScorpion Calcium channels Omega conotoxin (-CTX-GVIA)Blocks N-type channelPacific cone snail Agatoxin (-AGA-IVA)Blocks P-type channelFunnel web spider Ligand-gated Nicotinic ACh receptor -BungarotoxinIrreversible antagonistMarine snake GABA A receptor PicrotoxinBlocks channelSouth Pacific plant Glycine receptor StrychnineCompetitive antagonistIndian plant AMPA receptor PhilanthotoxinBlocks channelWasp Some Toxins Used to Characterize Ion Channels

Excitatory postsynaptic potentials (EPSP)

Interaction of excitatory and inhibitory synapses

Site of drug action

Identification of central neurotransmitters  More difficult for CNS Anatomic complexity Limitation of available techniques

Criteria for neurotransmitter identification Localization  Microcytochemical  immonocytochemical Release  Simulation of Brain slices  Calcium dependency of release Synaptic mimicry  Microiontophoresis  Physiological view  Pharmacological view

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

Pathways

Central neurotransmitters  Amino acids Neutral amino acids Acidic amino acids  Acetylcholine  Monoamines Dopamine Norepinephrine 5-hydroxytryptamine  Peptides  Nitric oxide  endocananbiniods

TransmitterAnatomy Receptor Subtypes and Preferred Agonists Receptor AntagonistsMechanisms Acetylcholine Cell bodies at all levels; long and short connections Muscarinic (M 1 ): muscarinePirenzepine, atropine Excitatory: in K + conductance; IP 3, DAG Muscarinic (M 2 ): muscarine, bethanechol Atropine, methoctramine Inhibitory: K + conductance; cAMP Motoneuron-Renshaw cell synapse Nicotinic: nicotine Dihydro--erythroidine, - bungarotoxin Excitatory: cation conductance Dopamine Cell bodies at all levels; short, medium, and long connections D1D1 PhenothiazinesInhibitory (?): cAMP D 2 : bromocriptine Phenothiazines, butyrophenones Inhibitory (presynaptic): Ca 2+ ; Inhibitory (postsynaptic): in K + conductance, cAMP GABA Supraspinal and spinal interneurons involved in pre- and postsynaptic inhibition GABA A : muscimolBicuculline, picrotoxinInhibitory: Cl – conductance GABA B : baclofen2-OH saclofenInhibitory (presynaptic): Ca 2+ conductance; Inhibitory (postsynaptic): K + conductance Summary of Neurotransmitter Pharmacology in the Central Nervous System

TransmitterAnatomy Receptor Subtypes and Preferred Agonists Receptor AntagonistsMechanisms 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: AMPACNQX 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, -alanineStrychnine Inhibitory: Cl– conductance 5-Hydroxytryptamine (serotonin) Cell bodies in midbrain and pons project to all levels 5-HT1A: LSDMetergoline, spiperone Inhibitory: K+ conductance, cAMP 5-HT2A: LSDKetanserin Excitatory: K+ conductance, IP3, DAG 5-HT3: 2-methyl-5-HTOndansetron Excitatory: cation conductance 5-HT4Excitatory: K+ conductance

Summary of Neurotransmitter Pharmacology in the Central Nervous System TransmitterAnatomy Receptor Subtypes and Preferred Agonists Receptor AntagonistsMechanisms Norepinephrine Cell bodies in pons and brain stem project to all levels 1: phenylephrinePrazosin Excitatory: K+ conductance, IP3, DAG 2: clonidineYohimbine Inhibitory (presynaptic): Ca2+ conductance; Inhibitory: K+ conductance, cAMP 1: isoproterenol, dobutamine Atenolol, practolol Excitatory: K+ conductance, cAMP 2: albuterolButoxamine Inhibitory: may involve in electrogenic sodium pump; cAMP Histamine Cells in ventral posterior hypothalamus H1: 2(m-fluorophenyl)- histamine Mepyramine Excitatory: K+ conductance, IP3, DAG H2: dimapritRanitidine Excitatory: K+ conductance, cAMP H3: R--methyl-histamineThioperamideInhibitory autoreceptors

Summary of Neurotransmitter Pharmacology in the Central Nervous System TransmitterAnatomy Receptor Subtypes and Preferred Agonists Receptor AntagonistsMechanisms Opioid peptides Cell bodies at all levels; long and short connections Mu: bendorphinNaloxone Inhibitory (presynaptic): Ca2+ conductance, cAMP Delta: enkephalinNaloxone Inhibitory (postsynaptic): K+ conductance, cAMP Kappa: dynorphinNaloxone 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 EndocannabinoidsWidely distributedCB1: Anandamide, 2- arachidonyglycerol RimonabantInhibitory (presynaptic): Ca2+ conductance, cAMP

Schematic diagram of a glutamate synapse