Introduction to CNS pharmacology

By S.Bohlooli, PhDSchool 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 Types Mode of Toxin Action SourceVoltage-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

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

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

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

Summary of Neurotransmitter Pharmacology in the Central Nervous System

Summary of Neurotransmitter Pharmacology in the Central Nervous System

Transmitter Anatomy Receptor Subtypes and Preferred Agonists

Receptor Antagonists Mechanisms

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

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

Summary of Neurotransmitter Pharmacology in the Central Nervous System

Transmitter Anatomy Receptor Subtypes and Preferred Agonists

Receptor Antagonists Mechanisms

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

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

Summary of Neurotransmitter Pharmacology in the Central Nervous System

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

Schematic diagram of a glutamate synapse