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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
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
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
Summary of Neurotransmitter Pharmacology in
the Central
Transmitter NervousReceptor
Anatomy System Subtypes Receptor Mechanisms
and Preferred Antagonists
Agonists
Acetylcholine Cell bodies at all Muscarinic (M1): Pirenzepine, atropine Excitatory: in K+
levels; long and short muscarine conductance; IP3, DAG
connections
Muscarinic (M2): Atropine, Inhibitory: K+
muscarine, methoctramine conductance; cAMP
bethanechol
Motoneuron-Renshaw Nicotinic: nicotine Dihydro--erythroidine, Excitatory: cation
cell synapse -bungarotoxin conductance
Dopamine Cell bodies at all D1 Phenothiazines Inhibitory (?): cAMP
levels; short, medium,
and long connections
D2: bromocriptine Phenothiazines, Inhibitory
butyrophenones (presynaptic): Ca2+;
Inhibitory
(postsynaptic): in K+
conductance, cAMP
GABA Supraspinal and spinal GABAA: muscimol Bicuculline, picrotoxin Inhibitory: Cl
interneurons involved conductance
in pre- and
postsynaptic inhibition
GABAB: baclofen 2-OH saclofen Inhibitory
(presynaptic): Ca2+
conductance;
Inhibitory
Summary of Neurotransmitter Pharmacology in
the Central Nervous System
Transmitter Anatomy Receptor Subtypes Receptor Mechanisms
and Preferred Antagonists
Agonists
Glutamate Relay neurons at N-Methyl-D- 2-Amino-5- Excitatory: cation
all levels and some aspartate (NMDA): phosphonovalerate conductance,
interneurons NMDA , dizocilpine particularly Ca2+
AMPA: AMPA CNQX Excitatory: cation
conductance
Kainate: kainic
acid, domoic acid
Metabotropic: MCPG Inhibitory
ACPD, quisqualate (presynaptic):
Ca2+ conductance
cAMP; Excitatory:
K+ conductance,
IP3, DAG
Glycine Spinal interneurons Taurine, -alanine Strychnine Inhibitory: Cl
and some brain conductance
stem interneurons
5- Cell bodies in 5-HT1A: LSD Metergoline, Inhibitory: K+
Hydroxytryptamine midbrain and pons spiperone conductance, cAMP
(serotonin) project to all levels
5-HT2A: LSD Ketanserin Excitatory: K+
conductance, IP3,
DAG
5-HT3: 2-methyl-5- Ondansetron Excitatory: cation
Summary of Neurotransmitter Pharmacology in
the Central Nervous System
Transmitter Anatomy Receptor Subtypes Receptor Mechanisms
and Preferred Antagonists
Agonists
Norepinephrine Cell bodies in pons 1: phenylephrine Prazosin Excitatory: K+
and brain stem conductance, IP3,
project to all levels DAG
2: clonidine Yohimbine Inhibitory
(presynaptic):
Ca2+ conductance;
Inhibitory: K+
conductance, cAMP
1: isoproterenol, Atenolol, practolol Excitatory: K+
dobutamine conductance, cAMP
2: albuterol Butoxamine Inhibitory: may
involve in
electrogenic
sodium pump;
cAMP
Histamine Cells in ventral H1: 2(m- Mepyramine Excitatory: K+
posterior fluorophenyl)- conductance, IP3,
hypothalamus histamine DAG
H2: dimaprit Ranitidine Excitatory: K+
conductance, cAMP
H3: R--methyl- Thioperamide Inhibitory
histamine autoreceptors
Summary of Neurotransmitter Pharmacology in
the Central Nervous System
Transmitter Anatomy Receptor Receptor Mechanisms
Subtypes and Antagonists
Preferred
Agonists
Opioid peptides Cell bodies at all Mu: bendorphin Naloxone Inhibitory
levels; long and (presynaptic):
short Ca2+
connections conductance,
cAMP
Delta: Naloxone Inhibitory
enkephalin (postsynaptic):
K+ conductance,
cAMP
Kappa: Naloxone
dynorphin
Tachykinins Primary sensory NK1: Substance Aprepitant Excitatory: K+
neurons, cell P methylester, conductance,
bodies at all aprepitant IP3, DAG
levels; long and
short
connections
NK2
Schematic diagram of a glutamate synapse