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
Tetrodotoxin (TTX)
Blocks channel from outside
Puffer fish
Batrachotoxin (BTX)
Slows inactivation, shifts activation
Colombian frog
Apamin
Blocks "small Ca-activated" K channel
Honeybee
Charybdotoxin
Blocks "big Ca-activated" K channel
Scorpion
Omega conotoxin (-CTX-GVIA)
Blocks N-type channel
Pacific cone snail
Agatoxin (-AGA-IVA)
Blocks P-type channel
Funnel web spider
Irreversible antagonist
Marine snake
Blocks channel
South Pacific plant
Competitive antagonist
Indian plant
Blocks channel
Wasp
Voltage-gated
Sodium channels
Potassium channels
Calcium channels
Ligand-gated
Nicotinic ACh receptor
-Bungarotoxin
GABAA receptor
Picrotoxin
Glycine receptor
Strychnine
AMPA receptor
Philanthotoxin
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 Nervous System
Transmitter
Anatomy
Receptor Subtypes and
Preferred Agonists
Acetylcholine
Cell bodies at all levels;
Muscarinic (M1): muscarine Pirenzepine, atropine
long and short connections
GABA
Mechanisms
Excitatory: in K+
conductance; IP3, DAG
Atropine, methoctramine
Inhibitory: K+ conductance;
cAMP
Motoneuron-Renshaw cell Nicotinic: nicotine
synapse
Dihydro--erythroidine, bungarotoxin
Excitatory: cation
conductance
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
GABAA: muscimol
Bicuculline, picrotoxin
Inhibitory: Cl–conductance
GABAB: baclofen
2-OH saclofen
Inhibitory (presynaptic):
Ca2+ conductance;
Inhibitory (postsynaptic): K+
conductance
Muscarinic (M2):
muscarine, bethanechol
Dopamine
Receptor Antagonists
Supraspinal and spinal
interneurons involved in
pre- and postsynaptic
inhibition
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 N-Methyl-D-aspartate
and some interneurons
(NMDA): NMDA
2-Amino-5phosphonovalerate,
dizocilpine
Excitatory: cation
conductance, particularly
Ca2+
CNQX
Excitatory: cation
conductance
Metabotropic: ACPD,
quisqualate
MCPG
Inhibitory (presynaptic):
Ca2+ conductance cAMP;
Excitatory: K+
conductance, IP3, DAG
AMPA: AMPA
Kainate: kainic acid,
domoic acid
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
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
Histamine
Cells in ventral posterior
hypothalamus
Summary of Neurotransmitter Pharmacology in
the Central Nervous System
Transmitter
Anatomy
Receptor Subtypes
Receptor Antagonists Mechanisms
and Preferred Agonists
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
NK1: Substance P
neurons, cell bodies at methylester,
all levels; long and
aprepitant
short connections
Aprepitant
Excitatory: K+
conductance, IP3, DAG
Rimonabant
Inhibitory
(presynaptic): Ca2+
conductance, cAMP
NK2
NK3
Endocannabinoids
Widely distributed
CB1: Anandamide, 2arachidonyglycerol
Schematic diagram of a glutamate synapse