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
Nicotinic acetylcholine receptor
The synapse & synaptic potentials
 Excitatory
 Excitatory post-synaptic potential (EPSP)
 Ionotropic receptor
 Inhibitory
 Inhibitory post-synaptic potential (IPSP)
 Presynaptic inhibition
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
Apamin
Blocks "small Ca-activated" K channel
Honeybee
Charybdotoxin
Blocks "big Ca-activated" K channel
Scorpion
Omega conotoxin (w-CTXGVIA)
Blocks N-type channel
Pacific cone snail
Agatoxin (w-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
Potassium channels
Calcium channels
Ligand-gated
Nicotinic ACh receptor
a-Bungarotoxin
GABAA receptor
Picrotoxin
Glycine receptor
Strychnine
AMPA receptor
Philanthotoxin
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
Central neurotransmitters
 Amino acids
 Neutral amino acids
 Acidic amino acids
 Acetylcholine
 Monoamines
 Dopamine
 Norepinephrine
 5-hydroxytryptamine
 Peptides
 Nitric oxide
 endocananbiniods
Table 21-2. Summary of neurotransmitter pharmacology in the central nervous system.
(Many other central transmitters have been identified [see text].)
Transmitter
Anatomy
Cell bodies at
all levels; long
Acetylcholine
and short
connections
MotoneuronRenshaw cell
synapse
Receptor
Subtypes and
Preferred
Agonists
Receptor
Antagonists
Mechanisms
Pirenzepine,
atropine
Excitatory:  in K+
conductance; ↑ IP3,
DAG
Muscarinic
(M2):
muscarine,
bethanechol
Atropine,
methoctramine
Inhibitory: ↑ K+
conductance; 
cAMP
Nicotinic:
nicotine
Dihydro-berythroidine,
abungarotoxin
Excitatory: ↑ cation
conductance
Muscarinic
(M1):
muscarine
Transmitter
Anatomy
Receptor
Subtypes and
Preferred
Agonists
Receptor
Antagonists
Mechanisms
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
Bicuculline,
picrotoxin
Inhibitory: Cl–conductance
2-OH saclofen
Inhibitory (presynaptic): Ca2+
conductance; Inhibitory
(postsynaptic): K+ conductance
GABA
Supraspinal and spinal GABAA: muscimol
interneurons involved
in pre- and
postsynaptic inhibition
GABAB: baclofen
Transmitter
Anatomy
Receptor
Subtypes and
Preferred
Agonists
Receptor
Antagonists
Mechanisms
Glutamate
Relay neurons at all
levels and some
interneurons
N-Methyl-D-aspartate 2-Amino-5(NMDA): NMDA
phosphonovalerate,
dizocilpine
Excitatory: cation conductance,
particularly Ca2+
AMPA: AMPA
CNQX
Excitatory: cation conductance
Metabotropic: ACPD,
quisqualate
MCPG
Inhibitory (presynaptic): Ca2+
conductance cAMP; Excitatory: K+
conductance, IP3, DAG
Taurine, -alanine
Strychnine
Inhibitory: Cl–conductance
Kainate: kainic acid,
domoic acid
Glycine
Spinal interneurons and
some brain stem
interneurons
Transmitter
Anatomy
5-Hydroxytryptamine Cell bodies in midbrain
(serotonin)
and pons project to all
levels
Receptor
Subtypes and
Preferred
Agonists
Receptor
Antagonists
Mechanisms
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
Norepinephrine
Cell bodies in pons
and brain stem
project to all levels
a1:
Prazosin
Excitatory: K+ conductance,
IP3, DAG
a 2: clonidine
Yohimbine
Inhibitory (presynaptic): Ca2+
conductance; Inhibitory: K+
conductance, cAMP
b1: isoproterenol,
Atenolol, practolol
Excitatory: K+ conductance,
cAMP
Butoxamine
Inhibitory: may involve in
electrogenic sodium pump;
cAMP
phenylephrine
dobutamine
b2: albuterol
Transmitter
Anatomy
Receptor
Subtypes and
Preferred
Agonists
Receptor
Antagonists
Mechanisms
Histamine
Cells in ventral
posterior
hypothalamus
H1: 2(mfluorophenyl)histamine
Mepyramine
Excitatory: K+ conductance,
IP3, DAG
H2: dimaprit
Ranitidine
Excitatory: K+ conductance,
cAMP
H3: R--methylhistamine
Thioperamide
Inhibitory autoreceptors
Transmitter
Opioid peptides
Tachykinins
Anatomy
Cell bodies at all
levels; long and
short connections
Primary sensory
neurons, cell bodies
at all levels; long
and short
connections
Receptor
Subtypes and
Preferred
Agonists
Receptor
Antagonists
Mechanisms
Mu: bendorphin
Naloxone
Inhibitory (presynaptic):
Ca2+ conductance, cAMP
Delta: enkephalin
Naloxone
Inhibitory (postsynaptic): K+
conductance, cAMP
Kappa: dynorphin
Naloxone
NK1: Substance P
methylester,
aprepitant
Aprepitant
Excitatory: K+ conductance,
IP3, DAG
NK2
NK3
Endocannabinoids
Widely distributed
CB1: Anandamide, 2- Rimonabant
arachidonyglycerol
Inhibitory (presynaptic): Ca2+
conductance, cAMP
Schematic diagram of a glutamate synapse