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 Nervous System
Transmitter Anatomy Receptor Subtypes and Receptor Antagonists Mechanisms
Preferred Agonists
Acetylcholine Cell bodies at all levels; Muscarinic (M1): muscarine Pirenzepine, atropine Excitatory: in K+
long and short connections conductance; IP3, DAG

Muscarinic (M2): Atropine, methoctramine Inhibitory: K+ conductance;

muscarine, bethanechol cAMP
Motoneuron-Renshaw cell Nicotinic: nicotine Dihydro--erythroidine, - Excitatory: cation
synapse bungarotoxin conductance
Dopamine Cell bodies at all levels; D1 Phenothiazines Inhibitory (?): cAMP
short, medium, and long
connections
D2: bromocriptine Phenothiazines, Inhibitory (presynaptic):
butyrophenones Ca2+; Inhibitory
(postsynaptic): in K+
conductance, cAMP

GABA Supraspinal and spinal GABAA: muscimol Bicuculline, picrotoxin Inhibitory: Cl–conductance
interneurons involved in
pre- and postsynaptic
inhibition

GABAB: baclofen 2-OH saclofen Inhibitory (presynaptic):

Ca2+ conductance;
Inhibitory (postsynaptic): K+
conductance
 Summary of Neurotransmitter Pharmacology in
the Central Nervous System
Transmitter Anatomy Receptor Subtypes and Receptor Antagonists Mechanisms
Preferred Agonists
Glutamate Relay neurons at all levels N-Methyl-D-aspartate 2-Amino-5- Excitatory: cation
and some interneurons (NMDA): NMDA phosphonovalerate, conductance, particularly
dizocilpine Ca2+
AMPA: AMPA CNQX Excitatory: cation
conductance
Kainate: kainic acid,
domoic acid
Metabotropic: ACPD, MCPG Inhibitory (presynaptic):
quisqualate Ca2+ conductance cAMP;
Excitatory: K+
conductance, IP3, DAG
Glycine Spinal interneurons and Taurine, -alanine Strychnine Inhibitory: Cl–
some brain stem conductance
interneurons
5-Hydroxytryptamine Cell bodies in midbrain 5-HT1A: LSD Metergoline, spiperone Inhibitory: K+
(serotonin) and pons project to all conductance, cAMP
levels
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 Receptor Antagonists Mechanisms
Preferred Agonists

Norepinephrine Cell bodies in pons and 1: phenylephrine Prazosin Excitatory: K+

brain stem project to all conductance, IP3, DAG
levels

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 posterior H1: 2(m-fluorophenyl)- Mepyramine Excitatory: K+

hypothalamus histamine 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 Receptor Antagonists Mechanisms

and Preferred Agonists
Opioid peptides Cell bodies at all Mu: bendorphin Naloxone Inhibitory
levels; long and short (presynaptic): Ca2+
connections conductance, cAMP
Delta: enkephalin Naloxone Inhibitory
(postsynaptic): K+
conductance, cAMP
Kappa: dynorphin Naloxone
Tachykinins Primary sensory NK1: Substance P Aprepitant Excitatory: K+
neurons, cell bodies at methylester, conductance, IP3, DAG
all levels; long and aprepitant
short connections
NK2
NK3
Endocannabinoids Widely distributed CB1: Anandamide, 2- Rimonabant Inhibitory
arachidonyglycerol (presynaptic): Ca2+
conductance, cAMP
Schematic diagram of a glutamate synapse