Introduction to CNS pharmacology

Voltage gated channels, Ligand gated channels

2 types of channels on the membrane of nerve cells

Metabotropic receptors

• Membrane delimited

• Diffusible second messenger

HYPERPOLARIZATION

EFFLUX OF K, INFLUX OF CL-, CHANGE IN

CELL MEMBRANE POTENTIAL

DEPOLARIZATION

INFLUX OF NA AND CA- CELL BECOMES POSITIVE

REPOLARIZATION

CHANGE IN THE MEMBRANE POTENTIAL THAT

RETURNS IT TO NEGATIVE, HAPPENS AFTER DEPOLARIZATION

Excitatory post-synaptic potential (EPSP)

Excitatory, depolarization

Inhibitory post-synaptic potential (IPSP)

Inhibitory, hyperpolarization

Excitatory neurotransmitters

opens Na or Ca channels/ influx > depolarization (more positive) > nerve impulse

e.g. Norepinephrine, Dopamine, Acetylcholine, Glutamate,Aspartate

Inhibitory neurotransmitters

opens Cl channels > hyperpolarization (more negative) > no nerve impulse

e.g. glycine, gamma-aminobutyric acid (GABA)

Tetrodotoxin (TTX)

Voltage-gated Sodium channels, moa: Blocks channel from outside from Puffer fish

Batrachotoxin (BTX)

Voltage-gated Sodium channels, moa: Slows

inactivation, shifts activation from Colombian frog

Apamin

Voltage-gated Potassium Channels, moa: Blocks "small Ca-activated" K channel from Honeybee

Charybdotoxin

Voltage-gated Potassium Channels, moa: Blocks "big Ca-activated" K channel from Scorpion

Omega conotoxin (ω-CTX-GVIA)

Voltage-gated Calcium channels, moa: Blocks N-type

channel from Pacific cone snail

Agatoxin (ω-AGA-IVA)

Voltage-gated Calcium channels, moa: Blocks P-type channel from funnel web spider

α-Bungarotoxin

Ligand-gated Nicotinic ACh receptor, moa: Irreversible antagonist from Marine snake

Picrotoxin

Ligand-gated GABAa receptor, moa: Blocks channel from South Pacific plant

Strychnine

Ligand-gated Glycine receptor, moa: Competitive antagonist from Indian plant

Philanthotoxin

Ligand-gated AMPA receptor , moa: Blocks channel from Wasp

Localization

Biochemical analysis

Immunocytochemical (enzymes,peptides)

Release

Simulation of Brain slices

Calcium dependency of release

Synaptic mimicry

Microiontophoresis

Physiological view

Pharmacological view

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

Muscarinic (M1) receptor

Transmitter: Acetylcholine

Agonist: muscarine

Antagonist: Pirenzepine,atropine

Mechanism: Excitatory: in K+ conductance; IP3,

DAG

Muscarinic (M2) receptors

Transmitter: Acetylcholine

Agonist: muscarine, bethanechol

Antagonist: atropine, methoctramine

Mechanism: Excitatory: Inhibitory: K+

conductance;cAMP

Nicotinic receptors

Transmitter: Acetylcholine

Agonist: nicotine

Antagonist: Dihydro-- erythroidine, - bungarotoxin

Mechanism: Excitatory: cation conductance

D1 receptors

Transmitter: dopamine

Agonist: n/a

Antagonist: Phenothiazines

Mechanism: Inhibitory (?): cAMP

D2 receptors

Transmitter: dopamine

Agonist: bromocriptine

Antagonist: Phenothiazines, butyrophenones

Mechanism: Inhibitory (presynaptic): Ca2+; Inhibitory

(postsynaptic): in K+ conductance, cAMP

GABAa receptors

Transmitter: GABA

Agonist: muscimol

Antagonist: Bicuculline, picrotoxin

Mechanism: Inhibitory: Cl-conductance

GABAb receptor

Transmitter: GABA

Agonist: baclofen

Antagonist: 2-OH saclofen

Mechanism: Inhibitory: Inhibitory (presynaptic):

Ca2+ conductance; Inhibitory (postsynaptic): K+ conductance

N-Methyl-D-aspartate (NMDA)

Transmitter: Glutamate

Agonist: NMDA

Antagonist: 2-Amino-5- phosphonovalerate, dizocilpine

Mechanism: Excitatory: cation conductance, particularly Ca2+

AMPA

Transmitter: Glutamate

Agonist: AMPA

Antagonist:CNQX

Mechanism: Excitatory: cation conductance

kainate receptor

Transmitter: Glutamate

Agonist: kainic acid,domoic acid

Antagonist: n/a

Mechanism: n/a

metabotropic receptors

Transmitter: Glutamate

Agonist: ACPD,quisqualate

Antagonist: MCPG

Mechanism: Inhibitory (presynaptic): Ca2+ conductance cAMP; Excitatory: K+ conductance,

IP3, DAG

Taurine, -alanine receptor

Transmitter: Glycine

Agonist: n/a

Antagonist: Strychnine

Mechanism: Inhibitory: Cl-conductance

5-HT1A receptor

Transmitter: 5-Hydroxytryptamine (serotonin)

Agonist: LSD

Antagonist: Metergoline, spiperone

Mechanism: Inhibitory: K+conductance, cAMP

5-HT2A receptors

Transmitter: 5-Hydroxytryptamine (serotonin)

Agonist: LSD

Antagonist: Ketanserin

Mechanism: Excitatory: K+conductance, IP3, DAG

5-HT3 receptor

Transmitter: 5-Hydroxytryptamine (serotonin)

Agonist: 2-methyl-5-HT

Antagonist: Ondansetron

Mechanism: Excitatory: cation conductance

5-HT4 receptor

Transmitter: 5-Hydroxytryptamine (serotonin)

Agonist: n/a

Antagonist: n/a

Mechanism: Excitatory: K+conductance

Norepinephrine a-1 receptor

Transmitter: Norepinephrine

Agonist: phenylephrine

Antagonist: Prazosin

Mechanism: Excitatory: K+conductance, IP3, DAG

Norepinephrine a-2 receptors

Transmitter: Norepinephrine

Agonist: clonidine

Antagonist: Yohimbine

Mechanism: Inhibitory (presynaptic): Ca2+ conductance; Inhibitory: K+ conductance, cAMP

Norepinephrine b-1 receptors

Transmitter: Norepinephrine

Agonist: isoproterenol,dobutamine

Antagonist: Atenolol,practolol

Mechanism: Excitatory: K+conductance, cAMP

Norepinephrine b-2 receptors

Transmitter: Norepinephrine

Agonist: albuterol

Antagonist: Butoxamine

Mechanism: Inhibitory: may involve in electrogenic sodium pump; cAMP

H1 receptor

Transmitter: Histamine

Agonist: 2(m-fluorophenyl)-histamine

Antagonist: Mepyramine

Mechanism: Excitatory: K+conductance, IP3,DAG

H2 receptors

Transmitter: Histamine

Agonist: dimaprit

Antagonist: Ranitidine

Mechanism: Excitatory: K+conductance,cAMP

H3 receptor

Transmitter: Histamine

Agonist: R--methyl-histamine

Antagonist: Thioperamide

Mechanism: Inhibitory autoreceptors

Mu receptors

Transmitter: Opioid peptides

Agonist: bendorphin

Antagonist: Naloxone

Mechanism: Inhibitory (presynaptic): Ca2+ conductance, cAMP

Delta receptors

Transmitter: Opioid peptides

Agonist: enkephalin

Antagonist: Naloxone

Mechanism: Inhibitory (postsynaptic): K+conductance, cAMP

Kappa receptors

Transmitter: Opioid peptides

Agonist: dynorphin

Antagonist: Naloxone

Mechanism: n/a

NK1 receptor

Transmitter: Tachykinins

Agonist: Substance P methylester,aprepitant

Antagonist: Aprepitant

Mechanism: Excitatory: K+ conductance, IP3,DAG

CB1 receptors

Transmitter: Endocannabinoids

Agonist: Anandamide, 2-arachidonyglycerol

Antagonist: Rimonabant

Mechanism: Inhibitory (presynaptic): Ca2+ conductance, cAMP

ANXIETY

DECREASE GABA INCREASE 5HT, D, NE

PSYCHOSIS

INCREASE GLUTAMATE INCREASE D

DEPRESSION

DECREASE NE, 5HT, D

MOOD DISORDER

IMBALANCE IN NT

SEIZURE

INCREASE NEURON FIRING INCREASE 5HT, NE, D

PARKINSON'S

DECREASE D INCREASE ACH

ALZHEIMER'S

DECREASE ACH