Introduction to the Pharmacology of CNS Drugs

By Mohammad H. Farjoo, M.D, Ph.DShahid Beheshti University of Medical Science

Introduction Ion Channels & neurotransmitters Synaptic Potentials Sites of Drug Action Identification of Neurotransmitters Cellular Organization of the Brain Central Neurotransmitters

Introduction to the Pharmacology of CNS Drugs

All drugs with CNS effects act on specific receptors General anesthetics and alcohol may be exceptions Drugs are among the most important tools for

studying all aspects of CNS physiology From the mechanism of convulsions to the laying

down of long-term memory. Specific agonists that mimic natural transmitters and

antagonists are extremely useful in such studies.

Introduction

The actions of drugs with known clinical efficacy has led to unraveling the mechanisms of CNS diseases: Antipsychotic drugs on dopamine receptors => the

pathophysiology of schizophrenia. Effects of ligands on γ aminobutyric acid (GABA)

receptors => the pathophysiology of anxiety and epilepsy.

Introduction

Snake, scorpion, snail, bee, wasp, frog and even plant

toxins are very important in the study of CNS.

A genus of marine snail (Conus ) includes at least 500 different species.

Each species kills its prey with a venom that contains 50–200 different peptides or proteins.

There is little duplication of peptides among Conus species!

These toxins are excellent investigational tools for ion channels study.

Introduction

Ion Channels & neurotransmitters

The membranes of nerve cells contain two types of channels.

They are defined on the basis of the mechanisms controlling their gating: Voltage-gated Ligand-gated

Voltage-sensitive Na+ channel

Voltage-sensitive K+ channel

Neurotransmitters exert their effects on neurons by binding to two classes of receptor: Ligand-gated channels, or ionotropic

Their activation is brief (milliseconds) opening Involved in fast transmission in hierarchical pathways

Metabotropic receptors G protein-coupled Their effects last tens of seconds to minutes Involved in the diffuse neuronal systems in the CNS Affect two types of voltage-gated ion channels:

Calcium channels (for presynaptic inhibition) Potassium channels (for postsynaptic inhibition)

Ion Channels & neurotransmitters

Types of ion channels and neurotransmitter receptors in the CNS. A shows a voltage-gated channel in which a voltage sensor component of the protein controls the gating (broken arrow ) of the channel. B shows a ligand-gated channel in which the binding of the neurotransmitter to the ionotropic channel receptor controls the gating (broken arrow ) of the channel. C shows a G protein-coupled (metabotropic) receptor, which, when bound, activates a G protein that then interacts directly to modulate an ion channel. D shows a G protein-coupled receptor, which, when bound, activates a G protein that then activates an enzyme. The activated enzyme generates a diffusible second messenger, eg, cAMP, which interacts to modulate an ion channel.

Receptor-mediated channel opening

Receptor-activated channels

Amplification in signal transduction pathways

When an excitatory pathway is stimulated, a excitatory postsynaptic potential (EPSP) is recorded.

When an inhibitory pathway is stimulated, an inhibitory postsynaptic potential (IPSP) is produced.

There is also a second type of inhibition, presynaptic inhibition, which is axoaxonic.

Synaptic Potentials

Single synapse Many synapses

Threshold

Resting membrane potential = -70 mV

Excitatory Post Synaptic Potential (EPSP)

Threshold

Resting membrane potential = -70 mV

Inhibitory Post Synaptic Potential (IPSP)

Excitation Identical ExcitationInhibition

Inhibitoryinterneurone

Ach (nic)

Ach)nic(

GlycineIncreases Cl-

permeabilityMotor neurone

Motor axo

n

Disinhibition of inhibitory fibers can cause convulsion (e.g. Strychnine which blocks inhibitory substance Glycine)

Virtually all CNS drugs produce their effects by modifying some step in chemical synaptic transmission.

These transmitter-dependent actions can be divided into presynaptic and postsynaptic.

The selectivity of CNS drug action is based on the fact that: Different transmitters are used by different groups of

neurons. These transmitters are segregated into neuronal systems

that subserve broadly different CNS functions.

Sites of Drug Action

Identification of Neurotransmitters

Localization to prove that a suspected transmitter resides in the

presynaptic terminal of the pathway under study

Release To determine whether the substance is released from a

particular region

Synaptic Mimicry Application of the suspected substance should produce

a response that mimics the action of the transmitter released by nerve stimulation

Cellular Organization of the Brain

Hierarchical systems Sensory perception and motor control Has 2 types of neurons:

Relay or projection neurons Local circuit neurons

Nonspecific or Diffuse Neuronal Systems Contain one of the monoamines—norepinephrine,

dopamine, or serotonin

Central Neurotransmitters

Inhibitory Amino Acids Excitatory Amino Acids Acetylcholine Monoamines Peptides Nitric Oxide Histamine

Glycine, GABA

Dopamine, Norepinephrine and 5-hydroxytryptamine

Glutamate

Schematic diagram of a glutamate synapse. Glutamine is imported into the glutamatergic neuron (A) and converted into glutamate by glutaminase. The glutamate is then concentrated in vesicles by the vesicular glutamate transporter. Upon release into the synapse, glutamate can interact with AMPA and NMDA ionotropic receptor channels (AMPAR, NMDAR) in the postsynaptic density (PSD) and with metabotropic receptors (MGluR) on the postsynaptic cell (B). Synaptic transmission is terminated by active transport of the glutamate into a neighboring glial cell (C) by a glutamate transporter. It is synthesized into glutamine by glutamine synthetase and exported into the glutamatergic axon. (D) shows a model NMDA receptor channel complex consisting of a tetrameric protein that becomes permeable to Na+ and Ca2+ when it binds a glutamate molecule.

SummaryIn English

Thank youAny question?

GABA

EndorphineEnkephaline

EndorphineEnkephaline

Dopamine

Acetyl choline

NoradrenalinSerotonin

Noradrenaline