Transcript HOW DO NEURONS COMMUNICATE

How Do Drugs Affect the Nervous System? ….
Understanding Neural Transmission
Drugs act on Neurons and their communication with other cells
Beauty in the nervous system?
The Basis of the Nervous System
• Neurons – Single cell unit of the nervous
system
– 10 billion in the brain alone
– Receives, processes and transmits information
• Each neuron in the brain received signals from
thousands of other neurons.
In most respects the neuron is like
other cells of our body
But is different in that it can produce electrical
impulses near its cell body region
A Classical Study showing the
RESTING MEMBRANE POTENTIAL
(RMP) of the Neuron
The RMP
• The RMP for a typical neuron is about -70mv
“Threshold” voltage change
(depolarization) triggers the
“Action Potential”
Hyperpolarizationin the case of
neurons means to
make the RMP
more negative.
Depolarization
means to make the
RMP more positive
Threshold level of
depolarization
Triggers an
ACTION Pot.
Once triggered, the AP is all or none,
and “one-way.”
The AP will travel
to the terminal
and there initiate
a chemical event
The Neuronal communication process can be
thought of as an “electro-chemical” event.
Most Psychoactive drugs directly affect the
chemical portion of the process
Action Potential at the Terminals
Terminal Boutons end adjacent to
other cells…
The Synapsea very small space
between the boutons
of one neuron and
typically the
dendrites of another.
The Synapse: PRESYNAPTIC and POSTSYNAPTIC
processes
Any process associated with the terminal bouton of Neuron “A”
are considered to be presynaptic processes.
Any process associated with effects of NT release on neuron
“B” are considered postsynaptic processes.
PRESYNAPTIC Exocytosis
The Action Potential leads to release of
Neurotransmitter substance (exocytosis) into the
synapse.
Synaptic release of Neurotransmitter substances may
in turn affect “postsynaptic” neurons
Neurotransmitters
There are many different Neurotransmitter Families.
Different NTs are found in different pathways and are involved in
different functions/ or different components of functions.
Some Classical NTs, terminology and
postsynaptic effects
NTs
Terminology
Acetylcholine/ACH
Serotonin/5-HT
Cholinergic
serotonergic
+/+/-
GABA
GABA-ergic
-
(gamma-amino-butyric acid)
Glutamate/Glu
Glutamatergic
Norpinephrine /NEAdrenergic
Dopamine /DA
Dopaminergic
Enkephalin/Endorphin
Post synaptic effects
+
+/+/+/-
Some Basic Functions Associated
with Different NT Families:
• Acetylcholine-(ACH,cholinergic)
-Skeletal Muscle control
-Parasympathetic Autonomic functions
-Thirst
-Memory: Alzheimer’s disease
Pattern of projection pathways associated with acetylcholine brain nuclei ( cholinergic
systems
Norepinephrine- (NE,
noradrenergic, a catecholamine)
–Sympathetic ANS functions
–hunger
–mood
Noradrenergic system (Norepinephrine)
Dopamine- ( DA, dopaminergic, a
catecholamine)
– movement (Parkinson’s disease)
– “wanting”
– mood
–attention, and learning.
–Dopamine excess may be involved in
Schizophrenia.
Dopamine
Parkinson’s Disease
• Parkinson’s disease, dopamine and the
substantia nigra
Parkinson’s disease and MPTP
• 1980’s “designer drugs” MPPP/MPTPP and the
case of the frozen addicts
•
Serotonin ( 5-HT, serotonergic, an
indolamine)
• -sleep, dreaming, mood
Serotonergic System (Serotonin)
Endorphins
• Modulate the experience of pain
• Involved in breathing and heart rate, cough
reflex, nausea and vomiting
• Involved in feelings of euphoria and reward
GABA
• Most prevalent inhibitory neurotransmitter in the
brain
• GABA secreted by “local” interneurons all over the
brain.
• Implicated in relaxation/anti-anxiety
Glutamate
• Most prevalent excitatory NT.
• Involved in many brain circuits, but especially
important in the formation of memories.
• Brain injury is associated with release of Glut.
In high concentration, which in turn may be
toxic to neurons.
Neurotransmitters bind to receptor sites
to produce postsynaptic effects
NT-Receptor Specificity
A given NT substance will only activate specific receptor
proteins, and can not activate receptors for other NTs
l
l
l
Lock & Key Model
NT = key
Receptor = lock
Activation of a receptor will lead to either
Excitation or Inhibition.
How can one NT sometimes produce
excitatory postsynaptic effects and in
other cases produce inhibitory
postsynaptic effects?
NTs
Terminology
Acetylcholine/ACH
Serotonin/5-HT
Cholinergic
serotonergic
+/+/-
GABA
GABA-ergic
-
(gamma-amino-butyric acid)
Glutamate/Glu
Glutamatergic
Norpinephrine /NEAdrenergic
Dopamine /DA
Dopaminergic
Enkephalin/Endorphin
Post synaptic effects
+
+/+/+/-
One Neurotransmitter may activate
any of a “family” of receptor subtypes
ACH in the ANS can activate the
“Muscarinic” ACH receptor (mACH),
a metabotropic receptor type.
Activation of the mACHr leads to an
inhibitory response.
ACH release in the somatic branch
of the PNS activates the “Nicotinic”
ACH receptor (nACHr). An
ionotropic receptor type.
Activation of the nACHr leads to an
excitatory response.
Effects depend on receptor subtype
Deactivation of NT’s
• Enzyme Breakdown
• Reuptake
NT-receptor interactions must stop!
Enzymatic degradation
ACH is broken apart in the
synapse by the enzyme
acetylcholine-esterase
(ACHE).
The importance of the termination of NT-receptor interactions
is critical for normal function…..
“Nerve Gases” – and their typical
mechanism of action…
Most nerve gases produce their effects by
blocking the breakdown of ACH ( by binding to
and blocking the action of ACHE).
The blockade of ACHE leads to too much ACH in ACH synapses, and
exaggerated postsynaptic effects.
Effects of Nerve gas exposure
Neuromuscular
Effects
•Twitching
•Weakness
•Paralysis
•Respiratory
failure
Autonomic
Nervous
System Effects
•Reduced Vision
•Small pupil size
•Drooling
•Sweating
•Diarrhea
•Nausea
•Abdominal pain
•Vomiting
Central Nervous
System Effects
•Headache
•Convulsions
•Coma
•Respiratory
arrest
•Confusion
•Slurred speech
•Depression
•Respiratory
depression
Monoamine Oxidase: MAO
• MAO acts to break down NE and 5-HT
Reuptake
The serotonin transporter
enzyme is responsible for
terminating the effects of 5-HT in
serotonergic synapses
Of Interest???
Selective serotonin reuptake inhibitorsBind to and reduce the effectiveness of the 5-HT transporter
SSRIs approved to treat depression, with their generic, or chemical, names followed by
available brand names in parentheses:
Citalopram (Celexa)
Escitalopram (Lexapro)
Fluoxetine (Prozac, Prozac Weekly)
Paroxetine (Paxil, Paxil CR, Pexeva)
Sertraline (Zoloft)
These medications may also be used to treat conditions other than depression.
Side effects of SSRIs
All SSRIs have the same general mechanism of action and side effects. However,
individual SSRIs have some different pharmacological characteristics. That means you
may respond differently to certain SSRIs or have different side effects with different
SSRIs.
Of interest??
SSRI possible side-effects
Side effects of SSRIs include:
Nausea
Sexual dysfunction, including reduced
desire or orgasm difficulties
Dry mouth
Headache
Diarrhea
Nervousness
Rash
Agitation
Restlessness
Increased sweating
Weight gain
Drowsiness
Insomnia
How Do Drugs affect the nervous
system?
Ligand – a fancy term for substances that bind to receptors
-neurotransmitters
-drugs
In general we classify drug effects
into 2 basic types:
Drugs may act as Agoniststhe Ligand may mimic the NT and activate
the receptor, or facilitate the natural effects
of the NT in indirect ways
• Drugs may act as Antagonists:
• The ligand may block the receptor, or in indirect ways
decrease the effect of the NT at its receptor.
Drug Action
• Direct Agonist: Ligand Activates receptor
• Direct Antagonist: Ligand Blocks receptor
• Indirect agonism or antagonism
• Alters enzyme activity
• Blocks reuptake
• Etc…
Forms of Drug Action at the Synapse
• Ways to agonize
–
–
–
–
–
Stimulate release
Receptor binding
Inhibition of reuptake
Inhibition of deactivation
Promote synthesis
8.
Autoreceptors
• Ways antagonize
– Block release
– Receptor blocker
– Prevent synthesis
Acetylcholine
Agonists
Nicotine
Physostigmine
Antagonists
Muscarinic receptor Atropine
Nicotinic receptor Curare
Dopamine
• Cocaine
– dopamine reuptake
inhibitor
• Amphetamine
– increases DA release
• Antipsychotics
– block post-synaptic
dopamine receptor
Cocaine acts as a monoamine agonist by
blocking the reuptake transporter enzyme
Serotonin
• Selective-serotonin
reuptake inhibitors
(SSRIs) – used to treat
depression
GABA
•Valium, Xanax, Ativan
•Act as GABA agonists
•GHB, Rohypnol
•GABA agonist