Transcript Chemical Events at the Synapse

Chapter 3
Synapses
The Concept of the Synapse
• Neurons communicate by transmitting
chemicals at junctions called “synapses”
• In 1906, Charles Scott Sherrington coined the
term synapse to describe the specialized gap
that existed between neurons.
• Sherrington conducted his research
investigating how neurons communicate with
each other by studying reflexes (automatic
muscular responses to stimuli).
The Concept of the Synapse
•
Sherrington observed three important points
about reflexes:
1. Reflexes are slower than conduction
along an axon.
2. Several weak stimuli presented at slightly
different times or slightly different
locations produces a stronger reflex than
a single stimulus does.
3. As one set of muscles relaxes, another
set becomes excited.
The Concept of the Synapse
• Sherrington observed a difference in the
speed of conduction in a reflex arc from
previously measured action potentials.
• He believed the difference must be
accounted for by the time it took for
communication between neurons.
• Evidence validated the idea of the synapse.
The Concept of the Synapse
• Sherrington observed that repeated stimuli
over a short period of time produced a
stronger response.
• Led to the idea of temporal summation or that
repeated stimuli can have a cumulative effect
and can produce a nerve impulse when a
single stimuli is too weak.
The Concept of the Synapse
• Sherrington also noticed that several small
stimuli on a similar location produced a reflex
when a single stimuli did not.
• This led to the idea of spatial summation or
that synaptic input from several locations can
have a cumulative effect and trigger a nerve
impulse.
The Concept of the Synapse
• Presynaptic neuron – the neuron that delivers
the synaptic transmission
• Postsynaptic neuron – the neuron that
receives the message
• Excitatory postsynaptic potential (EPSP) is a
graded potential that decays over time and
space.
• The cumulative effect of EPSPs are the basis
for temporal and spatial summation.
The Concept of the Synapse
• Sherrington also noticed that during the reflex
that occurred, the foot of a dog that was
pinched retracted while the other three feet
were extended.
• He suggested that an interneuron in the
spinal cord sent an excitatory message to the
flexor muscles of one leg and an inhibitory
message was sent to the other three legs.
The Concept of the Synapse
• This led to the idea of inhibitory postsynaptic
potential or the temporary hyperpolarization
of a membrane.
• An ISPS occurs when synaptic input
selectively opens the gates for positively
charged potassium ions to leave the cell or
negatively charged chloride ions to enter the
cells.
• Serves as an active “brake”, that suppresses
excitation.
The Concept of the Synapse
• Neurons can have thousands of synapses.
• Both temporal and spatial summation can
occur within a neuron.
• The likelihood of an action potential depends
upon the ratio of IPSPs to EPSPs at a given
moment.
The Concept of the Synapse
• The spontaneous firing rate refers to the
periodic production of action potentials
despite synaptic input.
• EPSPs increase the number of action
potentials above the spontaneous firing rate.
• IPSPs decrease the number of action
potentials below the spontaneous firing rate.
Chemical Events at the Synapse
• German physiologist Otto Loewi was the first
to convincingly demonstrate that
communication across the synapse occurs
via chemical means.
• Neurotransmitters are chemicals that travel
across the synapse and allow communication
between neurons.
Chemical Events at the Synapse
•
The major sequence of events allowing
communication between neurons across the
synapse:
1. The neuron synthesizes chemicals that
serve as neurotransmitters.
2. Neurons store neurotransmitters in axon
terminals or transport them there.
3. An action potential triggers the release of
neurotransmitters into the synaptic cleft.
Chemical Events at the Synapse (cont.)
4. The neurotransmitters travel across the cleft
and attach to receptors on the postsynaptic
neuron.
5. The neurotransmitters separate from the
receptors.
6. The neurotransmitters are taken back into
the presynaptic neuron, diffuse away, or are
inactivated by chemicals.
7. The postsynaptic cell may send negative
feedback to slow the release of further
neurotransmitters.
Chemical Events at the Synapse
• Major categories of neurotransmitters include
the following:
– Amino acids.
– Neuropeptides.
– Acetylcholine.
– Monoamines.
– Purines.
– Gases.
Chemical Events at the Synapse
• Neurons synthesize neurotransmitters and
other chemicals from substances provided by
the diet.
– Acetylcholine synthesized from choline
found in milk, eggs, and nuts.
– Tryptophan serves as a precursor for
serotonin.
• Catecholimines contain a catechol group and
an amine group. (epinephrine, norepinephrine
and dopamine)
Chemical Events at the Synapse
• Smaller neurotransmitters are synthesized in
the presynaptic terminal and held there for
release.
– Example: acetylcholine
• Larger neurotransmitters are synthesized in
the cell body and transported down the axon.
– Example: neuropeptides
Neurotransmitters
Amino Acids: glutamate, GABA, glycine,
aspartate, maybe others
A Modified Amino Acid: acetylcholine
Monoamines (also modified from amino acids):
indoleamines: serotonin catecholamines: dopamine,
norepinephrine, epinephrine
Peptides (chains of amino acids): endorphins, substance P,
neuropeptide Y, many others
Purines: ATP, adenosine, maybe others
Gases: NO (nitric oxide), maybe others
Chemical Events at the Synapse
• Vesicles are tiny spherical packets located in
the presynaptic terminal where
neurotransmitters are held for release.
• MAO (monoamine oxidase) is a chemical that
breaks down excess levels of some
neurotransmitters
• Exocytosis refers to the excretion of the
neurotransmitter from the presynaptic
terminal into the synaptic cleft.
– Triggered by an action potential arriving fro
the axon.
Chemical Events at the Synapse
• Transmission across the synaptic cleft by a
neurotransmitter takes fewer than .01
microseconds.
• Most individual neurons release at least two
or more different kinds of neurotransmitters.
• Neurons may also respond to more types of
neurotransmitters than they release.
Chemical Events at the Synapse
• Proteins tether neurons together and guide
neurotransmitter molecules to receptors.
• An ionotropic effect refers to when a
neurotransmitter attaches to receptors and
immediately opens ion channels.
• Most effects occur very quickly and are very
short lasting.
• Most ionotropic effects rely on glutamate or
GABA.
Chemical Events at the Synapse
• Metabotropic effects occur when
neurotransmitters attach to a receptor and
initiates a sequence of slower and longer
lasting metabolic reactions.
• Metabotropic events include such behaviors
as hunger, fear, thirst, or anger.
• When neurotransmitters attach to a
metabotropic receptor, it bends the rest of the
protein .
• Bending allows a portion of the protein inside
the neuron to react with other molecules.
Chemical Events at the Synapse
• The portion inside the neuron activates a Gprotein –one that is coupled to guanosine
triphosphate (GTP), an energy storing
molecule.
• G-protein increases the concentration of a
“second-messenger”.
• The second messenger communicates to
areas within the cell.
– May open or close ion channels, alter
production of activating proteins, or
activate chromosomes.
Chemical Events at the Synapse
• Metabotropic effects utilize a number of
different neurotransmitters
• Neuropeptides are often called
neuromodulators
– Release requires repeated stimulation
– Released peptides trigger other neurons to
release same neuropeptide
– Diffuse widely and affect many neurons via
metabotropic receptors
Chemical Events at the Synapse
• A hormone is a chemical secreted by a gland
or other cells that is transported to other
organs by the blood where it alters activity.
• Endocrine glands are responsible for the
production of hormones.
• Hormones are important for triggering longlasting changes in multiple parts of the body.
Chemical Events at the Synapse
• Protein hormones and peptide hormones are
composed of chains of amino acids and
attach to membrane receptors where they
activate second messenger systems.
• Hormones secreted by the brain can control
the release of other hormones.
Chemical Events at the Synapse
•
The pituitary gland is attached to the
hypothalamus and consists of two distinct
glands that each release a different set of
hormones:
1. Anterior pituitary- composed of glandular
tissue and synthesizes six hormones.
2. Posterior pituitary- composed of neural
tissue and can be considered an extension
of the hypothalamus
Chemical Events at the Synapse
• Neurons in the hypothalamus synthesize the
hormones oxytocin and vasopressin which
migrate down axons to the posterior pituitary.
– Also known as antidiuretic hormones
• The hypothalamus secretes releasing
hormones.
– flow through the blood and stimulate the
anterior pituitary to release a number of
other hormones.
Chemical Events at the Synapse
• The hypothalamus maintains a fairly constant
circulating level of hormones through a
negative-feedback system.
– Example : TSH- releasing hormone
Chemical Events at the Synapse
• Neurotransmitters released into the synapse
do not remain and are subject to either
inactivation or reuptake.
• Reuptake refers to when the presynaptic
neuron take sup most of the neurotransmitter
molecules intact and reuses the.
• Transporters are special membrane proteins
that facilitate reuptake.
– Example: Serotonin is taken back up into
the presynaptic terminal.
Chemical Events at the Synapse
• Examples of inactivation and reuptake
include:
– Acetylcholine is broken down by
acetylcholinesterase into acetate and
choline.
• Some serotonin and catecholamine
molecules are converted into inactive
chemicals:
– COMT and MAO are enzymes that convert
catecholamine transmitters into inactive
chemicals.
Chemical Events at the Synapse
•
Negative feedback in the brain is
accomplished in two ways:
1. Autoreceptors are receptors that detect the
amount of transmitter released an inhibit
further synthesis and release.
2. Post synaptic neurons respond to
stimulation by releasing chemicals that
travel back to the presynaptic terminal
where the inhibit further release
Synapses, Drugs and Addiction
• The study of the influence of various kinds of
drugs has provided us with knowledge about
many aspects of neural communication at the
synaptic level.
• Drugs work by mimicking our own
neurochemistry.
– Example: receptors in the brain respond to
LSD and cocaine
• Drugs alter various stages of synaptic
processing.
Substance Abuse and Addictions
• Addictive substances increase dopamine
activity in certain areas of the brain.
• Olds and Milner (1954) placed rats in a
Skinner box that allowed self-stimulation of
the brain by the pressing of a lever.
• Rats sometimes pressed the lever 2000 times
per hour to stimulated the release of
dopamine in the nucleus accumbens.
Substance Abuse and Addictions
• Other behaviors that release dopamine
include sexual excitement, gambling, and
video games.
• fMRI research indicates dopamine is released
during viewing of “attractive” people.
Substance Abuse and Addictions
• Berridge and Robinson (1998) suggest an
important distinction be made between
“liking” and “wanting” behaviors.
• Activity in the nucleus accumbens seems to
be related to “wanting”.
– Results in a monopolization of attention.
Drugs and the Synapse
• Drugs either facilitate or inhibit activity at the
synapse.
– Antagonistic drugs block the effects of
neurotransmitters.
– Agonist drugs mimic or increase the effects
of neurotransmitters.
Drugs and the Synapse
•
Drugs work by doing one or more of the
following to neurotransmitters:
1. Increasing the synthesis.
2. Causing vesicles to leak.
3. Increasing release.
4. Decreasing reuptake.
5. Blocking the breakdown into inactive
chemical.
6. Directly stimulating or blocking
postsynaptic receptors.
Drugs and the Synapse
• A drug has an affinity for a particular type of
receptor if it binds to that receptor.
– Can vary from strong to weak.
• The efficacy of the drug is its tendency to
activate the receptor.
• Drugs can have a high affinity but low
efficacy.
Drugs and the Synapse
• Almost all abused drugs stimulate dopamine
release in the nucleus accumbens,
– small subcortical area rich in dopamine
receptors
– an area responsible for feelings of pleasure
• Sustained bursts of dopamine in the nucleus
accumbens inhibit cells that release the
inhibitory neurotransmitter GABA
Drugs and the Synapse
• Drugs are categorized according to their
predominant action or effect upon behavior
• Stimulant drugs increase excitement,
alertness, motor activity and elevate mood.
• Examples: amphetamines, cocaine,
methylphenidate (Ritalin), MDMA (Ecstasy),
nicotine
Drugs and the Synapse
• Amphetamine stimulate dopamine synapses
by increasing the release of dopamine from
the presynaptic terminal.
• Cocaine blocks the reuptake of dopamine,
norepinephrine, and serotonin.
• Methylphenidate (Ritalin) also blocks the
reuptake of dopamine but in a more gradual
and more controlled rate.
– Often prescribed for people with ADD
Drugs and the Synapse
• MDMD (ecstasy) increases the release of
dopamine at low doses that account for its
stimulant properties.
• Increases the release of serotonin at higher
doses accounting for its hallucinogenic
properties.
• Research indicates damage to neurons that
contain serotonin.
• Degree of risk to humans is not clear.
Drugs and the Synapse
• Nicotine is the active ingredient in tobacco.
• Nicotine stimulates one type of acetylcholine
receptor known as the nicotinic receptor.
• Nicotinic receptors are found in the central
nervous system, the nerve-muscle junction of
skeletal muscles and in the nucleus
accumbens.
• Nicotinic receptors are also abundant in the
nucleus accumbens and facilitate dopamine
release.
Drugs and the Synapse
• Opiate drugs are those that are derived from
(or similar to those derived from) the opium
poppy.
• Opiates decrease sensitivity to pain and
increase relaxation by attaching to endorphin
receptors in the brain.
• Examples: morphine, heroin, methadone.
Drugs and the Synapse
• The brain produces peptides called
endorphins.
• Endorphin synapses may contribute to certain
kinds of reinforcement by inhibiting the
release of GABA indirectly.
• Endorphin synapses inhibit ventral tagmental
neurons that release GABA
• Inhibiting GABA indirectly releases dopamine.
Drugs and the Synapse
• Tetrahydocannabinol (THC) is the active
ingredient in marijuana.
• THC attaches to cannabinoid receptors
throughout the brain but especially the
cerebral cortex, cerebellum, basal ganglia,
and hippocampus.
• Anandamide and 2-AG are the endogenous
chemicals that attach to these receptors.
Drugs and the Synapse
• The location of the receptors in the brain may
account for the subjective effects of loss of
time, an intensification of sensory experience,
and also memory impairment.
• The cannabinoid receptors are located on the
presynaptic neuron and inhibit the release of
glutamate and GABA.
Drugs and the Synapse
• Hallucinogenic drugs cause distorted
perception.
• Many hallucinogenic drugs resemble
serotonin in their molecular shape.
• Hallucinogenic drugs stimulate serotonin
type 2A receptors (5-HT2A) at inappropriate
times or for longer duration than usual thus
causing their subjective effect.
Drugs
Main Behavioral
Effects
Main Synaptic
Effects
Amphetamine
Excitement,
alertness, elevated
mood, decreased
fatigue
Increases release of
dopamine and
several other
transmitters
Cocaine
Excitement,
alertness, elevated
mood, decreased
fatigue
Blocks reuptake of
dopamine and
several other
transmitters
Methylphenidate
(Ritalin)
Increased
concentration
Blocks reuptake of
dopamine and
others, but
gradually
Drugs
Main Behavioral
Effects
Main Synaptic
Effects
Low dose: stimulant
Releases dopamine
Higher dose: sensory
distortions
Releases seratonin,
damages axons
containing seratonin
Nicotene
Mostly stimulant
effects
Stimulates nicotinictype acetylcholine
receptor, which
(among other effects)
increases dopamine
release in nucleus
accumbens
Opiates (e.g., heroin,
morphine)
Relaxation,
withdrawal,
decreased pain
Stimulates endorphin
receptors
MDMA (“ecstasy”)
Drugs
Main Behavioral
Effects
Main Synaptic
Effects
Cannabinoids
(marijuana)
Altered sensory
experiences,
decreased pain and
nausea, increased
appetite
Excites negativefeedback receptors
on presynaptic
cells; those
receptors ordinarily
respond to
anandamide and
2AG
Hallucinogens (e.g.,
LSD)
Distorted sensations Stimulates
seratonin type 2A
receptors (5-HT2A)
Drugs and the Synapse
• Alcohol is a drug that has a long historical
use and is used widely throughout the world.
• In moderate amounts, alcohol is associated
with relaxation.
• In greater amounts it impairs judgment and
damages the liver and other organs.
• Alcoholism/alcohol dependence is the
continued use of alcohol despite medical or
social harm even after one has decided to
quit or decrease drinking.
Drugs and the Synapse
• Alcohol has a number of diverse physiological
effects including:
– Inhibition of sodium across the membrane.
– Expansion of the surface of membranes.
– Decreased serotonin activity.
– Enhanced response by the GABAA
receptor.
– Blockage of glutamate receptors.
– Increased dopamine activity.
Drugs and the Synapse
•
The genetic basis for early-onset alcoholism
is stronger than for later-onset, especially in
men.
• Researchers distinguish between two types
of alcoholism
1. Type I/Type A
2. Type II/Type B
Substance Abuse and Addictions
• Type I/Type A characteristics include:
– Later onset.
– Gradual onset.
– Fewer genetic relatives with alcoholism.
– Equal quantity between men and women.
– Less severe.
Substance Abuse and Addictions
• Type II/Type B characteristic include:
– Earlier onset (usually before 25).
– More rapid onset.
– More genetic relatives with alcoholism.
– Men outnumber women.
– Often severe.
– Often associated with criminality.
Drugs and the Synapse
• Various factors contribute to continued
substance abuse:
• Tolerance develops
• Cravings in response to cues
• Brain reorganization (nucleus accumbens
and prefrontal cortex)
Drugs and the Synapse
• Genes influence the likelihood of alcoholism
in various ways:
– Sensitivity of Dopamine type 4 receptor
– Control of COMT enzyme that breaks
down dopamine
Drugs and the Synapse
• Medications used to combat alcoholism
include:
– Antabuse.
– Methadone.
– Many do not respond to other treatments
so medications have been used to reduce
cravings.
Drugs and the Synapse
• Antabuse (disulfiram) works by antagonizing
the effects of acetaldehyde dehydrogenase.
• After alcohol consumption, enzymes in the
liver metabolize it into a poisonous substance
called acetaldehyde.
• Acetaldehyde is converted by the enzyme
acetaldehyde dehydrogenase into acetic acid,
a chemical that the body can use as a source
of energy.
• Accumulation of acetaldehyde results in
sickness.
Drugs and the Synapse
• Most studies suggest that Antabuse has been
only moderately effective.
• When effective, it supplements the alcoholic’s
own commitment to quit.
• Daily routine of pill ingestion may reaffirm
commitment not to drink.
• Many quit taking the pill and continue to drink.
Drugs and the Synapse
• Methadone is an opiate similar to heroin and
morphine but is absorbed and metabolized
slowly.
• Perceived to be less harmful than other
drugs.
• Assumed to satisfy the cravings associated
with the previous drug use and allow the
person to carry on with their life.