Download Lecture 4

Prepare
• Christof Koch a in the National Geographic
Live! - Mapping the Brain:
https://www.youtube.com/watch?v=7_drJy
NMXbw
• At 8min there is the best presentation of a
slice of a mouse brain with:
– synapses shown in magenta,
– neurons shown in green and
– microtubulin of axons shown in blue
Review of
neuromuscular
junction
• Chemical or electrical
synapse?
• How is signal
transmitted across the
gap between cells?
• What is the
transmitted chemical?
• Where is
neurotransmitter
stored?
• What is the signal for
vesicle release?
• What happens in the
postsynaptic cell?
Drugs of abuse
• There are plenty of ways
to hack a synapse.
• It just so happens that
some neurotransmitters
are used to communicate
pleasure in the brain
more than other
neurotransmitters
• E.g.: dopamine
• Increase dopamine
concentration at the
synaptic cleft 
experience more
pleasure
• What are some ways to
increase dopamine
concentration at a
synapse?
Cocaine
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Cocaine is obtained from the leaves of
the coca plant ….communal chewing of
coca dates 8,000 years back
Cocaine acts as a dopamine–
serotonin–norepinephrine reuptake
inhibitor increases neurotransmitter
concentration in the synaptic cleft –
what is the effect?
Dopamine participate in reward
circuits more than in other neural
circuits. So increasing Dopamine
concentration at synapses usually
results in positive feeling
It is also a nonspecific voltage gated
sodium channel blocker – could you
predict the effect?
… which causes it to produce
anesthesia at low doses
Traditional medical uses of coca:
analgesic to alleviate the pain of
headache, rheumatism, wounds and
sores
Cocaine
Dopamine
• Cocaine was added to Coca-cola from 1886 to 1906
• Sigmund Freud in Über Coca: “Exhilaration and lasting euphoria, which
in no way differs from the normal euphoria of the healthy person. You
perceive an increase of self-control and possess more vitality and
capacity for work. In other words, you are simply normal, and it is soon
hard to believe you are under the influence of any drug. Long intensive
physical work is performed without any fatigue. This result is enjoyed
without any of the unpleasant after-effects that follow exhilaration
brought about by alcoholic beverages. No craving for the further use of
cocaine appears after the first, or even after repeated taking of the
drug.”
• Since 1879 cocaine was used to treat morphine addiction
• Sherlock Holmes uses cocaine to offset the boredom
• was often supplied by employers as a stimulant to increase productivity
• Legal use declined since Jones-Miller Act of 1922 put serious
restrictions on cocaine manufactures
Dopamine
• Dopamine is released in the forebrain (in the striatum and
cortex, and presumably the hippocampus) at the time of
reward, especially when reward is not expected by the
animal.
• DA teaches us to repeat pleasurable activity (like eating and
sex and anything else that resulted in release of DA).
Dopamine (DA)
• Abnormalities in
DA system are
implicated in
schizophrenia and
Parkinson’s disease.
• All Dopamine
receptors are G
protein-coupled
receptors (many
different subtypes).
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A metabotropic receptor is a type of membrane receptor that acts through a intracellular
secondary messengers.
Ionotropic receptors (that form an ion channel pore) = Ligand-gated ion channels. Examples:
nicotinic AChR, Ionotropic GABA receptors, Ionotropic glutamate receptors (AMPA, NMDA),
Ionotropic serotonin receptors.
Metabotropic receptor examples: muscarinic AChR (compare to nicotinic AChR),
metabotropic GABA receptors, metabotropic glutamate receptors.
Most receptors for serotonin, norepinephrine, epinephrine, histamine, dopamine,
neuropeptides are metabotropic receptors.
G protein-coupled receptors (Metabotropic )
• The common theme of metabotropic
receptors is amplification of signal
via a cascade of intracellular
secondary messengers
Side effects of cocaine
• Can you predict side effects?
• Anxiety, paranoia and restlessness can also occur, especially
during the comedown.
• With excessive dosage, tremors, convulsions and increased
body temperature are observed.
• Severe cardiac adverse events, particularly sudden cardiac
death, become a serious risk at high doses due to cocaine's
blocking effect on cardiac sodium channels
• Overdoses cause hyperthermia and a marked elevation of
blood pressure, which can be life-threatening, arrhythmias,
and death.
• Chronic use: insatiable hunger, aches, insomnia/oversleeping,
lethargy, persistent runny nose, anxiety and depression.
• Cocaine withdrawal: vivid and unpleasant dreams, insomnia or
hypersomnia, increased appetite and psychomotor retardation
or agitation
Drugs with action similar to Cocaine
• Cocaine blocks DA
reuptake.
• ADD drug Ritalin
also blocks DA
reuptake.
• Amphetamine
(Adderall) increases
DA as well as 5-HT
and NE) due to its
effects on
monoamine
transporters.
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Cocaine
Caffeine
Nicotine
Amphetamines (Ritalin
(methylphenidate),
Adderall (amphetamine)).
MDMA (ecstasy)
Stimulant is a drug that
increases the activity
of the sympathetic
nervous system and
produces a sense of
euphoria or the feeling
of being more awake.
adenosine
Caffeine
• As neurons fire, they use ATP and produce adenosine.
• Over time adenosine from ATP accumulates in synapses
• Adenosine binds to and activates adenosine receptors that produce a
cellular response that ultimately increases drowsiness – fatigue sensor.
• The caffeine molecule is structurally similar to adenosine, and is capable of
binding to adenosine receptors without activating them, acting as a
competitive inhibitor.
• As a result, caffeine temporarily prevents drowsiness, and thus maintains
alertness. Other caffeine effects:
– Caffeine potentiates NE. Can you predict the effect of potentiated NE?
– Caffeine can cause and worsen anxiety; for some people, discontinuing
caffeine use can significantly reduce anxiety
– inhibits ACh esterase. Can you predict the effect of inhibited ACh esterase?
– raises intracellular cAMP
– activates protein kinase A
– reduces inflammation and innate immunity.
Tobacco  Nicotine
• Nicotine activates nicotinic acetylcholine ionotropic receptors (nAChR). It has a
higher affinity for nAChR in the brain than those in skeletal muscle, so it primarily
affects the nAChR in the brain.
• Nicotine is named after the French ambassador in Portugal, Jean Nicot de
Villemain, who sent tobacco plants to Paris in 1560 and promoted their medicinal
use. At the time smoking was believed to protect against the black plague.
• At low doses, nicotine enhances the actions of norepinephrine and dopamine. Can
you predict the effect?
• It is a stimulant and affects the same DE reward pathways. Nicotine also extends
the duration of positive effects of dopamine and increases sensitivity in brain
reward systems.
• At higher doses, nicotine enhances the effect of serotonin and opiate activity. Can
you predict the effect?
• At higher doses, nicotine may produce a calming, pain-killing effect.
• Nicotine also increases acetylcholine response  enhances concentration and
memory
Tobacco  Monoamine oxidase inhibitor
• Tobacco contains naturallyoccurring monoamine oxidase
inhibitor compounds in addition to
the nicotine.
• Monoamine oxidase is the enzyme
that breaks down monoaminergic
neurotransmitters (5-HT, DA, NE,
EPI)
• What happens with DA when you
block MAO?
• DA concentration increases in
synaptic cleft.
• Monoamine oxidase inhibitors are
one of the major classes of drug
prescribed for the treatment of
depression
• What does it tell you about
addictiveness of tobacco?
MAO
Ecstasy
• MDMA acts as a
serotoninnorepinephrinedopamine releasing agent
and reuptake inhibitor.
• Could you predict the
effect?
• During World War II,
amphetamine and
methamphetamine were
used extensively by both
the Allied and Axis forces
for their stimulant and
performance-enhancing
effects
A depressant or
"downer" act on the CNS
to increase the activity of
gamma-aminobutyric
acid (GABA).
• Alcohol
• Barbiturates
• Benzodiazepine
Alcohol  Gamma-aminobutyric acid (GABA)
• GABA is the major inhibitory
neurotransmitter: flow of negatively
charged chloride ions into the cell
causes hyperpolarization.
• For example, deficiency in GABA
neurotransmitter or GABA receptors
is one cause of epilepsy.
• Ethanol at large doses increases
conduction of GABA channels.
• Can you predict the effect?
• Ethanol at large doses  general
inhibition of CNS.
• Ethanol at low doses is an exciter.
• Note that not all GABA receptors are
ionotropic. Some GABA receptors
are G protein-coupled receptors that
open or close ion channels via
intermediaries (cAMP).
Endorphins (endogenous opiates)
• Analgesic effect
• Hypnotic effect
• Sense of wellbeing
• Decrease of
gastric motility
• Runner’s high
Opium
• Opium was known for
centuries as a painkiller.
• Prepared by drying and
powdering the milky juice
taken from seed capsules of
opium poppy just prior to
ripening.
• In 1803 an active substance
was isolated from opioid
and named morphine after
the Greek god of dreams.
• Morphine is 10% of opium
by weight.
Heroin
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• Why heroin is so much more potent?
• Morphine is polar  has poor lipid solubility 
it does not escape from capillaries into the brain easily
• Heroin is nonpolar and therefore membrane
permeable and therefore easily escapes into the brain
Heroin toxicity
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• Over 50,000 overdose deaths a
year in USA alone
• Naloxone is a fast acting opioid
antagonist
• Naltraxone is a slow acting opioid
antagonist
Respiratory depression
Cardiac arrhythmias
Constipation
Addiction, tolerance
Needle infection
Withdrawal
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Drug craving
Anxiety
Runny nose
Perspiration
Pupil dilation
Nausea, vomiting
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Diarrhea
Bone and muscle pain
Tremors
Even when withdrawal
is gone the addiction
remains
Case study: Painlessness in Humans
• Broad-spectrum sodium channel blockers are used as local anaesthetics, but they
are not suitable for long-term pain management as they cause complete numbness
and can have serious side-effects over time.
• Opioid painkillers such as morphine are highly effective at reducing pain, but longterm use can lead to dependence and tolerance. As the body becomes used to the
drug it becomes less effective so higher doses are needed for the same effect, side
effects become more severe, and eventually it stops working altogether.
• Can combination of sodium channel blockers and opioids work better?
• People born with non-functioning sodium channel Nav1.7 do not feel pain. The
Nav1.7 is particularly important for signaling in pain pathways
• To examine if opioids were important for painlessness, the researchers gave
naloxone, an opioid blocker, to mice lacking Nav1.7 and found that they were able
to feel pain.
• Similarly, they then gave naloxone to a woman with the rare genetic mutation and
she felt pain for the first time in her life.
•  "we have now filed a patent for combining low dose opioids with Nav1.7
blockers. This should replicate the painlessness experienced by people with rare
mutations, and we have already successfully tested this approach in unmodified
mice … Used in combination with Nav1.7 blockers, the dose of opioid needed to
prevent pain is very low."
Certain drugs can affect the
subjective qualities of
perception, thought or
emotion, resulting in altered
interpretations of sensory
input or hallucinations.
• LSD (acid)
• Psilocybin (psychedelic
mushrooms)
• Cannabinoids
Psychedelic drugs 
Serotonin (5-HT)
• Psychedelic drugs
like LSD activate 5HT receptors as well
as some DA
receptors.
• Most 5-HT receptors
are G proteincoupled receptors
selective
serotonin
reuptake
inhibitors
placebo
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LSD
“… under LSD, compared to placebo, disparate regions in the brain communicate with each
other when they don’t normally do so. In particular, the visual cortex increases its
communication with other areas of the brain, which helps explain the vivid and complex
hallucinations experienced under LSD, and the emotional flavour they can take.”
“On the other hand, the neuronal networks that normally fire together when the brain is at
rest, sometimes called the ‘default mode network’, we saw reduced blood flow — something
we’ve also seen with psilocybin — and that neurons that normally fire together lost
synchronization. That correlated with our volunteers reporting a disintegration of their sense
of self, or ego. This known effect is called ‘ego dissolution': the sense that you are less a
singular entity, and more melded with people and things around you. We showed that this
could be experienced independently of the hallucinatory effects — the two don’t necessarily
go together.”
Serotonin
(5-HT)
• Serotonin is involved in regulation mood, sleep and
arousal, sexuality, aggression, body temperature.
• Abnormalities in 5-HT system are implicated in
depression, obsessive-compulsive disorder.
• Drugs used to treat psychosis
("loss of contact with reality“).
Chlorpromazine
• The term antipsychotic is applied to a group of drugs
used to treat psychosis ("loss of contact with reality“).
• Chlorpromazine was the first antipsychotic drug, used
during the 1950s and 1960s leading to closing of majority
of long-stay psychiatric hospitals (deinstitutionalization).
• It has also anxiolytic (alleviation of anxiety) properties.
• Today, chlorpromazine is considered a typical
antipsychotic.
• Chlorpromazine: Blocks dopaminergic-receptors
• Blocks some serotonergic-receptors
• Blocks some histaminergic-receptors
Long-term memory
• Long-term memory is stored in __________?
• …but it takes hours to days to consolidate long-term memory,
since we need to synthesize, deliver and organize many proteins
• How do we store memory before new synaptic spines can form?
NMDA ionotropic
glutamate receptorchannel
• NMDA glutamate
receptors have an internal
binding site for an Mg++
ion, creating a block.
• [Mg++]in =5mM;
[Mg++]out=2mM.
So strong positive voltage
can push Mg++ out of the
channel.
• Mg++ is removed by
positive voltage during a
peak of action potential.
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During action
potential
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NMDA receptor
• Once Mg++ ion is removed
during a peak of action
potential, Ca++ can enter
the neuron through NMDA
receptors-channel.
• The flow of Ca++ causes
long-term potentiation by
regulating gene expression
(Ca2+ is a second
messenger) that lasts
hours.
• How is action potential
initiated in the
postsynaptic cell in the
first place?
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During action
potential
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Ionotropic glutamate receptors
• In addition to NMDA, there are also non-NMDA
ionotropic glutamate receptors-channels (AMPA,
Kainate) that activates when glutamate binds to
the receptor, allowing the flow of K+, Na+.
Non-NMDA Glu receptor: AMPA receptors
are simple ligand-activated channels
14nm
12nm
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Each AMPA receptor has four sites to which glutamate can bind. The channel opens when
two sites are occupied and increases its current as more binding sites are occupied.
The AMPA receptor is permeable to sodium and potassium, some subtypes are also
permeable to calcium.
Once open, the channel can rapidly inactivate, stopping the current.
Glutamate AMPARs are responsible for most fast excitatory synaptic transmission in the
central nervous system.
Long-term potentiation (LTP) is the best model
for long-term memory that lasts hours
Pyramidal
neurons
• Green dots =
synapses of the
black neuron
on the red
neuron
• Blue dots
synapses of the
red neuron on
the black
neuron
Long-term potentiation (LTP)
• Christof Koch a in the National Geographic
Live! - Mapping the Brain:
https://www.youtube.com/watch?v=7_drJy
NMXbw
• At 8min there is the best presentation of a
slice of a mouse brain with:
– synapses shown in magenta,
– neurons shown in green and
– microtubulin of axons shown in blue
• Stop.
Types of neurotransmitters (You are not responsible for learning
different types of neurotransmitters, their function, and location)
Neurotransmitter
Function
Biogenic amines (contain NH2 amino group)
Acetylcholine (Ach)
Neurotransmitter at the neuromuscular junction; in brain, involved in learning, etc.
Dopamine (DA)
Involved in reward circuits in the PFC. Abnormalities in DA system are implicated in
schizophrenia and Parkinson’s disease. Cocaine blocks DA reuptake. ADD drug Ritalin also
blocks DA reuptake. Amphetamine (Adderall) modulates DA as well as 5-HT and NE).
Serotonin (5-HT)
Involved in regulation mood, sleep and arousal, sexuality, aggression, body temperature.
Abnormalities in 5-HT system are implicated in depression, obsessive-compulsive disorder.
Psychedelic drugs like LCD activate 5-HT receptors as well as some DA receptors.
Norepinephrine (NE)
Released during stress. Neurotransmitter in the brain to increase arousal and attentiveness
to events in the environment. ADD drug Strattera affects only NE.
Epinephrine (Epi)
A stress hormone related to norepinephrine. Also called Adrenalin.
Histamine (His)
Modulates sleep: antihistamines induce sleepiness (Dramamine)
Amino Acids
Glutamate (Glu)
The major excitatory neurotransmitter in the brain and spinal cord.
Gamma-aminobutyric acid
(GABA)
The major inhibitory neurotransmitter. Its receptors respond to alcohol and the class of
tranquilizers called benzodiazepines. Deficiency in GABA or receptors is one cause of
epilepsy.
Glycine (Gly)
Inhibitory neurotransmitter in the spinal cord and lower brain. Works by opening Chloride
channels that hyperpolarizes the cell. The poison strychnine causes convulsions and death by
Garrett: Brain & Behavior 4e
blocking Gly binding site on the Chloride channels.
Neurotransmitter
Function
Neuropeptides
Endorphins (over 85
different
neuropeptides)
Endogenous opioids (5 amino acid polypeptide) reduce pain and enhance
reinforcement. Exogenous opioids: morphine, heroine.
Substance P
Neurotransmitter in neurons sensitive to pain.
Neuropeptide Y
Initiates eating and produces metabolic shifts.
Gases
Nitric Oxide
Viagra enhances male erections by increasing nitric oxide’s ability to relax
blood vessels and produce penile engorgement.
CO
carbon monoxide
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Every molecule of neurotransmitter has a number of different target
receptors, increasing the system complexity
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Why do we need so many neurotransmitters?
Compartmentalization. Neurotransmitters can accomplish the goal without
interfering with unrelated systems.
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Branch of Neuroscience: Neurochemistry
Neurotransmitters vs. hormones
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Why there is no interference between epinephrine hormone and epinephrine neurotransmitter?
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