Lecture 3: Peptides, lipids, nucleosides

and gases
What is Neuromodulation?
Neuromodulation is the physiological process by which a given neuron uses one or more
chemicals to regulate diverse populations of neurons. This is in contrast to classical synaptic
transmission, in which one presynaptic neuron directly influences a single postsynaptic partner.
Neuromodulators secreted by a small group of neurons diffuse through large areas of the
nervous system, affecting multiple neurons. Major neuromodulators in the central nervous
system include dopamine, serotonin, acetylcholine, histamine, and norepinephrine.

Neuromodulation can be conceptualized as a neurotransmitter that is not reabsorbed by

the pre-synaptic neuron or broken down into a metabolite. Such neuromodulators end up
spending a significant amount of time in the cerebrospinal fluid (CSF), influencing (or
"modulating") the activity of several other neurons in the brain. For this reason, some
neurotransmitters are also considered to be neuromodulators, such as serotonin and
acetylcholine.[1]

Neuromodulation is often contrasted with classical fast synaptic transmission. In both cases the
transmitter acts on local postsynaptic receptors, but in neuromodulation, the receptors are
typically G-protein coupled receptors while in classical chemical neurotransmission, they
are ligand-gated ion channels. Neurotransmission that involves metabotropic receptors (like G-
protein linked receptors) often also involves voltage-gated ion channels, and is relatively slow.
Conversely, neurotransmission that involves exclusively ligand-gated ion channels is much
faster. A related distinction is also sometimes drawn between modulator and driver synaptic
inputs to a neuron, but here the emphasis is on modulating ongoing neuronal spiking versus
causing that spiking.

There are other chemicals that usually have other functions but can also work as neurotransmitters. These
include peptide, nucleosides, lipids and gases. These dont satisfy all the criteria of the neurotransmitter but they
function like neurotransmitters.
Criteria for Neurotransmitter (Non- traditional neurotransmitters DONT satisfy all of these criteria):
1) Present in all presynaptic terminals
2) Released from presynaptic terminals after neuron fires
3) Existence of receptors on postsynaptic neurons.

Peptides:
A molecule containing more than 2 amino acids joined by peptide bonds. Proteins are larger the peptides.
In the brain, they are made from the breakdown of larger proteins (instead of being synthesised by smaller
compounds). This breakdown impacts the way neurons fire. Peptide transmission is the same as traditional
neurotransmitters. Most peptides that work as hormones can also work as neurotransmitters and are often co-
released with other neurotransmitters. Peptides that work as hormones are transmitted in the blood.
Opioids (peptide neurotransmitters)- endogenous opioids (originate internally), opiates (morphine, heroin,
opium). These two are not the same.
Opioids are not the same as Opiates!
Just because we find an external compound that fits perfectly into an existing receptor in the brain doesnt mean
that the natural compound for the receptor will have the same effect as the external drug
When we find an external compound that binds perfectly to a receptor (e.g. heroin) people assume that there
must be a compound occurring naturally that has the same effect as heroin. This is not true. A lot of these opiate
receptors in the brain are involved in pain.
Opiate receptor (Mu) is associated with analgesia, euphoria, sedation.
Many Opiates come from natural sources and provide pain relief and euphoria.
Opiate Drugs

Heroin is addictive but not neurotoxic- you can die from too much of it because of its extreme sedating
properties, but it doesnt really damage the brain. Its addictive- can destroy life without destroying
brain.

Full agonists act the same as heroin but its SLOW,

so people on methadone dont associate the drug with the immediate high too much- this controls
addiction. Partial Agonist (buprenorphine) mimics heroin to a less extent that methadone, and works to
block the receptor. Naloxone rapidly blocks the effects the heroin- good for heroin overdose, blocking
heroin receptors stops its activation. However it puts people into withdrawal.

LIPIDS- STRUCTURE AND SYNTHESIS

Most lipids play a structural role (peptides have more a functional role). Lipids are hydrophobic and main function
is energy storage, signalling and provide structural components of cell membranes. Synthesis pathways for lipids
remains unclear for the lipids that act as neurotransmitters/ modulators.
ENDOCANNABINOIDS
Endogenous, cannabis like structures. 2 known cannaboid receptors CB1 and CB2- both are G Protein
receptors.
CB1 is in the brain and responsible for psychological effectors. The receptors are in the terminal buttons of
neurons that release most of the NTs. When its activated it shortens the duration of action potentials in the
presynaptic neuron and decreases the amount of neurotransmitter released. If a lot of one neuron is fired then
C1 receptors reduce the firing (modulating modulators).
CB2 is in peripheral tissue.
C1 receptor location can determine its function. Receptor has the same structure and causes the same response
but its location will cause different overall effects.
Lipids- cannabis/marijuana
Active compound is THC. Plant is consumed by inhalation. Effects range from changes in appetite, time
perception, arousal, relaxation/anxiety, and can lead to apathy and underachievement. Therapeutically used to
reduce nausea, relives asthma attacks decreases pressure within the eyes in glaucoma.
Medicinal Cannabis
2016- Access to medicinal cannabis act passed in VIC.
2017- kids with severe intractable epilepsy will be the first to access the cannabis. But the efficacy of cannabis in
severe refractory epilepsy or catastrophic epilepsy COMPARED to approved therapies is not known. Research
(open label) with cannabis has found that its effect is similar to existing drugs.

Nucleosides
Subunit of nucleic acids (DNA/RNA). Obtained by nucleic acid breakdown- consists of a molecule of sugar linked
to a nitrogen containing compound. These can also modulate the release of NT ( like lipid neurotransmitters).
Modulating the modulators.
NUCLEOSIDE EXAMPLE
Adenosine is released from astrocytes (glial
cell type). Glial cells support neurons and
important for giving energy to neurons.

Adenosine is an inhibitory neurotransmitter

that forms as ATP breaks down. Adenosine increase leads to sleep and suppresses arousal. Also decrease
heart rate and blood vessel dilation as well as other organ effects.
Caffeine.
Occurs naturally in plants- pesticide that paralyses insects.
In humans, it blocks adenosine receptor (adenosine receptor antagonist). Increases alertness by reducing firing
activation (not a stimulant). Adenosine works by increased firing so caffeine works by decreasing caffeine.

Gases
Expand in every space.
Soluble-dissolve in fluid (depending on pressure and temp).
Neurons use two gases as NT: nitric oxide and carbon monoxide.
Nitric Oxide
Nitric Oxide causes vasodilation and muscle dilation. Used to treat pulmonary hypotension in premature babies.
Helps maintain blood pressure.
In the brain its made from arginine by the enzyme nitric oxide synthase which is found in 1-2% of neurons in
cortex. Exact function of nitric oxide is not clear- could be involved in learning and memory synaptic plasticity.
NO is not synthesised and stored in vesicle, its made in whole cell (even dendrites) it just diffuses out as it is
made and just enters the receiving cell- no receptor activation.
Its short lived and is degraded or reacted in a few seconds of being produced.
It can act on several nearby neurons, even those not connected by synapse. But NOs short half-life means that
its action will be restricted to a limited area without necessity for enzymatic breakdown or cellular reuptake

Lecture 4 (Serotonin and mood disorders)

SEROTONIN SYNTHESIS AND PURPOSE
It regulates the activity of neurons throughout the brain. Generally low serotonin means sad.
All serotonin is made and released from neurons in the raphe nucleus. Raphe nucleus is important in regulating
basic brain function.
Synthesis: precursor is tryptophan. Tryptophan is converted by hydroxylase to make serotonin. Serotonin is
broken down to monoamine oxidase (this is no longer functional).

Depression
Does not include depression due to general medical condition.
5 of the following symptoms must be present to be diagnosed with depression
1) Depressed mood every day
2) Decreased interest in activities
3) Weight loss or gain and change in appetite
4) Insomnia everyday
5) Fatigue every day
6) Worthlessness or excessive guilt
7) Lots of thought about death
8) Cant concentrate
These symptoms need to have a big impact on daily interactions with society and personal maintenance. These
symptoms cant be due to the direct physiological effects of a drug.
Depression from bereavement is still recognised as depression!
Depression from bereavement used to also not count as depression but now it does because grief rarely
produces the cognitive symptoms of depression (low self esteem, self loathing). There was a risk that people
were not diagnosed with depression (due to death) did actually have depression.
More women experience depression than men, and the first onset occurs in adolescence. If you have depression
the chances of your identical twin also having depression is only 80% so there is an environmental role in
depression as well as genetic contribution.

Depression and Serotonin

Brain imaging studies show a reduction in serotonin receptors in depressed patients.
Between depressed and severely depressed patients: the greatly depressed people had a greater reduction in
serotonin receptors.
There is a gene that controls serotonin transportation that plays an important role in depression. Tryptophan
depletion studies involve drinking a milkshake with no tryptophan (hence reduce serotonin synthesis). Results
show that it induces transient depressive system in recovered unmedicated depressed patients as well as
people who dont have depression. The hypotheses was that this milkshake will cause a return of depression.

Proposed Model of depression

An impairment in serotonin availability or production increases the vulnerability to developing depression.
Depression is more likely after stressful events.
Serotonin is important in regulating the hormones released in stress. Decreased serotonin means
decreased capability to cope- depression.

Solutions to lows serotonin

Serotonin Antidepressants
Bind to the serotonin receptors

Reuptake inhibitors (SSRI)

Decreases the rate of serotonin removal at the synapse so more serotonin receptors in the post synaptic
neurons are activated. These inhibitors are really slow acting and will reach brain 1hr after consumption.
Reasons why SSRI takes long to have an effect:

May shut off high stress response

High level of new brain cells that can change or strengthen important mood related circuits in the brain-
could protect brain from future damage associated with depression
Monoamine Oxidase Inhibitors

Blocks breakdown of serotonin

Lecture 5 (wk11) Dopamine and Desire

Dopamine Pathways

Substantial Nigra
Ventral tegmental area
Dopamine Synthesis

L-DOPA- drug that can create Dopamine.

Dopamine and Parkinson

Parkinsons is caused by death of dopamine
cells in the substantia nigra.
The disease starts off with motor tremors which progress to cognitive impairments and dementia. There is no
cure but drugs can reduce the symptoms and so can brain stimulation.
Treatment of the disease can cause impulsivity and hypersexuality.

Reward Prediction Error

Stimulus presentation must be random and unexpected.
If an unexpected reward occurs DA neurons become more active and release a burst of dopamine. Dopamine
neurons are always active, they just increase activity when a reward is given.
If a reward is repeatedly given after a stimulus then the reward become expected and no dopamine is released
with the reward but instead is released at the time of stimulus presentation-due to expectation of reward.
If the reward is expected but NOT given, then the DA neurons become supressed.
Reward (such as getting money) are mainly positive experiences that we associate with things. The thing (like
money) doesnt usually have inherent value though. If we UNEXPECTEDLY gain or lose this reward then our
feelings are more intense because its not anticipated.
Rewards can be real (food), symbolic (money) or virtual (points in a game, followers, likes)- Dopamine is involved
in all cases.
Cognitive Control and Reward.
Its not clear why attention and cognitive tasks are effortful (like studying) and why task engagement is aversive.
The feeling of cognitive effort seems particularly linked to working memory and cognitive control. Its proposed
that DA codes both goal reward and effort costs and that the aversive feeling of cognitive effort reflects
opportunity cost. For example, studying requires high cognitive effort and requires you to dissociate from your
surroundings (this is not pleasant). Opportunity costs are everything else rewarding you could be doing at the
time. Cognitive tasks with low success are particularly unpleasant (it feels like a waste of time). The longer you
persist, the harder it feels and the more likely it is you disengage. At this point its more likely you will go for the
low cost option (guess the answer, take a break, not do the question).
When doing a pleasant activity, metabolic activity in the brain is just as high.
Task persistence is justifiable only while progress outspaces accruing costs.
Pokies/ Gambling
Unpredictability adds to the boost of DA (better than expected)
If you predictably lost 70% of your money every bet it would not be addictive.
If you have unexpected large wins (but still losing an average of 70%, the wins are coded as extremely positive.
Drug Addiction
A chronic relapsing disorder that consists of compulsive pattern of drug seeking and drug taking behaviour. This
addictive behaviour must take place at the expense of other activities and persist despite adverse consequences.
DA drugs- Cocaine
Blocks the reuptake of dopamine leads to increased dopamine signalling.

DA Drugs- Amphetamine
Both ice and speed reverses the uptake transporter of dopamine and actively expels DA and NA out of the
neuron which also prevents DA uptake.
Addictive drugs hijack the reward response. When you expect a reward, NO additional dopamine gets released.
Addictive drugs cause additional dopamine to always be released in response to a reward. So every time you do
a line of cocaine, the actual drug itself causes the release of dopamine (your brain doesnt release it because it
was expecting the reward, and decreases dopamine release.)
The more DA released the greater the high produced by drugs.
The faster the DA release the more addictive it will be.

Addiction and free will

Drugs initiate desire in addicted people which leads to cravings. Cognitive control (top-down) is reduced by
impaired function of the prefrontal cortex caused by excessive dopamine. Imaging studies show PFC
abnormalities. A failure of top-down control contributes to a loss of control over the urge to take drugs.
There is a strong link to DA function and addiction but some drugs so seem to cause addiction with less
involvement of DA. The DA system might be more important in behaviour and cognitive control instead of the
pleasant feeling.

Addiction beyond drugs

Lecture 6 (wk11) Noradrenaline

Noradrenaline is broken down in the adrenal
gland to make adrenaline. Locus Coeruleus (tiny area
with few neurons) controls arousal responses. NA
important in SNA, arousal, anxiety,
exploitation/exploration, reward/addiction, memory
consolidation.
Locus Ceruleus
Highest rates of neuron firing here after a transient noxious or extremely positive stimulus/event. Silent during
REM (little NA released)
High LC/NA activity
4Fs: Fight, flight, freeze, Fornicate
State of hyperarousal adapted for evolutionarily important situations where individual or sexual fitness is
involved.
High levels of LC/NA activity can lead to stress, anxiety or panic attacks.
Stress is often experienced when LC/NA activity is sustained due to environmental factors.
Anxiety is caused by excessive, uncontrolled and often irrational worry, to be diagnosed, the symptoms
must persist for more than 6 months.
Panic Attacks are brief intense episodes believed to reflect spikes of LC/NA activity triggered by:
apparently random events, internal thoughts, learned associations (PTSD)
Stress and Arousal
Stress response involves intricate interactions between the brain and body. Optimal performance requires a
balance. Function is impaired with too little or too much stress.
NA Function beyond arousal and 4Fs
At moderate levels of LC activity, NA acts to consolidate decisions. Adaptive behaviour represents a tradeoff
between exploiting known sources of reward and exploring the environment for alternative sources of rewards
(food, water, sex etc.)
For any moment, an animal can do anything. Complete indecision, inaction or constantly changing decisions are
bad but inflexible, repetitive behaviour is also bad. There needs to be a Balance.

Once a decision has been made (Behaviour A or Behaviour B ) Then NA is released to complete this selection
process in favour of the more needed behaviour. This boosts the networks that enhances the winning decision.
Neurons in the LC fire when a behavioural response is selected and executed, After they fire the neurons are
inhibited allowing the selected behaviour to be exploited. The more important the behaviour is the more NA is
released.
LC neurons and during low arousal
 In the

absence of recent

decisions or
arousing
events the
baseline
levels of firing
increase
and more NA is released throughout the brain. Increased NA promotes a switch to a new decision, promoting
exploration of alternative behaviours.

LC-NA & Performance

Low levels of LC activity and NA release= tired, vague and poor performance
High levels of LC activity and NA release= restless, stressed and poor performance.
Optimal Performance requires moderate activity with large intermittent bursts.
Ambiguity and Perceptual Competition
Sensory experiences are mostly ambiguous. Brain does a lot of reconstructing since the image projected to
retina is 2D. In perception, a balance is also required- its not helpful to have a fixed perception or vague
perception.
NA and the pupil
In the dark dilation reflects NA levels. The pupil constriction induced by increased light is caused by ACh-
atropine and belladonna causes dilation by blocking ACh muscarinic receptors. Pupil diameter is constantly
changing even in constant light. When we make a cognitive decision, our pupils will dilate slightly

Lecture 7 ACh Attention, Memory and Alzheimers Disease

ACh is a major NT of the CNS and the PNS. ACh is made from choline (derived from breakdown of lipids) and
acetate (or acetic acids).
ACh Receptors
There are two types: Ionotropic and metabotropic receptor.
Ionotropic receptors are stimulated by nicotine (hence nicotinic receptor). In the PNS, muscle fibres must be able
to contract rapidly so they contain rapid ionotropic nicotinic receptors.
The metabotropic receptor is stimulated by muscarine (this name because its named after the mushroom
amanita muscaria)
In the CNS we have both nicotinic and muscarinic, but muscarinic receptors are more dominant.

ACh in the peripheral NS

In the peripheral nervous system, ACh is the primary NT that acts on nicotinic receptors at the neuromuscular
junction. ACh transmits signal from the motor neuron and causes muscle to contract.
ACH drugs in the Periphery
Botulinum toxin is made by bacteria that grows in canned food (most lethal toxic known). It prevents the release
of ACh. The toxin can be used in a dilute solution and injected into the muscle. This creates muscle weakening
that lasts 3-6 months. Botox can be used cosmetically to relax facial muscle. Botox can be used to treat
spasticity (muscle tightening) in cerebral palsy (non-specific brain damage).
Venom of black widow can stimulate the release of ACh.
The action of Botulinum Toxin and Black Widow Venom shows that too much or too little can have catastrophic
consequences.

Acetylcholine in the brain.

Pons (sleep regulation)
Basal Forebrain (memory and attention)
Medial Septum (modulates shippocampus function

Alzeimers Disease
Reduction in ACH innervation is responsible for the cognitive decline. ACH neurons in the basal forebrain are the
first to be affected in the disease. ACh receptors and acetyltransferase (involved in ACh production) are found to
be affected in Alzeheimers.
ACh in memory
Drugs blocking ACH muscarinic receptor cause memory loss for period under the drug effects (block
consolidation)
Effect of ACh on memory is very complex- separates the encoding and retrieval of memories. ACh reduces
interference between memories into clear segments which can be easily retrieved later.
ACh attention experiment
Does ACh improve attention function in healthy people?
1) Involuntary Attention- also referred to as bottom up/pop-out/exogenous attention. Outside our control.
Example: flashing light in an empty dark room.
2) Voluntary Attention-also referred to as sustained/top-down/goal directed/endogenous
Drug: 5mg donepezil (used to treat dementia)
It is a cholinesterase inhibitor, so there is a build up of ACh in the synapse as it us not broken down.
The participants were given a placebo (tablet- they didnt know if it was the active drug). All participants did both
conditions. The order at which the placebo drug and normal drug was taken was random (50% did placebo then
drug, the other 50% did drug then placebo). The experiment was double blind (neither participant nor
experimenter knew what the drug was).
The task was to look at Gabor patches. These dont have edges and you can vary the contrast- good for
measuring small changes in contrast detection. Instead of asking them did you see the patch you ask a question
that forces them to make a choice (was the central patch oriented to the right or left?) This is because people say
they havent seen the patch but then performance on other tasks indicate that they have seen it.

First they were asked to focus on the central dot, then a cue is given. The cue (unavoidable) forces them to pay
attention to that area (black box in this case).
Voluntary Attention (longer SOA)- in this task, you should have moved your attention towards the opposite box.
This condition tests whether participants are paying attention.
Results: People were slower when the target was in the opposite location instead of the cued location. ACh drug
improved performance when the target was opposite of cue.
ACh and attention-mechanism
Gabor task can activate a small selection of neurons. If we can understand how these neurons can behave- can
explain other neural processes.

Firing of neuron is highest when the stimulus is vertical and lowest when it is horizontal.
ACh boosts the signal that is corresponding with the target, the neuron that is responding to the target is
enhanced. Attention leads to improved discrimination signal to noise making it easier to identify/select target.
This is what ACh helps with.

Neuroethics-cognitive enhancement.
Medicines treat disease, cognitive enhancers improve healthy function. Drug companies are spending millions to
design drugs that treat dementia/Alzheimers.
Drugs that improve memory and attention in Alzeheimers work because they improve/facilitate the normal
mechanisms underlying memory and attention. These drugs can also improve memory and attention in healthy
people

Lecture 8: Glutamate and GABA

Glutamate and GABA
 First to evolve and found in simple organisms
Most common NT in CNS
True NT
Glutamate is the main excitatory NT in the brain (increases the likelihood
that the next neuron will fire
Over half all brain synapses release glutamate

Glutamate Synthesis

Glutamic acid
AA that acts as a NT in its original from but it doesnt pass the blood brain
barrier (needs to be made by the brain)
Found in most long projection neurons in the cortex

Excitatory NT
Point to point communication
Glutamate NMDA receptor
Many types of glutamate receptors
NDMA has 6 different binding sites- many different molecules can bind to it and
slightly alter its conformation. It only works if theres also a glycine molecule and
the Magnesium ion cant be bound on the inside.
NDMA receptors
Alcohol is an antagonist
Decrease in glutamate leads to sedative effects and decreases brain ability to
send info. Memory inhibition
NDMA Receptors: PCP and Ketamine
PCP=angel dust and Ketamine= used as horse tranquiliser
Both are NDMA antagonist and both caused dissociative hallucinations (people
feel disconnected- not really visual hallucinations). There is a risk of suicidal
behaviour.
Glutamate: NDMA Receptors
Alcohol, PCP and Ketamine all act prinicipallu as NDMA antagonists but have
different effects on the mind.
The exact mechanisms of action are not completely known but because all
3 drugs effect some additional receptors it illustrates how complex
drug/brain effects can be.
NMDA Receptors provide a great illustration of the complexities of
psychopharmacology

Psychosis
Psychosis is not a diagnosis its a symptom cluster.
 Schizophrenia ~1% population > psychosis ~ 3%

delusions

hallucinations

depression

anxiety

suicidal thoughts or actions

difficulty functioning

disorganized speechswitching topics erratically

There may be a link between glutamate and psychosis- more likely to involve
other neurotransmitters like DA.
Symptoms suggest that there is a widespread disruption and lack of coherent
intergration of sensory information.
No major structural differences in psychosis- so illustrates the importance of
chemical balance in healthy perception and cognition

GABA
Main inhibitory NT- decreases likelihood of post synaptic neuron firing. Prevents
seizures occurring due to consistent firing
Most short local neurons are inhibitory and form a web around excitatory neurons
Inhibitory networks reduce the likelihood neurons fire for their non- preferred
stimulus.
GABA synthesis
Made from glutamic acid. Glutamate is converted into GABA and GBA can be
converted back to glutamate.
Two types of GABA receptors
GABA (A) receptors-ion channels. GABA (B) receptors are G protein coupled
GABA and Seizure disorders
Epilepsy can caused by abnormality of GABA neurons or receptors
Seizure disorders can be generalised ( widespread, involve most of the brain) or
partial (restricted to a small part of the brain-often due to scarring of the brain
caused by injury or developmental abnormality.
Simple: can cause changes in consciousness (altered sensory,
autonomic responses etc) but not loss of consciousness
Complex: lead to loss of consciousness
Febrile Seizures (kids)
Seizures associated with high fevers.
There is a gene that is linked with epilepsy, people with the gene generally have
their first epileptic seizure at 2-3 yrs when they get a fever. Vaccination might
trigger fever and seizure but without vaccinations seizures still continue.