Neuropharmacology Flashcards
1
Q
Dementia
A
-Cognitive or behavioural symptoms that interfere with function
-patient suffer from decline in fuction
-not due to delirium or psychiatric illness
-associated with cognitive impairment in 2+ domains
• Umbrella term for a symptom of underlying disease; many underlying aetiologies
2
Q
Epidemiology of demtia
A
- Typically a condition of older age (65+)
- Aging population means increasing prevalence
- Improved understanding, healthcare, education means decreasing incidence
- Currently about 500,000 Australians living with dementia
- Will be >1 million by 2028 without a medical breakthrough
- Second leading cause of death in Australia
- Cost $15 billion in 2018, will be $19 billion by 2025 and $37 billion by 2056
3
Q
Alzheimer’s disease
A
- Most common cause of dementia
- Accounts for about 70% of cases of dementia
- About 30% of the population aged over 85 have AD pathology
4
Q
Pathophysiology of AD
A
- Proteinopathy ( issue with protein) :Amyloid-mediated tauopathy
- Aetiology
- Sporadic, late onset (≥98%): failure of clearance of Aβ
- Carriage of APOE e4 only recognised genetic risk factor
- Likely other polygenic risk factors, under investigation
- Familial (extraordinarily rare): overproduction of Aβ
- Caused by a known mutation in APP, presenilin-1, or presenilin-2 genes
- Autosomal dominant, penetrance approaching 100%
- Environmental factors moderate symptom onset, progression
- 40% of cases of dementia potentially modifiable
5
Q
amyloid Beta
A
- Chain of 40-42 amino acid peptides
- Cleaved from amyloid precurserprotein (APP) by β-and γ-secretase enzymes
- Aβ40-42 oligomers aggregate to form insoluble plaques on the surface of neurons
- Triggers a cascade of events that ultimately cause neurodegeneration
6
Q
Aβ formation
A
- Two step process dependent on the action of two cleaving enzymes on APP (amyloid precusor protein)
- If APP is cleaved by β-secretase and then γ secretase, product is Aβ
- Oligomers are then released into the extracellular space
- Aβ oligomers are chemically “sticky”. They aggregate to form plaques on the cell surface
7
Q
Aβ detection in vivo – amyloid detection test
A
- a PET scan with marker that bind to the Aβ
• CSF analysis
• Presumed inverse relationship between CSF Aβ and CNS Aβ
→ Reduced CSF Aβ a positive biomarker result for AD
• Blood test
• First published in 2018 (Nakamura, 2018)
• Preliminary results show the test can predict amyloid positivity as measured by PET with >80% specificity and sensitivity
• Replication and validation ongoing
• Cardiovascular and central nervous systems are functionally distinct
• Not as simple as measuring absolute levels of Aβ in the blood
• Protein expression affected by very many variables
8
Q
Tau
A
- A protein involved in stablising microtubules of axons
- 6 different varieties (“isoforms”)
- Tau can be phosphorylated at a number of sites on the protein, which decreases its ability to bind microtubules
- Pathological tau becomes hyperphosphorylated, and aggregates into neurofibrillary tangles
- Implicated in many different neurodegenerative diseases (“tauopathies”)
9
Q
Neurofibrillary tangles - formation
A
- normal Tau stabilizes microtubules
- Tau hyperphosphorylation causes microtuble depolymerisation
- Tau ologomers aggregation lead to formation of paired helical filament which lead to neural death and release of tau ologmer into extracellular environment
10
Q
Neurofobrillary tangles – disease staging
A
- NFT Stages I-II (entorhinal stages) problem with memory fuction
- NFT stages III-IV ( Limbic stages) futher cognition impairment
- NFT Stages V-VI (Neocortical stage) demented
11
Q
Tau detection in vivo
A
- Tau PET
- Tracer has to cross cell membrane, in addition to blood-brain barrier
- Tau tracer has to bind to the right conformation (isoform) of tau
- CSF analysis
- Quantification of levels of total and p-tau (specific to AD)
- Blood tests under development to measure tau in blood plasma
- Validation in real world clinical populations to commence in selected clinical settings in Australia and overseas this year
12
Q
Neuronal loss in dementia
A
- Presence of Aβ and tau tangles causes activation of microglia (an immune response → inflammation) and, ultimately, apoptosis
- Precise interaction between Aβand tau unknown
- Cell death follows the pattern of tau deposition; begins in mesial temporal lobes
13
Q
Pathological sequence of AD
A
• Aβ and tau → synaptic dysfunction → cell loss → cognitive and functional decline (dementia)
14
Q
Temporal sequence of Aβ accumulation in AD
A
- It takes 12 years to go from no amyloid to “at risk” levels
- It takes 19 years to go from “at risk” to levels seen in AD
- It takes over 30 years to go from no amyloid to levels seen in AD
- …we have a 19 year window to intervene in the AD process in the hope of slowing, stopping, or reversing the pathology
15
Q
Clinical syndrome of AD
A
- Exists on a spectrum
- Long preclinical phase
- Prodromal/mildly symptomatic (~3 years)
- Frankly demented (~5 years)
- Coincides with progression of pathology throughout the cortex
- Earlier stages: high level association cortex implicated, relative sparing of primary sensory and motor areas
- Later stages: disease impacts lower level sensory and motor cortex
- Leads to physical decline and frailty
- Terminal stages: patient bedridden, at risk of respiratory complications
16
Q
Diagnostic criteria for probable
Alzheimer’s disease
A
- Person is demented
- Insidious symptom onset (over months to years)
- Clear history of cognitive decline (from informant or observation)
- Initial and predominant deficits in:
- Memory (amnestic presentation, typical onset)
- Language, visuospatial, or executive function (non-amnestic presentation, atypical onset)
- No other likely explanation (e.g. vascular disease, Lewy body disease, other neurological, psychiatric or systemic disease that might cause cognitive impairment)
17
Q
AD-related cognitive changes
A
Memory impairment (typical onset)
• Insidious onset, recent memory difficulties
• A failure to learn and remember new information
• cf. errors of capture, or problems with retrieval
Patient’s subjective report of limited utility Navigation/orientation difficulties
• Getting lost
• Unable to keep track of time/place
Language decline
• Anomia (“without name”)
• Circumlocution
18
Q
Clinical diagnosis of AD in practice
A
•decied base on Decline in cognition (usually) or behaviour causing functional impairment
• Estimate patient’s baseline
• Assess performance on multiple tests measuring all the key domains of cognition
• Compare performances to established normative data sets to determine impairment vs normal ageing
-if cognition has declined but the person is not demented it could be Mild Cognitive Impairment or Prodromal AD
19
Q
Implications – why does timely clinical
diagnosis matter
A
- Dementia is progressive → permits future planning
- One day, that will include advanced decision making such as threshold for assisted suicide
- Considerations around fitness to drive, Mandatory reporting requirements to VicRoads
- Assessment of decision-making capacity Protection of the vulnerable/preservation of autonomy
- Access to possible treatments No point treating people after 20 years of damage has accumulated
- Relief of having a label/explanation
20
Q
Prevention of AD
A
- Modifiable risk factors
- Probably modify rate of disease progression, symptom onset rather than the pathology per se
- Mechanisms sometimes unclear (e.g. deafness)
- The question of education and cognitive reserve
- What about brain training?
21
Q
different method for Treatments for AD
A
Symptomatic relief
• Donepezil, rivastigmine, galantamine and memantine → not disease modifying
Anti-amyloid
• Antibodies (facilitate clearance) → promising; FDA approved Aducanumab in 2021
• BACE inhibitors/moderators (inhibit production) → liver toxicity
Anti-tau
• Antibodies → too early to tell
Downstream
• Promote BDNF/synaptic generation
• Remove iron, reduce oxidative stress
• Anti inflammatories, reduce immuno-mediated damage
22
Q
Treatment for AD
A
The solution will be in rational combination therapy
-Early inhibition of production (avoids toxic overdosing) using β- and/or γ- secretase inhibitors/moderators
- Facilitation of clearance in those at risk :Genetic profiles, lifestyle factors
- Adjunct therapy to promote brain health
• Reduce inflammation
• Foster synaptic activity, neurogeneration, plasticity
• Waiting for symptoms is too late
• We will succeed
• In sporadic, late onset AD the clearance failure rate compared to non-AD is only 5%
• The discrete amount of Aβ in an AD brain is only 5mg
23
Q
Signalling in the Brain: Neuron
A
-At rest the neuron has a negative charge, an action potential is triggered when the charge becomes sufficiently positive due to signal arriving at the dendrite (can be positive or negative)
-Signal received by dendrites & travels down the axon where the signal is sent to dendrites on the next neuron
Neuron fires (action potential) – All or none….
- single units of activity
24
Q
Structure from brain to synapse
A
Brain & spinal cord have 100 billion neuron
-each nerone can fomr more than on synapse
~ 0.15 quadrillion synapses in the cortex
25
Cell membrane
- Neurons have a cell “membrane”that acts like a wall preventing things from entering or leaving the neuron.
- The cell wall as two layers with the fatty inside of each layer sticking together like a sandwich.
- Because of the fatty inside layer, fluids and other chemicals like neurotransmitters are not able to pass through.
26
Receptors
Receptors located on the outside of the cell membrane allow the released neurotransmitters to influence the post-synaptic neuron.
Two types of receptors:
- Ion Channels
- G-Protein coupled
27
Receptor specificity
Receptors are very selective (lock and key).
Each receptor can generally only be activated by one neurotransmitter (or a drug that is designed to mimic that neurotransmitter).
They also have a very specific function/action. When a neurotransmitter binds to the receptor this will trigger the same event every time (either opening a channel or triggering a second messenger event).
28
Ion Channels
Ion channels act like a “gate” for ions.
When a neurotransmitter binds to the receptor outside the neuron, this causes the gate to open and ions (positively and negatively charged molecules), can flow through.
Channels are normally “selective”and only allow one or a few types of ions to pass through when they are open (e.g. a calcium ion channel).
29
G protein-coupled receptor
G-Protein receptors work through second messengers.
When the neurotransmitter binds to the receptor it activates a “second messenger system”that can either open a channel or cause other things to change within the cell (e.g. DNA being transcribed and new proteins being made).
30
Neurotransmitter
A chemical substance released from a neuron at an anatomically specialised junction (synapse), which diffuses across a narrow cleft to affect one or sometimes two postsynaptic neurons, a muscle cell, or another effector cell.
31
Neuromodulation:
A chemical substance released from a neuron in the central nervous system, or in the periphery, that affects groups of neurons, or effector cells that have the appropriate receptors. It may not be released at synaptic sites, it often acts through second messengers and can produce long-lasting effects.
32
Neurotransmitter Vs Neuromodulators
§Neurotransmission: Either EXCITATORY or INHIBITORY and serves rapid (millisecond), precise, point to point communication.
§Neuromodulation: Describes slower (milliseconds to seconds) processes that alter the subsequent responsiveness of neurons.
33
Neuromodulation at presynaptic and post synaptic
§Presynaptic: Alters neurotransmitter release
§Postsynaptic: Alters neurotransmitter action (e.g., alters excitability/ firing pattern)
§Neuromodulation may cause changes in neural function or structure (i.e. sustained neuromodulator activity can drive changes in the brain related to synaptic plasticity).
34
Neurtransmitters/Neuromodulators (CNS)
Originate in small clusters of neurons (nuclei) deep within the brain stem. But are released throughout the CNS via long neuron
35
Neurotransmitters: Slow & Fast
§Synthesis and transport to the synapse is relatively slow.
BUT
§The neurotransmitter action is extremely fast because it sits ready for release.
36
Psychopharmacology
The study of drug induced changes in mood sensation, thinking & behavior.
37
Action of drug at the receptor
§Drugs act by “mimicking” natural neurotransmitters or
neuromodulators.
§Can act as AGONISTS activating the receptor like the
natural compound.
§Or can act as an ANTAGONIST blocking the receptor
and preventing the natural compound from activating it.
38
Cycle of Neurotransmitters
```
1 Synthesis
2 Release from synaptic vesicles
3 Binds to receptors
4 +/- influence on post synaptic neuron
5 Broken down by enzymes
6 reuptake of transmitter
7 formation & storage in synaptic vesicles
```
39
Drug Action on cycle of Neurotransmitters
Drugs can effect all stages
40
Synthesis interruption
-drug can affect different stage in the synthesis of neurotransmitter
Synthesis interruption
Neurotransmitter function can be altered by increasing or decreasing synthesis of the neurotransmitter
41
Non-traditional “neurotransmitters”`
DO NOT satisfy ALL criteria for a Neurotransmitter
§Present in presynaptic terminals
§Released from presynaptic terminals after neuron fires
§Existence of receptors on postsynaptic neurons
42
Hormones
§Signaling molecules produced by glands and
transported through the blood to regulate physiology
(muscles, neurons etc) and behaviour.
43
Psychology vs Pharmacology
§Pharmacology can effect psychology
Natural neurotransmitters and artificial drugs can clearly effect mood, cognition & behaviour
§Psychology can also effect pharmacology
Emotional or stressful events, thoughts and behaviour effect us BECAUSE they influence our neurotransmitters.
§Cognitive therapy and pharmacology acts on
the same brain!!
44
Glutamate & GABA
§Glutamate & GABA both believed to be the first to evolve and are found in very simple organisms
§Glutamate & GABA are the most common neurotransmitters in the CNS
§Glutamate & GABA both act as a “true” neurotransmitter – directly affecting the likelihood of the post-synaptic neuron firing
45
Glutamate
§Glutamate is the MAIN excitatory neurotransmitter in the brain (increasing likelihood of the post-synaptic neuron firing)
§The neurotransmitter released by ALL excitatory neurons.
§Estimated that over half of all brain synapses release Glutamate
46
Glutamate: Synthesis
§Glutamate = Glutamic Acid
§Glutamate is an amino acid that acts as a neurotransmitter in its “original” form but this amino acid does not pass the blood brain barrier so it still needs to be synthesized in the brain
§synthesized from glutamine which is released by cells neighboring the neurons
47
Neurotransmitters: Excitatory
§Found in most of the long projection neurons throughout the cortex.
§Excitatory connections are “point-to-point”.
§Many region-specific functions (e.g. connections along the visual pathways)
48
Glutamate: Receptors
```
§4 major types
§3 are ion channels (ionotropic)
- NMDA receptor
- AMPA receptor
- Kainate receptor
§1 is G-Protein-coupled (metabotropic)
- the metabotropic glutamate receptor
```
49
Glutamate: NMDA Receptors
It has at least 6 different binding sites so has lots of complex functions
§For example it only works if
1) there is also a glycine molecule (another amino acid) attached
2) if magnesium ion is NOT bound to inside
§The other binding cites modulate receptor function
50
NMDA Receptors: Alcohol
§Alcohol is an NMDA antagonist
§Reduction in glutamate is believed to contribute both to the general sedative effects & memory effects of alcohol
§Alcohol is also GABA agonist which further leads to brain inhibition.
51
NMDA Receptors: PCP & Ketamine
§Phencyclidine (PCP) = “Angel dust”
§Ketamine =“Special K”, Horse tranquilizer
§Both are NMDA antagonist
§Both cause dissociative hallucinations (people feel disconnected rather than perceiving visions etc)
§Risk of suicidal behavior (ketamine itself is remarkably safe on the body)
52
NMDA Receptors and drugs
§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
53
Psychosis
§Psychosis = Symptom Cluster not a Diagnosis
§Schizophrenia ~1% population > psychosis ~ 3%
Ødelusions
Øhallucinations
Ødepression
Øanxiety
Øsuicidal thoughts or actions
Ødifficulty functioning
Ødisorganized speech—switching topics erratically
54
Glutamate & Psychosis
§Some have suggested a link between Glutamate & Psychosis, but this is controversial and is likely to involve other neurotransmitters such as DA.
§Regardless of exact neurotransmitter involvement, the symptoms suggest widespread disruption & lack of coherent integration of sensory information
§No MAJOR structural differences in psychosis – so illustrates the importance of chemical balance in healthy perception & cognition
55
NMDA role
§NMDA receptor activity is critical for learning, memory, perception and synaptic plasticity in general.
§Large genetic studies identify NMDA receptor genes as likely being relevant in schizophrenia, but also relevant to general function and IQ.
§These genetic studies point to a large number of genes that all may each contribute to a small amount of risk for psychosis.
56
GABA (Overview)
§GABA (gamma-amino butyric-acid) is the primary inhibitory neurotransmitter - decreasing likelihood of the post-synaptic neuron firing
§Without inhibitory synapses the brain would be unstable with neurons firing uncontrollably >> Each excitatory neuron exciting the next neuron >> Causing SEIZURE
§Most short local neurons are inhibitory, so they form a dense web around and between the excitatory neurons.
57
GABA effect on neuron preference
§In the healthy brain GABA helps the delicate coordination of neurons to signal very specific information
§Neurons are “selective” but not perfect. Inhibitory networks reduce the likelihood neurons fire for their non-preferred stimulus
58
GABA : Synthesis
§GABA is produced from glutamic acid
| §Glutamate is converted into GABA & GABA can be converted back to Glutamate
59
GABA receptors
2 type
GABAa is ion channel
GABAb is G protein
60
GABA & Seizure Disorders
§Are relatively common with 400,000 in Australia
§Seizure = sudden excessive activity of neurons (Can cause muscle convulsion but not always)
§Epilepsy is a neurological disorder characterized by seizures
§Epilepsy is believed to be caused by abnormality of the GABA neurons and/or in the GABA receptors.
61
Seizure types
§Generalized Seizures: widespread & involve most of the brain.
§Partial seizures: definite focus and restricted to small part of the brain (often a scarred region 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
62
Febrile Seizures (kids)
§3% of children under the age of 5 years have a seizure associated with high fevers. Vaccinations have been linked to epilepsy...but!!.
§Sam Berkovic & Ingrid Scheffer from Melbourne Uni discovered the first genes linked to epilepsy. Then showed that those with the gene generally have first epileptic fit at ~2-3 years of age when they get a fever.
§Vaccination might trigger fever + seizure.. but without vaccinations seizures arrive within a few months anyway.
63
Seizures & Genetics
§The majority of genes identified so far control ion channels (which control the level of positive and negative charge in the neuron that drive the action potential)
§But most are not genetic and instead are due to abnormal brain tissue and require surgical treatments
64
Dopamine (DA) pathways
-Dopamine is mainly produced in Substantial Nigra (SN) Motor Control and VTA (controll motivation and emotional respond)
65
Dopamine Synthesis
-made from tyrosine (an amino acid found in foods)
=tyrosine is converted into DOPA and the dopamine
-an artificial drug L-DOPA can be used by the body as dopa for dopamine synthesis
66
Dopamine & Parkinson’s
§Caused by death of dopamine cells in the Substantia Nigra
§Disease initially characterized by motor tremor. Later symptoms include cognitive impairments and dementia.
Symptoms often include reduced “executive function”.
§There is currently NO CURE of the disease, but symptoms can be reduced through drugs and deep brain stimulation.
§Sometimes treatment of the disease can cause impulsivity, hypersexuality, gambling, addictive like behaviours
67
Reward Prediction Error
- If an unexpected reward occurs DA neurons become more active and release a burst of DA
- If a reward is repeatedly given after a stimulus (such as a beep) then the reward will be “expected”& no DA will be released with the reward but will now be released at the time of the beep
- If a reward is “expected”but not provided, DA neurons will be suppressed
68
What can be a rewards
```
§Rewards can be
- real (e.g. food or sex)
- symbolic (e.g. money)
- virtual (e.g. points in a game)
§DA is involved in all cases.
```
69
Cognitive control and reward of task
§It is currently unclear why attention and cognitive tasks are “effortful” and why task engagement is aversive (our brains are also very active when we relax or watch TV).
§The feeling of cognitive effort seems particularly linked to working memory and “cognitive control”
§It is proposed that DA codes both goal reward and effort costs and that the aversive feeling of cognitive effort reflects ”opportunity cost”
§Task persistence is justifiable only while progress outpaces accruing costs.
70
Cognitive effort and reward
Cognitive tasks with low success are particularly unpleasant (it feels like a waist of time) and might bias someone towards disengaging and selecting the low-cost “guess” option
Incentives can help with motivation because they counterbalance opportunity cost.
71
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.
72
what is Drug Addiction
* A chronic relapsing disorder which consists of a compulsive pattern of drug-seeking and drug-taking behaviour
* takes place at the expense of other activities
* persists despite adverse consequences
73
DA Drugs - Cocaine
prevent the uptake of dopamine in the pre-synapase so more dopamine can bind to receptor of the post synaptic receptor
74
DA Drugs - Amphetamine
§Drugs = ice (most pure) and speed (less pure)
| §Reverses uptake transporter actively expelling DA and NA out of the neuron which also prevents DA uptake
75
Addictive drugs hijack reward response
- normal condition: When reward is expected NO additional dopamine is released
- ADDICTIVE DRUGS : Addictive dopamine drugs are ALWAYS coded by the brain as “Better than expected”
76
Animal “models” of addiction
- experiment on mice, two lever, on would give food the other give heroin/stimulation to brain region responsible for pleasure
- the mice alway choose pleasure till death
77
Addiction & Dopamine
§Addictive drugs produce increased dopamine signaling
§The more DA released the greater the high produced by drugs like cocaine and ice
§The faster the DA release the more addictive it will be
78
Addiction and free-will
1st problem
§Drugs initiate “wanting”and in addicted people, this leads to drug urges or cravings.
2st problem
§Cognitive (“top down”) control is reduced by impaired function of the prefrontal cortex (PFC) caused by excessive dopamine.
§Imaging studies show PFC abnormalities
Final Result – addictive behaviour
§Failures of “top down”control would contribute to loss of control over the urge to take drugs.
79
Addition of other substance
§While there is a strong link to DA function and addiction, some drugs do seem to cause addiction with relatively less involvement of DA.
Possibly depending on the opioid system
§DA system might be more important in the behaviour/habit and cognitive control aspects than the pleasant feeling
80
Addiction beyond drugs
§Cases of “addiction” exist for most things that are rewarding
- real (e.g. food or sex)
- symbolic (e.g. money/gambling)
- virtual (e.g. gaming)
§More individual differences in susceptibility compared to drug addiction.
81
Noradrenaline Synthesis
- is made from dopamine but only in noradrenaline neuron
82
Noradrenaline Breakdown
1 additional synthesis step in the adrenal gland results in the hormone adrenaline (drives effects in the body)
-Monoamine oxidase (MAO)BREAKDOWN ENZYME
83
Noradrenaline (NA) fuction
```
§Sympathetic nervous system (flight or fight)
§Arousal / Vigilance
§Anxiety
§Exploitation vs Exploration
§Reward / addiction
§memory consolidation
```
84
where is noradrenaline produced
Locus Coeruleus (LC): Very small area of the brain with very few neurons (~30,000).
85
Locus Ceruleus (LC) - Neuron Firing in different condition
§Silent during rapid eye movement (REM) sleep (very little NA released).
§Highest rates rapidly follow a transient noxious or extremely positive stimulus/event (lots of NA released).
86
High LC/NA activity = 4 F’s
Fight, Flight, Freeze or Fornicate
| §State of Hyperarousal adapted for evolutionarily important situations where “individual”or “sexual fitness”is involved.
87
High LC/NA activity = Stress & Anxiety
§Stress: often experienced when LC/NA Activity is sustained due to environmental Factors (social, emotional, physical etc).
§Anxiety: excessive, uncontrolled and often irrational “worry” (diagnosis requires symptoms for 6 months)
§Panic attacks: brief intense episodes believed to reflect spikes of LC/NA activity triggered by
- apparently random events
- internal thoughts
- learned associations (PTSD)
88
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 (inverted U).
89
NA Function beyond arousal & 4F’s
§At moderate levels of LC activity, Noradrenaline acts to consolidate decisions.
§Adaptive behaviour represents a tradeoff between exploiting known sources of reward and exploring the environment for alternative sources of reward (food,
water, sex etc).
-indecision is bad but inflexibility is also bad
90
NA & Behavioural Selection
Burst of NA release “tips the balance”in favor of the winner.
(Increases strength of activating & inhibiting signals)
91
LC neurons & Behavioural Selection
§Neurons in the Locus Coeruleus (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,”“salient,”“arousing”one of the alternatives the bigger the burst of LC neurons and more NA released.
92
LC neurons & during high arousal
LARGER burst of NA release “tips the balance”in favor of the winner with MORE STRENGTH
§The larger the response of neurons in the Locus Coeruleus (LC), the more NA released & and the longer the following period of inhibition.
§In highly arousing situations the chosen focus of attention/behaviour dominates more for longer .. “distracting”alternatives are inhibited.
93
LC neurons & 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 behaviors.
94
LC-NA & Performance
§Low levels of LC activity and NA release = tired, vague & poor performance.
§High levels of LC activity and NA release = restless, stressed & poor performance.
§Optimal performance requires moderate activity with large intermittent bursts.
95
NA & The Pupil
- In the dark dilation reflects NA levels. ( pupil expand when excited)
- This can be use for measurement
96
Measuring Pupil Diameter
- Pupil diameter recorded during stimulus presentation.
- subjects reported their perceptual switch with an immediate button press
- as the brain activity is noisy, pupil must be mesured several time
97
Pupil and other decision
Pupil responses should be seen with
1) motor decisions
§Instruction: “push a button when ever you feel like it during 10 seconds, if you push the button during the lucky 1 second you win money”
2) cognitive decisions?
§Instruction: “Select a number WHEN it is presented and remember it until the end of the trial. If you select the lucky number you win money”
98
Mind Reading with pupil exp
- german student play rsp with a computer
- Australian student try to beat the german student with pupil video and computer answer
- different condition: no eye, naive eye (no information given), inforom eye and reconstructed pupil
- inform and recon have the highest performance increase
99
Clinical uses of pupil dilations
it is possible to communicate with people that are minimally conscious or are suffering locked-in-syndrome using pupil dilation\
§Pupil dilation accompanies a switches during perceptual rivalry
§Pupil dilation can also be used as an index of cognitive decisions
100
Serotonin (Overview)
Serotonin = 5-Hydroxytryptamine (5-HT)
Acts as a neuromodulator influencing the activity of a variety of neurons throughout the brain.
Important in many functions like sleep, arousal, appetite, temperature, working memory, hallucinations and mood
101
Serotonin Pathways
All serotonin in the brain is synthesized and released from neurons originating in the Raphe Nucleus (Raphe = midline).
The 5-HT is synthesized in the cell body and then transported to the synapses where it is stored. When the neuron fires, the stored 5-HT is rapidly released from the synapse.
102
Serotonin (5-HT) – Receptor subtypes
Serotonin has different effects in different brain areas depending on the receptor subtypes. Drugs will often only activate one or a few receptor
subtypes, so will be more “selective” than the natural neurotransmitter.
103
Serotonin Synthesis
- made from the amino acid know as tryptophan which is found in food
- converted into serotonin by enzyme
- serotonine is break down by MAO
104
DSM–V diagnosis for Major Depression
A.At least 5 of the following symptoms have been present during the
same 2-week period; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
(1) depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood.
(2) markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others).
(3) significant weight loss when not dieting or weight gain (e.g., a
change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains.
(4) insomnia or hypersomnia nearly every day
(5) psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)
(6) fatigue or loss of energy nearly every day
(7) feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)
(8) diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others)
B. The symptoms cause clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
C. The symptoms are not due to the direct physiological effects of a substance (e.g. a drug of abuse, a medication) or a general medical condition (e.g. hypothyroidism).
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Depression vs Grief
§Grief-stricken patients frequently report symptoms that are also typical of major depression, such as sadness, tearfulness, insomnia, and decreased appetite.
but...
§Grief rarely produces the cognitive symptoms of depression, such as low self-esteem, feelings of worthlessness, self loathing or suicidal thoughts.
§It was argued that it is important not to miss people with clinical depression because the symptoms were associated with grief.
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Depression in family and society
§On Average 10-25% of women and 5-12% of men will
experience depression in their lifetime.
§1stonset often occurs in early adolescence (~15-18yrs)
§Estimated cost to Australia in terms of health care and lost productivity is approximately $15billion a year.
§Familial clustering: neighbor (16%), sibling 30%, identical twin >80%
§Both genes and environment are likely to play a role.
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Depression & Serotonin
Brain imaging studies show a reduction in some types of serotonin receptors in the brain of unmedicated depressed patients.
§A gene involved in the transportation of serotonin is linked to increased risk of developing depression.
§Tryptophan Depletion (TRD) Induces transient depressive symptoms in recovered unmedicated depressed patients (and in some people without depression).
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Depression & Serotonin Vulnerability
§There is variation in serotonin function across the population
§Impaired serotonin function may be a “risk factor” leading to people being “vulnerable” to developing depression.
§Depression is 5-6 x more likely after stressful events
§Stress leads to increased release of a range of hormones such as cortisol. Serotonin function is important in managing the feedback control of the brain’s stress response.
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Serotonin Antidepressants (SSRI’s)
-inhibit the uptake of serotonin in the presynaptic membrane, this allow for more serotonin to bind to the receptor
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SSRI Therapeutic effects
§SSRI’s are very slow acting and often takes weeks for any therapeutic effects to be achieved.
§If taken orally the drug reaches the brain after approximately 1 hour after consumption and should block serotonin reuptake immediately once in the brain.
§Therefore, improved mood CAN NOT result directly from increased serotonin around the synapse.
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Theories of Long Latency of Onset of SSRI
§Altered gene expression (information from genes is used to make new products – i.e. enzymes) leading to slow changes in the action of different processes within a neuron (neurotransmitter synthesis or storage), or even change the structure of the neuron (synaptic remodeling).
§Shuts off a pathologically elevated stress response underlying depressive symptoms, allowing for important neural adaptations.
§Increased levels of neurogenesis (birth of new brain cells) change or strengthen important mood related circuits in the brain.
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SSRI’s Mood & Personality
§SSRI’s alter mood and personality.
§In clinical populations: reduces symptoms of Depression
§In healthy people: increases empathy and prosocial behaviour
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effect of prozac on people
- Improved mood
- “Better than well”
- “feeling like myself for the first time”
- Increased social likeability
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Monoamine Oxidase Inhibitors (MAOIs)
§Blocks the breakdown of Serotonin.
§Powerful antidepressant drug.
§Can lead to lethal levels of serotonin and other neurotransmitters if ingested orally after people eat foods with too much or Tryptophan or Tyramine (amino acid needed for Noradrenaline and Dopamine synthesis) resulting in “cheese syndrome”.
§Now used as a last resort under strict control of diet and other medications.
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Peptides - Structure, Synthesis” & Release
Peptides consist of 2 or more amino acids
In the brain most peptides are NOT synthesized from smaller compounds but are the product of larger compounds (poly-peptides) being broken down into peptides within the neuron before release at the terminal button.
Most peptides serve as modulators, however many peptides known to be hormones also act as neurotransmitters and are often co-release with other neurotransmitters.
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Peptides - Opioids
Best known family of peptide neurotransmitters are the endogenous opioids. In the brain the highest density of opiate receptors are in areas involved in pain.
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Peptides - Opiate Drugs
Opiate drugs are most known for their analgesic (pain relief) and euphoric properties.
Heroin is highly addictive - not particularly neurotoxic – but can cause death by respiratory failure.
Buprenorphine is a partial agonist at the receptors used as a treatment for heroin dependence.
Naloxone is a full antagonist and can be used to rapidly block the effect of heroin and prevent overdose.
Methadone is also an agonist (like Heroin) and is used in treatment of dependence because it has a much slower time course than Heroin.
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Lipids – Structure & Synthesis
Naturally occurring molecules that include fats, waxes and many others ....
They are hydrophobic
Main biological function is energy storage, signaling and provide the structural components of the cell membranes
Synthesis pathways remain unclear for many lipids that serve as neurotransmitters/modulators
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Lipids - Endocannabinoids
In the brain the best known lipid neurotransmitters are the endocannabinoids (“endogenous cannabis-like substances”).
2 known cannabinoid receptors CB1& CB2:
-CB1 is found in the brain and is believed to be responsible for the main psychological effects (CB2 is found in peripheral tissue).
-CB1receptor activation >> shortens the duration of action potentials in the presynaptic neuron >> decreasing amount of neurotransmitter released
By regulating the activity of those neurons and release of neuromodulators these receptors act to modulate the modulators!!!
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Lipids – Cannabis/Marijuana
THC (tetrahydrocannabinol) is the active compound in marijuana.
The plant is dried and consumed by inhalation
Effects range from changes in appetite, time perception, arousal (relaxation/anxiety) .. and have also been linked to states of apathy and “underachievement”
Therapeutically used to reduce nausea, relieves asthma attacks, decreases pressure within the eyes in glaucoma.
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Medicinal Cannabis
In 2016 the Access to Medicinal Cannabis Act was passed in Victoria
From 2017 children with severe intractable Epilepsy were the first group to access cannabis as part of this scheme.
Currently in Victoria, any medical practitioner can prescribe a medicinal cannabis product for their patient, if they believe it is clinically appropriate to do so.
Medical practitioners do not need to gain accreditation, nor be specialists in a particular field.
Data is still limited but medicinal Cannabis has been considered as a treatment for conditions including: Epilepsy, Pain and Multiple Sclerosis
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Nucleosides - Structure & synthesis
Nucleoside are a subunit of nucleic acids, the heredity-controlling components of all living cells – such as DNA & RNA
Nucleosides are usually obtained by chemical/enzymatic breakdown of nucleic acids.
Often “co-transmitters” that serve to modulate the release of other transmitters.. Again modulating the modulators
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Nucleosides - Adenosine
One example of a nucleoside is Adenosine.Is a nucleoside that forms from the breakdown of adenosine triphosphate (ATP). ATP is the primary energy source in cells for transport systems and many enzymes.
When you are awake adenosine levels gradually rise and in normal conditions it promotes sleep & suppresses arousal.
At synapses where adenosine is the primary neurotransmitter, a high postsynaptic firing rate leads to sleepiness.
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Nucleosides - Caffeine
Occurs naturally in plants:
For plants, caffeine acts as a natural pesticide that paralyzes and kill insects that attempt to feed on the plants.
-in human Acts as adenosine-receptor antagonist and blocks the natural action of adenosine
-because adenosine increasing firing rate in brain areas that promote sleepiness, caffeine increases alertness by reducing the firing/activation of these neurons.
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Gases - Overview
Gas = air-like fluid substance which expands freely to fill any space available, irrespective of its quantity.
Soluble gases: dissolve in fluid(dependent on pressure & temperature)
Recently discovered that neurons use two gasses as neurotransmitters: nitric oxide and carbon monoxide.
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Gases – Nitric Oxide
In the brain NO is produced from the amino acid Arginine in a subpopulation of 1-2% of neurons in cortex.
NO’s exact function in the brain is unclear
§It is involved in learning and memory through effects on synaptic plasticity
§It dilates blood vessels in regions of the brain that become metabolically active
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How is nitric oxide different from traditional neuron transmitter
§NO is not synthesized and stored in vesicles like other neurotransmitters.
§NO is produced throughout the cell including dendrites and defuses out of the cell as soon as it is produced.
§NO does not activate receptors but simply enters the neighboring cell
§NO is very short lived and is degraded or reacted within a few seconds of being produced
It can act on several nearby neurons, even on those not connected by a synapse. However, NO’s short half-life means that its action will be restricted to a limited area, without the necessity for enzymatic breakdown or cellular reuptake.
