All of it Flashcards
What is the central nervous system made up of?
Brain and spinal cord
What is the peripheral nervous system made up of?
Cranial nerves and spinal nerves
Role of the peripheral nervous system
To act as a connection between the wider body parts and organs, and the CNS
What are the two main components that the peripheral nervous system is broken down into?
Autonomic nervous system and somatic nervous system
WHich out of the CNS or PNS only controls voluntary actions?
CNS
Examples of things controlled by the autonomic nervous system?
Heart muscle, smooth muscle, glands
Examples of things controlled by the somatic nervous system?
Voluntary skeletal muscle
Two divisions of the autonomic nervous system?
Sympathetic and parasympathetic
Role of parasympathetic nervous system?
Calming down
Role of sympathetic nervous system?
Alerting and increasing BP etc
Main functions of the nervous system?
Sensory processing, motor coordination, cognitive functions
What does the neural foundations refer to?
The neurons and networks that form the basis of how movement is initiated and coordinated
What does motor systems refer to?
Parts of the brain involved in planning, controlling and securing voluntary movements
What makes up the forebrain?
cerebral cortex, hippocampus, thalamus, hypothalamus, pituitary gland, amygdala and corpus callosum
What makes up the hindbrain
Pons, cerebellum, medulla oblongata
Role of cerebral cortex?
Higher cognitive function (thinking, decision making)
What makes up the subcortical structures?
Thalamus, hypothalamus and amygdala
Role of subcortical structures
Regulating essential functions like sleep, hormone balance and emotions
Four lobes of the brain
Frontal, parietal, temporal, occipital
Role of frontal lobe?
coordinates two halves, memory and movement
Role of parietal lobe?
Sensory functions, attention, mood and personality (somatosensory)
Role of temporal lobe?
Auditory and vision, emotional response, memory and information (speech and hearing)
Role of occipital lobe
Mainly vision processing
Role of the hindbrain?
Regulates vital autonomic functions like heart rate, respiration and blood pressure
Role of the cerebellum?
Motor control, coordination, balance and processing sensory info
Role of pons
Communication between different areas of the brain. Also regulates sleep and arousal
What is the brainstem made up of?
Midbrain, pons and medulla oblongata
Role of brainstem?
autonomic regulation
Types of motor function?
Gross and fine
Gross motor function?
Involve large muscle groups for activities like walking, running and jumping
Fine motor functions?
involve smaller muscles for precise tasks like writing and buttoning shirts
What are dendrites?
Short extensions that receive signals
What are axons?
Long extensions that transmit impulses
What makes up a neuron?
Dendrites, soma, axon hillock, axon terminals, synapses
Role of axon hillock?
initiates the AP
Role of axon?
Transmits AP
Role of dendrites?
Input
What is a polysynaptic reflex?
A reflex pathway that involves one or more interneurones between the sensory neuron and the motor neuron
What is a monosynaptic reflex?
A reflex pathway that has a direct connection between the sensory and motor neuron
How can neurons be classified?
Structurally, functionally and types of NT
What are the 4 structural groups of neurons?
Unipolar, bipolar, multipolar, and pseudounipolar
What are bipolar neurones?
Neurones with one axon and one dendrite extending from the soma
What is a pseudounipolar neuron?
A neuron that only has one thing extending from the soma, however this splits off into two distinct structures
What are the three functional classifications of neurons?
Sensory, motor, inter
What are glial cells?
Types of cell found in nervous tissue that arent neurons
Types of glial cells?
Astrocytes, satellite glia, microglia, oligodendrocytes, schwann cells, radial glia and ependymal cells
Role of astrocytes?
Make contact with capillaries and neurons in CNS, help form the blood-brain barrier
Role of satelite glia?
Provide structural support and nutrients for neurons in PNS
Role of microglia?
Scavenge and degrade dead cells
Role of oligodendrocytes?
Form myelin sheaths around the axons in the CNS
Role of schwann cells?
Myelinates a whole axon by surrounding it
Role of radial glia?
Serve as scaffolds for developing neurons, are also bipolar so can differentiate into neurons or other glial cells
Role of ependymal cells?
Line fluid filled ventricles of the brain, produce cerebrospinal fluid
For a molecule to be regarded as an NT, what must there be regarding it in the presynaptic neuron?
It itself must be present, as well as the mechanisms for its synthesis (enzymes etc)
For a molecule to be regarded as an NT, what must there be regarding it on the postsynaptic neuron?
Receptors to which the NT can bind
What are the three criteria for defining a NT?
Present in the presynaptic neuron
Capable of being released
Postsynaptic receptors to which it can bind
What kind of NT is glutamate?
An AA transmitter
What is the main excitatory NT in the CNS?
Glutamate
What is glutamate synthesised from?
Glutamine
What is glutamate reuptaken by?
Excitatory AA transporters
What other molecule can activate glutamate receptors?
Aspartate
What is excitotoxicity?
Too much signalling that leads to cell death
Where is glutamine first found in the glutamate synthesis pathway?
In glial cells
What first happens to glutamine in the glutamate synthesis pathway?
It is transported out of glial cells via glutamine transporters
Which enzyme converts glutamine to glutamate in the glutamate synthesis pathway?
Glutaminase
Where is glutaminase found?
In nerve cells
Which molecule helps glutamate be taken up into synaptic vesicles?
Vesicular glutamate transporters
In which cells are EAATs found?
Presynaptic neurons and glial cells
What are the two main classes of NT receptors?
Ionotropic and metabotropoic
What are ionitropic receptors?
Ligand gated ion channels
What type of receptor are metabotropic receptors?
G protein coupled receptors
What are the three classes of ionotropic receptor?
NMDA, AMPA, KAINATE
What are the three classes of metabotropic receptor?
Group I, Group II, Group III
What kind of ion channel does NMDA, AMPA, KAINATE all form?
tetrameric ligand gated ion channels
Which subunit must an NMDA receptor have?
GluN1
What separates the different groups of metabotropic receptors?
The second messengers they couple to
Which second messenger does Group 1 couple to?
G alpha Q
Which second messenger does Group 2 couple to?
G alpha i o
Which second messenger does group III couple to?
G alpha i o
How does glutamate bind so many receptors?
Not a rigid molecule, can adopt different conformations
What is present in the middle of the ionotropic subunits?
An ion channel pore
Which subunits of an ionotropic receptor are transmembrane?
1, 3, 4
Which subunits of an ionotropic receptor are not transmembrane?
2
Which subunit segment is facing inwards to the ion channel in a ionotropic glutamate receptor?
2
Which receptor can be homomeric?
AMPA
Which ions are an AMPA receptor permeable to?
K+ and Na+
What is the direction of K+ through an AMPA receptor?
Leaving the cell
What is the direction of Na+ through an AMPA receptor?
Entering the cell
Agonists of AMPA receptor?
glutamate, AMPA, KA
Antagonists of AMPA receptor?
NBQX (competitive), GYKI (non-competive)
What ions are NMDA receptors permeable to?
Ca2+, Na+, K+
What is the direction of K+ through an NMDA receptor?
leaving the cell
What is the direction of Ca2+ and Na+ through an NMDA receptor?
Entering the cell
What kind of gated is an NMDA receptor?
voltage and ligand
Which receptor requires a co-agonist?
NMDA
What co-agonists do an NMDA receptor require?
Glycine or serine
Why can a fast and slow time course be observed on the postsynaptic EPSP?
AMPA are fast, NMDA are slow and glutamate binds both
Meaning of a dual gating receptor?
both ligand and voltage sensitive
Which molecule blocks a NMDA receptor at resting potentian?
Mg2+
What does depolarisation do to the NMDA receptor?
Relieves the MG2+ block from the ion pore
Which ion are NMDA receptors highly permeable to?
Ca2+
WHat speed of excitation are metabotropic receptors involved in?
slow
Which molecules are NMDA receptor ion channel blockers?
Ketamine and memantine
What happens when glutamate binds to an mGluR presynaptically?
G beta gamma subunits dissociate and close a calcium ion channel (stops Ca2+ from entering), preventing release of an NT
What happens when glutamate binds to an mGluR postsynaptically?
G beta gamma subunits dissociate and close a potassium ion channel (stops K+ from leaving), leads to a slow depolarisation
What can mGluR affect in terms of calcium?
Its intracellular release
What do group 1 mGluRs do?
produce slow depolarisation and release Ca2+ from intracellular stores
What do group 2/3 mGluRs do?
Inhibit glutamate and other transmitters release
What is the major inhibitory NT in the brain?
GABA
What kind of receptors can GABA activate?
Ionotropic and Metabotropic
How is GABA synthesised?
Enzymatically via the krebs cycle
What molecule is used to synthesise GABA in the krebs cycle?
glucose
Where is GABA synthesised?
Nerve terminal
What is the direct precursor to GABA?
Glutamate
Which enzyme converts glutamate to GABA?
Glutamic acid decarboxylase
Where are GABA transporters found?
Astrocytes and presynaptic nerve terminals
If the GABA isn’t recycled, what is it converted to in the presynaptic terminal?
Succinic semialdehyde
Which enzyme converts GABA to succinic semialdehye?
GABA transaminase
What is succinic semialdehyde an intermediate of?
Krebs cycle
What happens to GABA once it is reuptaken by astrocytes?
Converted to succinic semialdehyde
In which brain areas is GABA found?
Cerebellum, basal ganglia, hippocampus, hypothalamus, cortex
In which type of neurons is GABA is principally found?
local interneurones
What could happen if the glutamate GABA balance gets out of control?
Seizures and epilepsy
How does a neuron having multiple synapses on its dendrites affect the APs it may/may not fire down its axon?
It sums all the potentials from them (e.g. +ve from glutamate, -ve from GABA) and then fires the AP depending on the overall potential
What kind of receptor is GABAa?
Ligand gated ion channel
What kind of receptor is GABAb?
GPCR
Where are GABAa receptors generally found?
postsynaptically
Where are GABAb receptors generally found?
pre and postsynaptically
What speed of inhibition does GABAa receptors mediate?
fast
What speed of inhibition does GABAb receptors mediate?
slow
To which ion is the GABAa ion channel permeable to?
Cl-
Which ion channels can be regulated as a result of the GPCR receptor GABAb?
Ca2+ and K+
Which GABA receptor can inhibit transmitter release?
GABAb
Why do GABAb receptors exhibit a slow inhibition?
Second messenger systems take time
What does the K+ Cl- transporter do?
Transports K+ and CL- out of the postsynaptic neuron
What is the result of the K+ Cl- transporter?
A low conc of Cl- is maintained within the cell (maintains conc grad)
How many subunits make up the GABAa receptor?
5
How many transmembrane domains does each GABAa subunit have?
4
What is the role of the transmembrane 2 domain on the GABAa?
Pore forming segment
What is the subunit makeup of a GABAa receptor?
2 alpha, 2 beta, 1 gamma
Where does GABA bind on GABAa?
Interface between alpha and beta subunit
Why isnt there 3 GABAa binding sites?
The orientation of one of the alpha beta interfaces is incorrect so it cant be used as a binding site
Which subunit do the δ, ε, π, θ and ρ take the place of?
gamma
What is dependent on the subunit composition of GABAa receptors?
The inhibitory effect and the spatial distribution of the receptors
GABA agonists?
Muscimol, GABA
GABA antagonists
bicuculline, gabazine
What effect does the barbiturate/anesthetic binding site have on the GABAa receptor?
Prolong open time of channel
What effect does the neurosteroid binding site have on the GABAa receptor?
Increase or decrease endogenous GABA inhibition
Which molecules can bind to the GABAa channel blocking site?
Picrotoxin, pentylenetetrazole
What effect does the channel blocking binding site have on the GABAa receptor?
block cl- permeability
What effect does the benzodiazepine binding site have on the GABAa receptor?
increase frequency of channel opening
What are GABAb receptors coupled to?
G alpha i/o
What do GABAb receptors negatively regulate?
Adenyl cyclase and cyclic amp
GABAb receptor agonists?
GABA, baclofen
What do G beta gamma subunits regulate?
Ion channels
What does the g beta gamma subunit do presynaptically?
Closes calcium ion channels
What do GABAb receptors do postsynaptically?
Open K+ channels, allowing K+ to leave the cell thus hyperpolarising the postsynaptic neuron
How many subunits are required to make a GABAb receptor?
2
Where is GABAbR1?
In the ER
Where is GABAbR2?
In the cell membrane
What happens if there is a GABAbR2 that needs to be expressed in the cell surface?
GABAbR1 travels to the cell surface
When GABAbR1 and 2 are expressed at the CSM, what type of interaction do their cytoplasmic domains form?
A coil-coil interaction
Which subunit on GABAb does GABA bind to?
GABAbR1
What is baclofen used to treat?
muscle spasticity
What are the monoamines?
Dopamine and norepinepherine
Which AA is 5-hydroxytryptamine derived from?
tryptophan
What kind of amine is 5-hydroxytryptamine?
An indolamine
What AA are catecholamines derived from
tyrosine
Which AA is histamine derived from?
histidine
Where are the cell bodies of cells that synthesise amines?
brainstem
What is specific ab the amine neuron axons?
They project widely
What is the main role of amine NTS?
Modulating the action of GABA and glutamate at synapses
What do amines play a key role in?
Arousal, sleep, attention and survival
Where are amine NTs released from?
Boutons
What is the origin of noradrenaline in the brain?
Locus coeruleus
Where do axons of nerves in the locus coeruleus innervate?
forebrain, cortex, spinal cord
What does noradrenaline act at?
GPCRs
Which GPCRs does noradrenaline act at?
alpha 1, 2, and beta 1, 2
What do the noradrenaline GPCRs in the brain stem control?
Blood pressure
What do the noradrenaline GPCRs in the descending pathways in the spinal cord control?
Movement and pain
What do the noradrenaline GPCRs in the ascending pathways in the spinal cord control?
Arousal and mood
How is tyrosine taken up by neurons?
Via tyrosine transporters
What is tyrosine first converted into in nerve terminals?
L-dihydroxyphenylalanine
What enzyme catalyses the conversion of tyrosine to L-dihydroxyphenylalanine?
Tyrosine hydroxylase
What is L-dihydroxyphenylalanine converted into?
dopamine
What enzyme converts L-dihydroxyphenylalanine into dopamine?
DOPA d carboxylase
What takes up dopamine (in norepinepherine synthesis)?
Vesicular monoamine transporter
What is the final intermediate before noradrenaline is synthesised?
dopamine
What converts dopamine to noradrenaline
dopamine beta hydroxylase
Difference between dopaminergic neurons and noradrenaline neurons?
Noradrenaline neurons have dopamine beta hydroxylase
Eventual consequence of blocking tyrosine hydroxylase?
depleting noradrenaline
Phenotypic consequence of blocking tyrosine hyroxylase?
depression like state induced
How is noradrenaline inactivated?
Reuptake and degradation
Which compounds degrade noradrenaline?
monoamine oxidase and catechol-o-methyltransferase
Where are noradrenaline transporters expressed?
Presynaptic neurons and glial cells
What is the phenotypic result of monoamine oxidase inhibitors?
Antidepressant
Where is the origin of dopamine?
midbrain
Three dopamine pathways?
Nigro-striatal pathway, mesolimbic, tubero-infidibular system
Where does the mesolimbic pathway project from and to?
From the ventral tegmental area to the cortex and hippocampus
Where is the tubero-infundibular system located?
Hypothalamus to the pituitary gland
What type of receptors does dopamine act at?
GPCRs
What is the tubero-infundibular system involved in?
Endocrine function
What is the same between dopamine and noradrenaline?
Their inactivation (reuptake and degradation)
Which pathway degenerates in parkinsons?
Nigro-striatal pathway
Which NT does NMDA increase?
5HT
Where does 5HT arise from?
Raphe nuclei
Where does 5HT project?
Forebrain (cerebral cortex, cerebellum), spinal cord
what are the 5HT neurons in the spinal cord involved in?
pain perception and pain regulation
5HT dysfuncion is associated with?
depression, sleepy, abnormal feeding
Increased activity of 5HT systems in regard to food?
Loss of appetite
Decreased activity of 5HT systems in regard to food?
Gain of weight
How is tryptophan taken up by NTs?
transporters
First thing to happen to tryptophan in 5ht synthesis?
Conversion to 5-hydroxytryptophan
Which enzyme catalyses the conversion of tryptophan to 5-hydroxytryptophan?
Tryptophan hydroxylase
What is 5-hydroxytryptophan converted to?
5-hydroxytryptamine
What enzyme catalyses the formation of 5-hydroxytryptamine
5-hydroxytryptophan carboxylase
What happens to 5-hydroxytryptamine after synthesis?
taken up by vesicles
Inactivation of 5ht?
Reuptake and degradation
5ht degredation enzyme?
Monoamine oxidase
What is unique ab 5HTs reuptake transporters?
They are specific to 5HT
Where does ACh project to from the magnocellular neurons?
cortex/limbic system
Types of ACh receptor?
Ionotropic and GPCR
Ionotropic ACh receptor?
Nicotinic
GPCR ACh receptor?
Muscarinic
Role of ACh?
Arousal, sleep, waking
Main substrate for ACh?
Choline
How is ACh formed?
Choline combines with acetyl-CoA
enzyme catalysing ACh formation?
Choline acetyltransferae
Which enzyme breakd down ACh?
Acetylcholineesterase
WHat is produced as a result of ACh breakdown?
Free choline, acetic acid
what is taken up after ACh degredation?
Free choline
Treatment for alzheimers regarding ACh?
Targets acetylcholineesterase to prevent ACh degradation
What is sleep?
A readily reversible state of reduced responsiveness to, and interaction with, the environment
What is obtundation?
a state of consciousness from which only painful stimuli will return the patient to full consciousness
Functions of sleep?
Restorative, protective adaptation, metabolism/weight homeostasis, memory consolidation and integration
What is restored during sleep?
cortical recovery and tissue repair
Why is sleep a protective adaptaiton?
protection from nocturnal predators
What does an electroencephalogram (EEG) record?
The activity of populations of neurons in the brain
What does the frequency of an EEG show?
How fast the neurons are firing
What does the amplitude of an EEG show?
The amount of neurons firing in synchrony
What does an EEG sum show?
The summed activity from multiple electrodes
What does it mean for nerve cells to be synchronised?
They are all firing together
What are the amplitude and frequency characteristics of desynchronised neurons?
Fast wavelength, low amplitude
What are the amplitude and frequency characteristics of synchronised neurons?
Slow wavelength, large amplitude
Delta rhythms?
Slow (4Hz) and large amplitude, deep sleep
Theta rhythms?
SLow (4-7Hz), light sleep
Alpha rhythms?
Fast ish (8-13Hz), conscious relaxation
Beta rhythms?
fastest (>14Hz), awake and alert
Gamma oscillations?
Memory encoding, recall and attention
Two categories of sleep?
Rapid eye movement (REM) and non-rapid eye movement (NREM)
REM characteristics?
~20 mins, dreaming
NREM length
60-90 mins
What happens to the length of NREM stages as you progress through the night
gets shorter
What happens to the length of REM stages as you progress through the night
gets longer
Awake rhythms?
alpha and beta
How long does stage one NREM sleep last?
5 min
Type of rhythms in REM sleep?
beta
Stage 1 NREM characteristics?
5 mins, theta rhythms, starting to fall asleep, nerves begin to become synchronized
Stage 2 NREM characteristics?
1-15 mins, spindle and k complex rhythms
Stage 3 NREM characteristics?
5-25 mins, no eye/body movements, delta rhythms, restorative sleep
Stage 4 NREM characteristics?
Deep sleep, 20-40 mins, delta rhythms
What is the EEG of REM sleep similar to?
an active, waking brain
When does dreaming occur?
REM sleep
What is REM sleep referred to as?
An active, hallucinating brain in a paralysed body
What kind of nerve activity predominates in REM sleep?
sympathetic
What is increased in REM sleep as a result of sympathetic activity?
Heart rate, respiration rate and blood flow to the penis
Changes in NREM sleep?
muscle tension reduced, temp lowered, energy consumption lowered, more parasympathetic activity
What area of the brain is important for control of sleep?
Reticular activating system
What are thalamo-cortical inputs used for?
controlling sleep
What happens if you stimulate the reticular activating system in the brainstem?
wake up an animal
Which brain areas make up the reticular activating system?
Locus coeruleus, raphe nuclei, brainstem/forebrain, midbrain
What are all the areas that are part of the RAS involved in?
Amine NT secretion
Increased firing of the RAS neurons is associated with?
waking up
Decreased firing of the RAS neurons is associated with?
falling asleep
Amine NT associated with locus coeruleus?
noradrenaline
Amine NT associated with raphe nuclei?
serotonin
Amine NT associated with brianstem/forebrain?
ACh
Amine NT associated with midbrain?
histamine
What is the activity of the RAS regulated by?
Hypothalamus
Which neuropeptide is expressed in the hypothalamus that helps regulate the RAS?
orexin
What does orexin do?
Stimulates RAS activity
What causes decreased firing of RAS neurons
GABA
What are “REM on” neurons?
cholinergic neurons in the brainstem
What are “REM off” neurons?
Serotonergic and noradrenergic neurons in the brainstem
RAS thalamus cortical interactions of an awake brain?
Awake–> RAS activates thalamus–> thalamus generates non-rhythmic activity–> cortex entrained into fast waking activity
RAS thalamus cortical interactions of an asleep brain?
Asleep–> RAS activity switched off–> thalamus generates rhythmic activity–> coretex entrained into slow sleep rhythms
Possible effects of insomnia?
Difficulty getting to sleep, difficulty staying asleep or feeling sleepy when having had sleep
What do drugs that can help you sleep target?
GABA
Why is GABA targeted by sleepy drugs?
GABA can inhibit the RAS,
What is decreased activity of RAS associated with?
Falling asleep
What kind of modulators of GABAa are benzodiazepines?
allosteric
Nitrazepam and flurazepam are?
Long acting benzodiazepines
Loprazelam and temazepam are?
Short acting benzodiazepines
What differentiates the acting time of benzodiazepines used to treat sleep issues?
The metabolism time of them (short acting are metabolized quickly)
What are the Z drugs?
Zolpidem, zolpiclone, zalpeon
Action of z drugs?
bind at GABA and enhance endogenous activity of GABA
What are orexin antagonists used for?
hypnotics
Where is melatonin secreted from?
pineal gland
What does melatonin regulate?
circadian rhythms
Rising melatonin levels means?
Need to go to sleep
Narcolepsy?
Pathological increase in sleep, sudden onset of sleep and sudden loss of motor control
What may cause narcolepsy?
Reduced numbers of orexin neurons, loss of RAS activation
Objective of anaesthesia?
Inducing a lack of feeling (lack of sensation and pain)
Who was the father of surgical anaesthesia?
Hua Tuo
Who was the first surgeon who used N2O as a GA?
Crawford Long
Triad of general anaesthetics?
Unconsciousness, analgesia, muscle relaxation
How many stages of anaesthesia are there?
4
What is stage 1 of anaesthesia?
Analgesia
Conditions of stage 1 of anaesthesia?
conscious, drowsy, anticonception, amnesia
What is stage 2 of anaesthesia?
Excitement
Conditions of stage 2 of anaesthesia?
loss of consciousness, delirium, irregular cardiorespiration, apnea, spasticity, gagging, vomiting
What is stage 3 of anaesthesia?
Anaesthesia
Conditions of stage 3 of anaesthesia?
regular respiration, loss of reflex and muscle tone
What is stage 4 of anaesthesia?
medullary paralysis
Conditions of stage 4 of anaesthesia?
Depression of cardiorespiration, death
Why is stage 1 of GA used for childbirth?
Want some lack of sensation but still need to be awake
How do you go from one stage of GA to a higher stage?
Increase the dose or potency of the GA
Which compound is used to induce stage 1 GA?
N2O
Which stage of GA causes erratic breathing?
2
What is a warning sign to an anaesthetist that a patient is too deeply anaesthetised?
Action of intercostal muscles decreasing
What are the four stages of stage 3 of GA?
Planes 1,2,3, and 4
When is the pupilary light reflex visible?
S3, planes 2-end of 3
When during GA does the corneal reflex stop?
S3P2
Precise aim of GA?
S3, P1 OR 2
When in GA is the respiratory response to skin inscision lost?
Midway through S3P2
When during GA are the muscles tense and struggling?
S2
Super ideal GA?
Stable, potent, non toxic, controllable, rapid on off, adjustable, minimal cardio and respiratory depressant
Why does the ideal GA need to be rapid on?
Through S2 quickly
Why does the ideal GA need to be rapid off?
Able to titrate dose depending on their reaction, to keep them in S3
Why is xenon not used as a GA?
V expensive
2 main types of administering GAs?
Inhalation and intravenous
Best aspect of inhaled GAs?
V controllable as the dose in the air is v quickly transferred
Main inhaled GAs?
Halogenated ethers, halogenated hydrocarbons
Halogenated hydrocarbon example?
Halothane, isofluorane
Advantages of halothane and isoflurane?
V potent and stable
Main pro of intravenous GAs?
V rapid
Which type of general anaesthetic is used for induction of GA?
Intravenous
Which type of anaesthetic is used for maintenance of GA?
Inhaled
Major surgery general anaesthetic order?
Benzazepine, then intravenous (thiopental), then inhaled (halothane)
Rapid unconsciousness anaesthetic?
thiopental (short acting)
General anaesthetic to maintain GA?
N2O, halothane, sevofluorane
When are analgesic drugs used?
post operative care
What is fentanyl used for?
analgesic effect after surgery when the general anaesthetic has worn off
Which compounds are used for paralysis of skeletal muscle?
Suxamethonium
How does Suxamethonium work?
It is a nicotinic ACh receptor antagonist
What drugs are people given pre-op?
Benzodiazepines, midazolam
Examples of inhaled anaesthetics?
N2O, halothane, enflurane, isoflurane, desflurane, sevoflurane
Side effect of halothane?
Toxic to liver
Which inhaled GA is used more in veterinary than human surgery?
Halothane
Why is sevoflurane used the most?
Has the least side effects
Types of intravenous GAs?
Thiopental, etomidate, propofol, ketamine, benzodiazepines
Most widely used intravenous GA?
propofol
Mechanism of local anaesthetics?
Voltage-gated sodium channel block
Two main theories of how GAs work?
lipid theory, and protein theory
Lipid theory of GAs?
good GAs are more lipophilic (can soak into lipids) and so soak into the lipid bilayer and block membrane spanning proteins (Na+ channels in neurons etc)
Protein theory of GAs?
More potent a GA is, less of it is needed to inhibit luciferase proteina action, so GAs might generally inhibit protein action
What type of proteins do GAs target?
Transmitter receptors, ion channels, transporters and release
What do GAs do regarding inhibitory receptors?
Potentiate them, meaning they are stronger (more hyperpolarisation)
What do GAs to to excitatory receptors?
Block them
How do GAs affect ion channels?
They reduce the frequency of them opening
What is anxiety?
a normal, physiological response to threatening situations that serves as a protective function
What is pathological anxiety?
concern about stressor is out of proportion to the realistic threat and can occur without exposure to an external stressor
How many people in the UK are affected by anxiety disorders?
8 million
Examples of anxiety disorders?
Specific phobias, social anxiety, panic disorder, PTSD, OCD, Generalised anxiety disorder, premenstrual dysphoric disorder
length of generalised anxiety disorder?
6 months
What are the core symptoms of anxiety disorders?
Negative cognition, physiology (heart racing etc), avoidance behaviour
What is negative cognition?
A bias to interpret unthreatening situations as threatening
Physiological symptoms of anxiety disorders?
Racing heart, restlessness, sweating, increased blood pressure
Part of anxiety disorder that the cortex is involved in?
negative cognition
Part of anxiety disorder that hippocampus the is involved in?
Memory
Part of anxiety disorder that the amygdala is involved in?
fear perception
Part of anxiety disorder that the hypothalamus is involved in?
Stress responsiveness
Part of anxiety disorder that the basal ganglia/cerebellum are involved in?
movement control
What hormone is released upon the perception of stress?
Corticotropin releasing hormone
Which part of the brain releases Corticotropin releasing hormone?
Hypothalamus
Where is Corticotropin releasing hormone released onto?
Pituitary gland
Which stress related hormone is released by the pituitary gland?
Adrenocorticotropic hormone (ACTH)
Where is ACTH released onto?
The adrenal gland
What is produced by the adrenal glands in response to ACTH?
Glucocorticoids, particularly cortisol
Why is cortisol released in response to stress?
To give you the energy for the fight or flight response, as it is responsible for metabolism of glucose and lipids
Where is adrenaline released from in response to stress?
Adrenal glands
Which brain area is first used in the fear response and why?
Thalamus as it deals with sensory stuff
Which brain area is used after the thalamus in the fear response?
Amygdala
Role of amygdala in fear response?
Switching on amine NTs (noradrenaline etc)
Role of periaqueductal grey in fear response?
Innate avoidance behaviour (e.g. stepping back)
Which brain area releases cortisol in response to stress?
Hypothalamus
Where are most anxiety disorders thought to originate?
Prefrontal cortex and hippocampus
Why is noradrenaline released in the fear response?
Need to be hyper aware of your surroundings
Which NTs are implicated in the fear response?
Serotonin and noradrenaline
Role of GABAa networks?
Fast inhibition
Treatments of anxiety disorders?
Beta blockers, benzodiasepines, antidepressants, buspirone
How do beta blockers work?
They block beta adrenergic receptors
What symptoms of anxiety do beta blockers target?
Autonomic systems
SSRI stands for?
Selective serotonin reuptake inhibitors
What specific anxiety type could propranolol (beta blocker) treat?
Phobias
How does propranolol treat phobias?
Give patient drug then expose them to thing they’re scared of
What is propranolol thought to work on?
Hippocampus–> where -ve memories of the thing are removed (positive association forms instead of -ve association)
How does buspirone work?
It is a partial agonist at 5-HT1a receptors (turning up inhibition in those neurons)
How do SSRIs work?
Bind to reuptake transporters, thus boosting levels of serotonin in synapse
What is the preferred treatment for generalized anxiety disorder, PD and PTSD?
Combined noradrenaline and 5HT uptake blockers
WHat are some combined noradrenaline and 5HT uptake blockers?
venflaxine, duloxetine
What do benzodiazepines bind to?
GABAa receptors
Role of GABA?
Inhibitory NT
What can the binding of drugs to allosteric site on GABAa receptors do?
Turn up or down gating of CL- ions in the presence of GABA
What is an inverse agonist?
Something that binds and turns down the receptor
What do benzodiazepine agonists do once bound to GABA?
Turn up the effects of endogenous GABA
Where on the GABAa receptor do benzodiazepines bind?
Alpha gamma interface
General structure of benzodiazapines?
Benzene ring joined to a 7 membered 1,4-diazepine ring (R 1 2 3 5 7 8 are side groups)
What do the R side groups change ab benzodizepine?
Affinity, intrinsic efficacy, lipophilicity, water solubility
Affinity meaning?
How likely something is to bind
Intrinsic efficacy meaning?
The effect of smthn once bound
What is the intrinsic efficacy of a BZ agonist?
+ve (100%)
What is the intrinsic efficacy of BZ inverse agonists?
-ve
What intrinsic efficacy to BZ antagonists have?
0
What is the intrinsic efficacy of partial or full agonists?
near 100%
What are full BZ agonists called?
Positive allosteric modulators
What are full BZ agonists used for?
Anxiolytic
What are inverse agonists used for?
Investigating GABA
Effect of inverse agonists on Cl- flow through GABAa?
Less chloride flux through the channel so less inhibition
Effect of alcohol on the CNS?
Depressant
Effect of alcohol on GABA receptors?
Causes increase inhibition
What does stroke cause?
Neuronal cell death
What is the root cause of a stroke?
Transient or permanent interruption in cerebral blood supply
What is ischaemia?
A lack of blood supply to a part of the body
Two main causes of stroke?
Ischaemic and haemorrhagic
What causes an ischaemic stroke?
Blocked blood vessels
What causes a hemorrhagic stroke?
Ruptured blood vessels
What are the two types of ischaemic stroke?
Thrombotic or embolic
What is a thrombotic blockage?
A blockage caused by the blood clotting
What is an embolic blockage?
Things like air or fat blocking the blood vessels
Which type of stroke is more fatal?
Haemorrhagic
What are the two types of haemorrhagic stroke?
Intracerebral or subarachnoid
Intracerebral hemorrhagic stroke?
Ruptured blood vessel is inside the brain/provides blood to the centre of the brain
Subarachnoid hemorrhagic stroke?
Ruptured blood vessels are around the outside of the brain
Symptoms of stroke?
Face falling on one side, difficulty raising arms, slurred speech
Time issue with stroke?
Must be treated within 3 hrs
What is necrosis?
cell/tissue death
Two regions of damage post-stroke?
Core and penumbra
What is the core of a stroke?
Where the ischaemia first happened
What is the penumbra in a stroke?
The region around the core
What happens to the core and penumbra regions of a stroke if treatment isnt applied?
The core will grow into the penumbra, damaging more regions of the brain
What is the primary cause of cell death in stroke?
Excitotoxicity
What causes excitotixicity?
Excessive release of glutamate
What happens as a result of excessive glutamate release?
A Ca2+ overload
What allows neurons to have a resting membrane potential of -70mV
The sodium potassium pump
Concentration difference of Na+ in neuronal cells?
Higher outside than inside
Conc grad of K+ in neuronal cells?
Higher inside than outside
What is required for the Na K pump to work?
ATP
Why does ischaemia cause neuronal cell death?
A lack of oxygen/glucose to the neurons
Why does a lack of oxygen/glucose to neurons cause excitotoxicity?
Cant generate ATP to fund NaK pump
What happens if the NaK pump stops working?
The resting potential goes from -70 to +40, all affected neurons will depolarise
What happens if the presunaptic neuron depolarises?
Ca2+ flows in and causes the release of glutamate
What happens if the postsynaptic neuron depolarises?
Positive ions flow in
Consequences of an excessive release of glutamate?
Activate AMPA and KAINATE receptors (both lead to Na+ going into the postsynaptic neuron (more depolarisation))
What happens to NMDA receptors at higher than -40mV?
The magnesium block is removed meaning Na+ can flow through
What does the sodium calcium exchanger do?
Protects the neurons from having too much sodium in them by swapping intracellular Na+ for extracellular Ca2+
Why does having excessive Ca2+ in a neuron cause issues?
It is a signalling molecule that can cause free radicals to form which damage the membrane and cytoskeleton
Which enzymes does Ca2+ activate?
Proteases, lipases, caspaces
What happens as a result of caspase activation?
Cell death
What happens if Ca2+ activates too much of its enzymes?
The lipid bilayer is digested (lipases), as well as anything made of proteins (proteases)
What happens to the neurons in the core of a stroke?
They never repoalrise
What happens to the neurons in the penumbra of a stroke?
They can repolarise
What is difficult about repolarising a penumbra neuron?
The ATPase NaK pump has to work very hard to restore the concentrations of the ions to the correct level for a -70mV membrane potential, and this uses a lot of energy
Which treatment is only for thrombotic ischaemic strokes?
Tissue plasminogen activator (tPA)
What does tPA do?
Breaks down blood clots
Treatment for hemorrhagic stroke?
Surgery to fix the ruptured blood vessel
What are targets for neuroprotective agents for stroke treatment?
AMPA/NMDA receptor blockers, Na+/Ca2+ blockers, enzyme inhibitors
How could neuronal cells be recovered after a stroke?
Stem cells
What are some things that prevent people from having a stroke again?
Antihypertensives
Why are antihypertensives used to prevent stroke?
Reduce high blood pressure
What lifestyle choices can increase risk of stroke?
Obesity, lack of exercise, smoking, alcohol
For which type of stroke are blood thinners prescribed?
Ischaemic
What is a transient ischaemic attack?
Short lived neurological signs similar to those from a stroke
What do the long term stroke symptoms depend on?
The brain region affected
Symptoms if motor cortex is affected?
Skeletal muscle movement affected
Symptoms if wernicke’s area of brain is affected?
Difficulty understanding language/listening
Symptoms if Brocas area of brain is affected?
speech and writing
Symptoms if right motor cortex is comprimised?
Left half of body is affected
What random molecule can cause exitoxicity?
Domoic acid
Why can domoic acid cause excitotoxicity?
It is a glutamate receptor agonist
Where is domoic acid found?
Amnesic shellfish
What produces domoic acid?
Algae
Which glutamate agonists can cause excitotoxicity?
Domoic acid, oxalydiaminopropionic acid, beta-Methylamino-L-alanine
Which foods can cause excitotoxicity?
Shellfish, grass pea, cycad seeds
What is pain?
The subjective conscious appreciation of a stimulus that is causing, or threatening to cause, tissue damage
What is nociception?
The physical process of detection and transmission of damaging or potentially damaging (noxious) stimuli
What are nociceptors?
Structures that detect noxious stimulus
What is algesia?
The induction of a condition leading to nociception and pain
What is analgesia?
Reduction or prevention of either nociception or pain without loss of consciousness
What is the detection of touch?
Mecanoception
Which specific structures are involved in the perception of touch?
Merkel’s Disc, Pacinian Corpuscle, Meissners Corpuscle
What are the two main types of nociceptor?
Polymodal, mechanical
What type of mechanical stimuli do both types of nociceptor respond to?
High intensity
What level of thermal input can stimulate polymodal nociceptors?
> 45 degrees, <10 degrees
What level of thermal stimuli can stimulate mechanical nociceptors?
> 60 degrees
What is the order of structures for detecting a noxious stimulus?
Skin/viscera–> Sensory receptor–> primary afferent axon–> spinal cord
What are the types of receptor in nociceptors?
ASIC (acid sensing ion channel), Purinergic receptors (P2x3), Voltage gated Na+ channels, VR-1/TRPV-1
What is the main agonist of ASICs?
Protons
What is the main agonist of Purinergic receptors?
ATP
What type of stimulation do purinergic receptors respond to?
High intensity mechanical stimulation
What type of stimulation do voltage gated sodium channels respond to?
Mechanical stimulation
What is the main agonist of VR-1/TRPV-1?
H+, high levels of heat and capsaicin
Speed of nociceptive APs compared to touch APs?
Slower
Why are nociceptive APs slower than touch ones?
The C fibres are very thin and unmyelinated
Which type of fibre is used for nociception?
C and a delta
Which type of nociceptor is linked to c fibres?
Polymodal
Which type of nociceptor is linked to A delta fibres?
Mechanical
Why do APs flow down Adelta fibres quicker than C fibres?
The Adelta fibres are myelinated
Why is there an initial pain felt, then a throbbing?
Different fibres transmit at different speeds so one transmits slower after the other
Which fibres are responsible for the initial pain?
A delta
Which pain fibres are responsible for the second pain?
C fibres
Which receptors detect reasonable temperatures (10-40 degrees)?
Thermoreceptors
Which receptors detect extreme temperatures?
Cold/heat pain receptors
Why do thicker fibres transmit APs quicker?
There is less resistance
Where does sensory input enter the spinal cord?
Through the dorsal root
Where is the first synapse (in the spinal cord) that is responsible for nociceptive input into the brain?
The most dorsal part of the spinal cord
Where does the AP go after it has gone through the first synapse in the spinal cord?
Crosses over to the other side of the body and goes up into the brain
What can the somatosensory part of the cortex receive input from?
Touch and nociception
What does the somatosensory cortex do with the touch and nociception?
Tells the brain where it has come from
Role of insular and anterior cingulate cortex in nociception?
Tells the brain that it is pain that is being experienced, affect your mood
How is the body mapped regarding pain perception and location?
As you go round the outside of the somatosensory cortex, different parts of it receive input form different body areas
What is the pain pathway to the brain?
Spinothalamic pathway/tract
Why is pain referred?
Not enough space in somatosensory cortex to have an acute sensation to map every part of the bodys pain
Which body parts have a good pain mapping (know where the pain is coming from)?
Skin
Which body parts have a poor pain mapping (don’t know where the pain is coming from)?
Internal organs
Where does pain sourced in the oesophagus feel like its coming from?
Heart
What can hurt when having a heart attack?
Left arm
Which neurons are shared in referred pain?
Second order
What is the second order neuron?
The one after the first synapse in the spinal cord
What is hyperalgesia?
Increased response to a noxious stimulus
What is allodynia?
Painful responses to a non-noxious stimulus
Why is hyperalgesia a thing?
To protect already injured/damaged areas of the body
How does nociceptor sensitisation work?
Cut skin–> skin cells break–> intracellular components of skin cells is released into extracellular space–> some of these components are H+, ATP, K+ which are nociceptor agonists
Why does an elevated conc of extracellular K+ increase the amount of APs fired from a neuron?
Conc grad is disrupted meaning it is harder for the neurons to repolarise, makes them more excitable
What is unusual about nociceptive neurons?
They can release NTs from their dendritic end
Which NT is released from the dendritic end of nociceptive neurons?
Substance P
What does substance P do to blood vessels?
Activate receptors on blood vessels that makes them leaky
Outcome of substance P’s action on blood vessels?
More nociceptor agonists are released, generating more nociceptive APs
Which cells does substance P recruit?
Mast cells
Action of mast cells?
Release histamine which makes blood vessels leaky
Which three molecules are used for healing the part of the body that has been damaged?
Bradykinin, prostagladin, neural growth factor
What does nerve growth factor do?
Sensitise the nociceptors by lowering their threshold for opening
What is peripheral sensitization?
Increased sensitivity of peripheral nociceptors
What is central sensitization?
Increased transmission in spinal cord
Which fibres do itch sensations travel down?
Adelta and C
Difference between pain and itch?
Analgesics don’t inhibit itch, can imagine an itchy sensation but not a painful one
What kind of input cures an itch?
Nociceptive (scratching it hard)
Where does peripheral sensitisaiton occur?
The primary nociceptive neurons (in the skin etc)
Where in the spinal cord is the first synapse?
Most dorsal aspect (lamina 1 or lamina 2)
Which NTs is released from the nociceptive neurons in the spinal cord?
Mostly glutamate, also some substance P and a little amount of GCRP
What is CGRP?
Calcitonin gene related peptide
Which receptors does glutamate activate?
AMPA and NMDA
Which receptor does substance P activate?
NK-1 receptor
What type of receptor is NK-1?
GPCR
Why is a fast slow time course observed in glutamate transmission?
AMPA are fast bc and NMDA are slow
Which second messenger does NK-1 release?
Gq
What does Gq second messenger do regarding PIP2?
Breaks down PIP2 into Diacylglycerol (DAG) and inisitol triphosphate (IP3)
What does inositol triphosphate do?
Activates calcium stores which leads to an increase in intracellular Ca2+ concentrations
What does DAG do?
Activates protein kinase C
What does Gq second messenger do regarding ion channels?
Activate Na+, Ca2+ entry ion channels and inhibit K+ exit ion channels–> more depolarisation
What happens if there is a burst of activity from the presynaptic neuron in the spinal synapse part of the pain pathway?
The synapse increases in strength over time (i.e. after 11th AP the postsynaptic response is bigger than previous)
What is synaptic plasticity?
The strength of a synapse changes over time
Why does the spinal synapse become more sensitive over time?
NMDA receptors and NK-1 receptors
How is it known that NMDA receptors affect synaptic plasticity?
Synaptic plasticity does not occur with AP5 (NMDA agonist) present
How is it known that NK-1 receptors affect synaptic plasticity?
Synaptic plasticity does not occur with SP agonist(NK-1 agonist) present
Where in the nociceptive pathway do inhibitory interneurons attach?
The dorsal horn projection neuron
How are inhibitory interneurons activated in the pain pathway?
Offshoots of mechanoreceptors that are in the spinal cord can activate inhibitory interneurons
What type of neurons activate inhibitory interneurons in the pain pathway?
Glutamatergic
What is nursing the injury?
Touching an injured part of the body
Why do we “nurse an injury”?
Touching it activates mechanoreceptors which can cause inhibitory interneurons to be activated, thus inhibiting the pain
What is TENS?
Transcutaneous electrical nerve stimulation–>An electrical pack that stimulates touch receptors on the skin
Why does TENS work?
Activates mechanoreceptors which can cause inhibition of pain
Which two types of pathway can inhibit nociception?
Descending inhibitory pathway and ascending inhibitory pathway
What is the ascending inhibitory pathway?
Mechanoreceptors causing inhibition
What is the descending inhibitory pathway?
Parts of the brainstem, when stimulated, can inhibit pain
Which parts of the brain can cause descending inhibitory input?
Periaqueductal grey and raphe nuclei
Where does the periaqueductal grey project to in inhibitory input?
The raphe
Where does the raphe project to in inhibitory input?
The first synapse in the spinal cord
Where in the brain does the periaqueductal grey receive inputs from?
Hypothalamus, amygdala, cortex
Where does the nucleus reticularis paragigantocellularis project to?
Raphe nuclei
Where does the locus coeruleus project to?
Spinal cord
Where does the hypothalamic paraventricular nuclei project to?
Periaqueductal grey
Can the environment you are in affect the amount of pain you are in?
YEs
Why may your environment having an effect on how much pain you are in be beneficial?
Get injured while running away from predator–> still need to run away so pain is reduced
What effect does opioids have on nociceptive neurons?
Inhibit the free nerve endings, hyperpolarizing them and making them less likely to fire APs up pain pathway
How does the PAG act as an inhibitor of pain?
Sends input to the raphe which causes the raphe to fire inhibitory APs down the spinal cord
How does the raphe send inhibitory APs down the spinal cord?
Via release of 5HT
How does the locus coeruleus inhibit pain pathways in the spinal cord?
Via the release of noradrenaline
Effect of opioids on PAG?
Excitatory effect so more APs from PAG
Effect of opioids on nucleus reticularis paragigantocellularis?
Excitatory so more APs from the NRP onto the raphe nuclei
How do opioids inhibit pain?
Inhibit nociceptive neurons and the neurons in the spinal cord, and have an excitatory effect on PAG and NRP
Three different types of opioid receptor?
Mew delta and kappa
What are all of the endogenous agonists of opioid receptor?
Peptides
What is similar between the four endogenous agonists of opioid receptors?
Their first 4 AAs are the same
What are the four peptide opioid endogenous agonists?
Beta-endorphin, met-enkephalin, leu-enkephalin, dynorphin
Which endogenous opioid agonist binds well at all receptors?
beta-endorphin
Which opioid receptors are found in the brain (PAG)?
Mu
Which opioid receptors are found in the spine?
Mainly mew and delta, also kappa
Which opioid receptors are found in the nociceptive neurons?
Mu and kappa
What type of receptor are all of the opioid receptors?
GPCRs
What are the opioid receptors second messengers?
Gi/o
What does the Gi/o unit of the opioid receptor inhibit once an agonist had bound?
The conservation of adenyl cyclase to cyclic AMP
What is the effect of inhibiting the formation of cyclic AMP?
Less protein kinase A is formed
Other than AMP, what does Gi/o of opioid receptors inhibit?
Calcium channels, meaning less calcium can enter the neuron so less NTs will be released
What can the Gi/o of opioid receptors open?
Potassium channels, so more K+ leaves so neuron is hyperpolarized
How does opioid receptors cause more APs to be fired down the PAG to the raphe nucleus and thus to the spinal cord?
They inhibit the release of GABA meaning less inhibition from GABA goes to the synapse between the PAG and raphe nuclei
What is disinhibition?
Inhibiting something that is inhibitory
Net effect of disinhibition?
Excitation
What do the two branches of input from the raphe to the dorsal horn carry?
5HT to directly inhibit the synapse. The second one activates opioid interneurons neurons with enkephalins which also inhibit the synapse in the dorsal root
What is the effect of enkephalin on an action potential?
Shortens them and leads to a lower frequency due to opening K+ channels (neuron hyperpolarises more quickly
What general process is boosted by analgesic drugs?
Descending inhibition of nociception
Which processes are inhibited by analgesic drugs?
Central sensitisation and peripheral sensitisation
How do nonsteroidal anti-inflammatories cause analgesia?
They inhibit the process of peripheral sensitisation
How do opioid analgesics cause analgesia?
Boost the descending inhibition of nociception
What do opioids mimic in order to have their analgesic effect?
Endogenous opioid agonists
Where do opioids act?
On opioid receptors
Examples of opioids?
Morphine, heroin, fentanyl, codeine
What are some low potency opioids?
Codeine, pethidine, buprenorphine
What is etorphine used for?
Veterinary medicine–> large animals
What is naloxone?
An opioid receptor antagonist
How does naloxone work?
It is a opioid mew delta and kappa antagonist
Which drugs are used for mild pain?
NSAIDs (nonsteroidal anti inflammatories)
Examples of NSAIDs?
Aspirin, ibuprofen
What are opioids given to people in moderate pain?
Codeine, buprenorphine
What are some opioids given to people in severe pain?
Morphine, fentanyl
How do the opioid receptors on free nerve endings have an inhibitory effect?
When an agonist binds K+ channels open and allow K+ to leave the cell–> hyperpolarisation
Where are supraspinal opioid receptors?
PAG and locus coeruleus
Which type of opioid receptor do most analgesics target?
Mu
Which opioid receptor do morphine, methadone and fentanyl target?
Mu
Can morphine and fentanyl also target delta and kappa receptors?
Yes
Main issue with mu opioid receptors?
When agonised they can cause respiratory depression
Benefit of targeting delta and kappa receptors over mu?
They do not cause respiratory depression when agonsied
Mood effect of mu receptor being agonised?
Euphoria
Mood effect of kappa receptor being agonised?
dysphoria
Effect of kappa receptors being agonised on bodily waste?
Diuresis
Mood effect of delta receptor being agonised?
none
Main issue with agonising delta opioid receptors?
Proconvulsant
Undesirable effects of mu opioid receptor?
Constipation, sedation, nausea and vomiting, itching
Why does mu opioid receptor agonists being activated cause constipation?
They activate mu opioid receptors in the gut
Why can methylnaltrexone be taken to prevent constipation but not the analgesic effect of opioids targeting mu receptors?
It cant cross the blood brain barrier meaning it can block the opioid receptors in the gut (so no constipation) but cant access the locus coeruleus or PAG
What is psychological dependance?
Addiction
What is physical dependance?
When someone stops taking a drug and they have physical withdrawal symptoms
Result of increasing potency of mu receptor agonist on side effects?
They increase
What changes need to be made to the dose of a drug if continued use occurs?
The dosage will need to increase
What is the main active ingredient in an opium poppy?
morphine
Main structural difference between morphine and heroin?
Heroin has two acetyl groups where morphine has two OH groups
What benefit does having two acetyl groups instead of two OH groups give heroin over morphine?
It crosses the blood brain barrier more easily
What drawback is there of having two acetyl groups instead of two OH in heroin compared to morphine?
Makes heroin completely ineffective against the mu opioid receptor (heroin itself is not an opioid receptor agonist)
Why does heroin not having the correct structure to be a mu opioid receptor agonist not really matter?
There are many enzymes in the brain which can cleave the acetyl groups off
What is a pro-drug?
A drug that has to be metabolised in order to be its active ingredient
Which analgesics are taken in pill form?
Morphine, codeine
Which analgesics are taken via intravenous injections?
morphine, diamorphine, fentalyl
Which method of administering analgesics can be patient controlled?
Intravenous injection
What is an epidural?
Delivering a drug directly into the spinal cord
When is epidural administration used?
Childbirth
Why is epidural administration used in childbirth?
Know where pain will come from so know where it will enter the spinal cord so can administer drug directly into that bit of the spinal cord
What are the benefits of epidural administration of drugs in childbirth?
Minimises opioids going into the mothers bloodstream
Why is fentanyl used often in surgery?
Short half life
Which drugs are administered via a transdermal patch?
fentanyl and buprenorphine
Big advantage of transdermal patches?
Good way to steadily administer drug, keep dose at a consistent level
Which level of administration is used for treating chronic pain?
Transdermal patch
What is buccal aborption?
Through the mouth
Why is fentanyl absorbed orally?
It is lipophilic
Benefit of a fentanyl lolipop?
Quick way of getting drug into bloodstream
Examples of nonsteroidal anti inflammatory drugs?
Aspirin, ibuprofen, diclofenac, paracetamol
What effects do NSAIDs have?
Anti inflammatory, antipyretic, analgesic
Antipyretic meaning?
Decreases fever
What normal effect of NSAIDs can paracetamol not do?
Be anti-inflammatory
How do the additive properties of paracetamol and ibuprofen work?
The positive effects are additive but the toxic effects are not
Who cannot take paracetamol and ibuprofen?
Childeren
What do all NSAIDs inhibit?
Prostaglandins
What do prostaglandins activate?
Prostanoid receptors
What happens when prostanoid receptors are activated?
Sensitisation of nociceptors
What is the first molecule in prostaglandin synthesis?
Phospholipids
What are phospholipids converted to in prostaglandin synthesis?
Arachidonic acid
What catalyses the formation of arachidonic acid from phospholipids?
Phospholipase a2
What is arachidonic acid converted to in prostaglandin synthesis?
Prostaglandin H2
What catalyses the formation of prostaglandin H2 in prostaglandin synthesis?
Cyclo-oxygenase-1 or -2 (COX-1 or COX-2)
What is prostaglandin H2 converted to in prostaglandin synthesis?
Prostaglandin E2 (PGE2)
What catalyses the formation of prostaglandin E2 in prostaglandin synthesis?
PGE synthase
Which step of prostaglandin synthesis do NSAIDs target?
The conversion of arachidonic acid to prostaglandin H2
How do NSAIDs inhibit prostaglandin synthesis?
They block COX-1 or COX-2
Disadvantages of NSAIDs?
Severe gastric irritation, kidney disorders
Where is COX-1 found?
Widespread throughout the body
What is COX 2 exclusively involved in?
Inflammatory response
Inhibition of which specific enzyme causes the desired effects of NSAIDs?
COX-2
Inhibition of which specific enzyme in the prostaglandin synthesis pathway causes causes gastric irritation?
COX-1
Which drugs are COX-2 inhibitors?
Rofecoxib (vioxx), Celecoxib (celebrex)
Main issue with Rofecoxib (vioxx)?
Cardiac side effects
Side effect occurrence in Rofecoxib (vioxx) patients?
1/10,000
What is an example of a disease that taking Rofecoxib (vioxx) or celecoxib (celebrex) helps?
Rheumatoid arthritis
What is neuropathic pain?
Pain unrelated to peripheral nociception
What can cause neuropathic pain?
Peripheral nerve damage, peripheral nerve terminal damage or infection, spinal damage, thalamic stroke
Issue with neuropathic pain?
Does not respond to opioids or NSAIDs
Which drugs work for shingles pain?
Tricyclic antidepressants
Example of a tricyclic antidepressant?
Imipramine
Why, is it thought, that tricyclic antidepressants help with shingles pain?
They boost noradrenaline
Which drugs can be useful in neuropathic main?
Antiepileptics (gabapentin), cannabinoid receptor agonists
Which condition can cannabinoid receptor agonists be used to treat in the uk?
Multiple sclerosis
Issues with glutamate receptor blockers (e.g. MK801)?
Side effects–> psychotic episode
How do neurokinin receptors work?
Blocking central sensitisation
Issue with analgesics that block centran sensitisation?
Would need to take them before any pain is going to occur, as central sensitisation has already occured after pain has been felt
Difference between rewarding and reinforcing?
Reward is a subjective term, reinforcing is objective
Which word is used in place of reward in animals?
Reinforcing
What are symptoms of psychological dependence?
Craving, compul drug use, loss of control
Symptoms of physical dependence?
When stopping a drug causes a withdrawal syndrome
What is tolerance?
When continued use of a drug results in the need for increasing doses for equivalent effect
Who first discovered brain sites where direct electrical stimulation is reinforcing?
Olds and Milner
How did Olds and Milner discover reinforcing brian sites?
Implanted electrodes into different parts of rat brains, Rat was in charge of which parts were stimulated–> idea was that theyd stimulate the reinforcing parts
What is the mesolimbic pathway?
The reward pathway
How were the NTs involved in the mesolimbic pathway determined?
Microdialysis
How does microdialysis work?
Probe is inserted into brain region (tip of probe has dialysis tubing)–> NT that is released from nerve terminals that are where the probe is will enter the tip–> contents are pumped out
Why is dialysis tubing used in NT determination?
It has a semi-permeable membrane
What machine is the solution acquired as a result of microdialysis pumped into?
HLPC
Which NT is involved in reward?
Dopamine
Where are the dopaminergic neurones projecting from and to in the mesolimbic pathway?
From the ventral tegmental area to the nucleus accumbens
How does self administration work?
Cannula is implanted into the brain–> anything that is put into the cannula will go straight into the brain, animal can control this
What is the effect of 6-hydroxydopamine?
It is toxic but only to dopaminergic neurons
What happens to animals self-administration of drugs if dopaminergic pathways in the brain are lesioned?
They don’t self administer anymore
What is lesioning a brain pathway?
Using a chemical to turn that pathway off
What happens to animals self-administration of drugs if dopamine D1 or D2 antagonists are used?
They wont self administer anymore
What does an increase of dopamine in the nucleus accumbens feel like?
Euphoric
What does an decrease of dopamine in the nucleus accumbens feel like?
Dysphoric
What was the effect of most drugs of abuse on the amount of dopamine in the nucleus accumbens?
They increased it
Why is it thought that rodents take diazepam?
Reduces their anxiety
How do cocaine and amphetamine increase dopamine levels in the nucleus accumbens?
They are both dopamine reuptake inhibitors
What can amphetamine do that dopamine cant?
Directly cause dopamine release
How is it thought that amphetamine causes dopamine release?
It allows reverse transport through the transporters that usually allow dopamine back into the presynaptic neuron
How do opioids increase the levels of dopamine in the nucleus accumbens?
Inhibit the GABA neurons that would otherwise inhibit the dopaminergic neurons in the ventral tegmental area
How does ethanol increase the amount of dopamine in the nucleus accumbens?
Close K+ channels on the postsynaptic neurons in NA, decreasing hyperpolarisation post one AP meaning APs will fire more frequently
Which class of drugs does ethanol have a similar effect to regarding GABAa receptors?
Benzodiazepines–> it is an allosteric modulator (anxiolytic)
How does nicotine increase dopamine levels in nucleus accumbens?
Nicotine acts on nicotinic ACh receptors on dopaminergic neurons in the VTA, increasing the firing rate so more dopamine is released
How does THC increase dopamine levels in nucleus accumbens?
Acts on cannabinoid receptors which are on GABAergic interneurons–> GI/GO coupled GPCRs–> causes inhibition of the GABAergic neuron so less inhibitory GABA is sent to the dopaminergic neurons in the VTA
What is neurodegeneration?
The destruction of neurons in any disease, i.e. it has to be beyond that or normal aging
Where is neurodegeneration found?
Neurodegenerative diseases, cancer, trauma, viral diseases, vascular/circulatory disorders
Main causes of stroke?
Atherosclerosis, thrombosis, embolism, vasospasm, hyper vasculopathy
What is atherosclerosis?
Narrowing of blood vessels
What is an embolism?
Damage to heart valves
What is vasospasm?
Vasculature begins to spasm
What can cause vasospasm?
Subarachnoid hemorhage?
Ischaemic stroke?
Blockage in brain area which causes loss of blood and O2 to that area–> cell death
Haemorrhagic stroke?
Blood vessel becomes broken–> blood enters the brain
What is a venous infarction?
Where a brain has been hemorrhaged or broken in the brain
What causes venous infarctions?
Venous sinus thrombosis
What is the pattern of damage after ischaemic damage?
Initial area where there is reduction of blood flow–> main area of concern–> definite neuronal loss
Damage can spread to areas outside of this
Ischaemic penumbra?
An area which is less affected by the ischaemic damage but still affected
What can cause ischaemic penumbra?
Loss of blood supply, and release of substances by already dead neurons
Size of the infarction over time compared to penumbra?
Infarction increases to where the penumbra is, so penumbra decreases
What are stroke treatments aimed at?
Reducing area of penumbra, as it is reversible damage
What are the main types of glial cells in the nervous system?
Oligodendrocytes
What are oligodendrocytes involved with?
Myelination of axons in the CNS
What are the meninges?
Blood vessel containing membrane over the surface of the brain
Different types of menginital infection?
Bacterial, fungal, viral
What is polio caused by?
An RNA virus
Effect of polio on CNS?
Destruction of neurons in the spinal cord
How were scientists able to map spinal cord areas to control of certain muscles?
Observed loss of muscle control depending on different areas of the spinal cord that was affected by polio
Main issues with neurodegenerative diseases?
Unknown cause, no cure, progressive, both sporadic and inherited forms and they are often age dependent
Which neurodegenerative disease is transmissable?
Prion diseases
What is alzheimers associated with?
Gross brain atrophy
What is gross brain atrophy?
The loss of neurons in the brain
Which proteins is alzheimers associated with?
Beta amyloid tangles and plaques
Which two diseases are forms of dementia?
Alzheimers and Prions disease
Which form of dementia is transmissable?
Prion disease
Which neurodegenerative diseases are movement disorders?
Parkinsons and Huntingtons
What kind of atrophy is parkinsons associated with?
Loss of dopaminergic neurons in the substantia nigra
Which protein and mutation is Huntingtons disease associated with?
Increased amount of Huntingten protein with CAG repeats in the sequence
Which diseases are amyloidogenic?
Alzheimers, parkinsons, prion
What are amyloidogenic diseases?
Diseases where aggregates of a protein form a deposit
Which disease is characterised by the formation of intracellular protein deposits?
Parkinsons
Which disease is characterised by the formation of extracellular protein deposits?
Alzheimers
What is the most common neurodegenerative disease?
Alzheimers
Most common cause of dementia?
Alzheimers
Two main theories of the cause of alzheimers?
Deposition of beta-amyloid protein (amyloid cascade hypothesis) or deposition of phosphorylated tau in the form of helical filaments or tangles
Third theory of cause of alzheimers?
Metal hypothesis
Function of amyloid precursor protein?
Unknown, possibly ion transport and memory
What happens to beta amyloid protein when it is broken down by the cell?
It is acted on by secretases
Which secretases can act on amyloid precursor protein?
alpha or beta
Which secretase acts most commonly on APP?
alpha
Which products are formed if alpha secretase acts on APP?
Aicd, p3 (both are harmless)
Difference between alpha and beta secretase pathway?
APP is cut at a different location
How can gamma secretase influence the formation of plaques?
Where the gamma secretase cleaves at the C-terminal end
At which AA position in the C terminal does gamma secretase cleave for beta amyloid aggregates to form?
42
At which AA position in the C terminal does gamma secretase cleave for beta amyloid aggregates to not form?
40
What causes parkinsons?
The loss of dopaminergic neurons in the substantia nigra
Where does the substantia nigra usually innervate to?
Striatum
What happens to striatum innervation from the substantia nigra in parkinsons?
It is lost–> cant control movement in the normal way
Which proteins are involved in parkinsons?
Alpha synuclein (PARK1), Parkin (PARK2), DJ-1 (PARK7), PINK01 (PARK6), LRRK2 (PARK8), UCHL1 (PARK5)
What are aggregates of alpha synuclein called?
Lewy bodies
Are lewy bodies intra or extra cellular?
Intracellular
Where are the cells containing lewy bodies found?
Substantia nigra
WHat is Creutzfeldt-Jakob disease(CJD)?
Main form of human prion disease
WHich disease results in animal models that replicate symptoms observed in humans?
Prion disease
Characteristics of prion diseases?
long incubation period (10-40yrs), large deposits of prion protein, rapid neuronal loss, gliosis, vacuoles
How does the prion protein misfold?
As a result of interaction with other misfolded prion proteins–> could by why it is transmissible
Why is there a metal hypothesis regarding neurodegenerative diseases?
The proteins associated with NDs (APP, alpha synuclein, prion protein) are all metal binding proteins
What are the two main families of demyelinating diseases?
Demyelinating diseases and dismyelinating diseases
What is a demyelinating disease?
Myelin on axons is destroyed
Most common demyelinating disease?
Multiple sclerosis
What is a dismyelinating disease?
A disease where myelination doesnt occur normally
Cause of multiple sclerosis?
CNS myelin is selectively destroyed–> axon is still there
Onset of MS?
30-40
Observable symptoms of MS?
Muscle weakness, difficulty moving (ataxia), difficulty speaking or swallowing
Main issue with current ND treatment?
Most ND have on cure, treatment only alleviates/delays symptoms
Main target of ND treatment?
Aggregates
Time course for an ND patient?
Usually over 50 with no evidence–> develop minor psychological/behaviour/motor issues–> develop memory loss, or issues with navigation–> begin differential diagnosis–> begin QOL treatments–>delay symptoms treatment–> alleviate symptoms–> palliative care–> death from another casue
Do ND kill people?
No, usually smthn like pneumonia
What is special about Wilsons Disease?
It can be treated
How does someone get Wilsons Disease?
Inherited–> genetic mutation
Main cause of Wilsons Disease?
Copper metabolism disease
Which protein is mutated in Wilsons disease?
Copper ion transporting P type ATPase (ATP7B)
Role of Copper ion transporting P type ATPase (ATP7B)?
Movement of copper scross the membrane
Symptoms of Wilsons disease?
Abdominal pain, dark urine, jaundice, mood changes, rings around edge of cornea, tremor and stiff muscles
How is wilsons disease treated?
A copper chelator–> helps remove copper from the body
What are two copper chelators used to treat wilsons disease?
Penicillamine and trientine
What are the two ways that aggregates are targeted in ND?
Preventing their formation or causing their breakdown
What are causes other than aggregates that can cause ND?
Oxidative stress (toxic radicals–> e.g. superoxide)
Mitochondrial damage–> could produce cytochrome C
How is aggregate formation prevented?
Target parent protein, stimulate breakdown enzymes, prevent misfolding
How are aggregate parent proteins targeted?
Antisense RNA, genetic knockout (CRISPR-Cas9)
How is breakdown of aggregates increased?
Increases the action of the proteasome on that specific protein, use antibody treatments
Which disease could be treated with antisense RNA?
Huntingtons
Which protein is targeted by antisense RNA in huntingtons?
Huntingtin (HTT)
Which (failed) treatment of Alzheimers involved gamma secretase inhibitors?
Brought in a gamma secretase to reduce the amount of beta amyloid being produced
How effective have antibodies against aBeta been in alzheimers?
Reduced cognitive decline by 20-40%
How are the antibodies for Azheimers treatment delivered?
Cannula infusion
How are alzheimers antibodies believed to work?
Recruitment of microglia
Main cause of PD?
Loss of dopaminergic neurons in substantia nigra in pathway to striatum
What are parkinsons treatments aimed at?
Restoring dopamine for the normal function of the striatum
What are the two kinds of receptor in the striatum?
D1 and D2
What are the two pathways running between the striatum and the motor cortex?
Facilitatory, direct pathway, and the inhibitory, indirect pathway
Effect of dopamine on the facilitatory pathway between the striatum and the motor cortex?
It enhances it
Effect of dopamine on inhibitory pathway between the striatum and the motor cortex?
It inhibits it
Which dopamine receptor is targeted by dopamine for the facilitatory pathway?
D1
Which dopamine receptor is targeted by dopamine for the inhibitory pathway?
D2
Effect of dopamine loss in PD?
Reduced motor cortex activity
How can dopamine be increased?
Provide more dopamine or more dopamine precursor, decrease its reuptake, inhibit its breakdown, provide a dopamine agonist
Most common parkinsons treatment?
Provide L-Dopa
Why is L-Dopa provided instead of dopamine?
L-Dopa can cross the blood brain barrier
Main issues with L-Dopa?
It can be converted to dopamine (which cant cross BBB) in the blood
Which drug is given alongside L-Dopa to prevent dopamine formation in the blood?
Cabidopa (dopa decarbodylase inhibitor)
Side effect of L-Dopa?
Dyskinesia–> severe involuntary movement
How is the dyskinesia of L-Dopa treatment managed?
Patients have an “off” time where they dont take any L-Dopa in order to reduce the prevalence of side effects
Second treatment aim at PD after L-Dopa?
Inhibit breakdown of dopamine
How is dopamine breakdown inhibited?
Monoamime oxidase B (MAOB) inhibitors
What is the main MAOB inhibitor?
Selegeline
PD treatment after L-Dopa and MAOB inhibitor?
Catechol O-Methyl Transferase (COMT) inhibitor
Side effects of L-Dopa?
Nausea and dizziness
Side effects of COMT?
Toxicity to liver cells, diarrhoea and sleep disturbances
Main COMT used for PD?
Tolcapone
How do dopamine agonists work?
Acts directly on dopamine receptors
Side effects of dopamine agonists?
Nausea, dizziness, hallucinations, sleep attacks, hypotension
Examples of dopamine agonists?
Pramipexole, Ropinirole, Bromocriptine
What is deep brain stimulation?
Implanting an electrode into the striatum–> can stimulate it directly and thus stimulate the activity
Benefits of deep brain stimulation?
Doesnt have the same side effects of L-Dopa
Complications of deep brain stimulation?
Brain hemorrhage, seizures, death
Issues with stem cell treatment for ND?
Cost and time
What is learning?
acquisition of new information or knowledge
What is memory?
storage or retention of acquired knowledge
What is an engram?
physical representation or location of memory, a collection of neurones
What are the three classificaitons of memory?
Declarative, emotional, procedural
Examples of declarative memory?
Daily episodes (remembering address), words and meanings, history
Example of emotional memory?
Preferences/aversions–> things we do/dont like depending on past expiriences
Examples of procedural memory?
Motor skills, solving puzzles, priming cues, association and linking
Which areas of the brain are involved in memory?
All
Which brain regions involve emotional memories?
Amygdala, hypothalamus
Which part of the brain is responsible for motor memory?
Cerebellum (used for playing instrument riding bike etc)
Which type of the brain is involved in declarative memories?
Hippocampus, entorhinal and parahippocampal cortex
Which areas of the brain are involved in procedural memories?
Cerebellum, striatum, brainstem and spinal motor output
Which brain area is seen as a hub of learning and memory?
Hippocampus
What is anterograde amnesia?
inability to form new memories/learn new things
What is retrograde amnesia?
Can’t recall things
What is working memory?
Short term memory
Order of solidifying a memory?
Input–> short term (working) memory–> long term memory
What is Hebbs law?
If there are two connected neurons in the brain, and one repetitively fires APs onto the other (and vice versa), the synapse that connects them becomes permanently stronger
What kinds of memories does the engram theory work with?
All of them
In terms of an engram, what is short term memory?
Reverberating activity between synapses
What does reverberating activity between synapses do to them?
Strengthens them
What happens once synapses between neurons reverberate enough?
The synapses become permanently strengthened, thus creating a long term memory
Why does only part of a stimulus need to be viewed for an engram to be activated?
Part of the stimulus only triggers a few neurons, but bc they have strengthened synapses they will all end up firing APs
What are all memories down to?
Strengthening synapses
Which brain area has been the focus of most of research in synaptic strengthening?
Hippocampus/entorhinal cortex
Which type of NT neurons are involved in memories?
Glutamatergic
How is synapse strengthening studied?
Stimulate axons in the entorhinal cortex that innervate the hippocampus, causing them to fire APs. Can record membrane potential of postsynaptic neuron
How does a synapse get stronger?
If a burst of activity happens in the presynaptic neuron (100APs in 100miliseconds) the strength of the synapse is increased–> there is a potentiated AMPAr EPSP which lasts forever–> a larger EPSP as a result of more APs being fired down
What is long term potentiation?
Increase in the strength of a synapse after repeated stimulation–> lasts long term
What is a tetanus?
A high frequency burst of APs
What is the memory response caused by?
Opening of AMPA receptors
What happens if NMDA receptors are blocked during memory formation/synapse strengthening?
The potentiated EPSP doesnt occur (LTP doesnt form)
What happens if Ca2+ entry via NMDA receptors is limited during synapse strengthening?
The LTP doesnt occur
Where is the change that allows a LTP to form?
AMPA receptor
Where is the change to AMPA receptors caused by?
NMDA receptors
State of NMDA receptor pore at normal membrane potential?
Blocked by Mg2+
What are NMDA receptors permeable to?
Ca2+ and Na+ both going in
How is an LTP manifested postsynaptically?
Intracellular AMPA receptors get trafficked to CSM, the AMPA receptors are more sensitive and there is more synapses
How is an LTP manifested presynaptically?
Increased release of NT, more release sites and more vesicles
Other than EPSP what can calcium be used for in the postsynaptic neuron?
Signalling
What can calcium do as a signalling molecule in the postsynaptic neuron?
Activate kinases, e.g. Protein Kinase C, calcium calmodulin kinase II
What can protein kinase C phosphorylate?
AMPA receptor
What does phosphorylating AMPA receptors do?
Make it more sensitive–> it opens wider per glutamate molecule that binds to it
What does calcium comodulase kinase II do?
Acts as the trigger for causing intracellular AMPA receptors to traffic to the cell membrane.
How does calcium cause nitric oxide?
Via activity of guanylyl cyclase
What is NO used as in LTP?
An NT
Good things ab using NO as an NT?
It is a gas so it can freely diffuse from postsynaptic to presynaptic
Role of NO presynaptically?
Increased amounts of vesicles, increase probability that a vesicle is released per AP
What is a retrograde transmitter?
Goes from postsynaptic to presynaptic
Morris water maze?
Opaque body of water with a platform that lets them stand
Morris water maze use?
Studying memory
How was a morris water maze used to study memory?
Trained them to find the platform (same place) then did that with a NMDA agonist–> when agonist was present they didnt learn where the platform was
What is a priming cue?
A stimulus that can trigger memories
What kinds of memories can a priming cue trigger?
Conscious–> remember event, subconscious–> feeling ill, anxious
What is pavlovian/classical conditioning?
To do with memory linkage: Dog will salivate in response to food, if you combine food and bell then the dog will salivate, if you do it enough the dog will end up salivating if you only ring the bell and don’t present food
Why is pavlovian conditioning linked to drug abuse?
People associate the place they are, people they are around, music that is playing with taking drugs–> people would crave a drug if they go into the room where they used to take them
Outcome of a cocaine user watching a video of nature, then someone doing coke?
Brain activity when nature video was normal but different when they watched someone take coke
What can cause a short term memory loss?
Alcohol, head trauma etc
Two different types of amnesia?
Retrograde or anterograde
Retrograde amnesia?
Lose ability to recall memories that have already been learned
Anterograde amnesia?
Cant create new memories
What are demetias?
A family of symptoms characterized by a decline in cognitive functions sufficient to cause impairment in social and occupational performance
What is the first presenting feature of demetia?
Decline in memory
Most common form of dementia?
Alzheimers
What are initiation deficits/apathy?
Lacking the will to do something
What are visuo-spatial deficits?
Forgetting visual things/locations e.g. forgetting the way home/where they are etc
Most common alzheimer’s symptoms?
Memory, initiation, visuo-spatial and language deficits
Paraphasia?
Struggling to identify the right words
What drives executive function?
Frontal cortex
What is executive funciton?
Risk assessment–> motivated to do x thing but there may be a risk, weighing up pros and cons
Symptoms of having executive function issues?
V risk averse/v risky
What is psychosis?
A psychotic epidose–> is a symptom not a disease itself
Does psychosis occur in AZ?
Yes
How is psychosis treated in AZ?
Antipsychotics that are used to control schizophrenia
Incidence of AZ with age?
Strongly correlated with age
Cause of AZ?
Neurons in the brain dying
Where is the first locus of AZ damage?
Temporal lobes
What is found in the temporal lobes?
Hippocampus and entorhinal corex
Why are memory deficits seen as the first symptoms of AZ?
FIrst affected parts are hippocampus and entorhinal cortex which are involved in memory
What happens to the rest of the brian as AZ spreads?
AZ spreads around the brain
Which parts of the brain are not affected by AZ?
Midbrain/brainstem
Cause of AZ?
Extracellular plaques that form as a result of abnormal beta amyloid, and intracellular tangles made up of abnormal Tau protein
Where is APP found?
Membrane spanning
First action on APP?
Cleaved by alpha secretase
What forms as a result of alpha secretase cleaving APP?
APP alpha (soluble)
What effects does APP alpha have?
Trophic–> positive (“nourishes the neurons”)
What happens to the rest of APP that isn’t cleaved into APP alpha?
Cleaved by gamma secretase into two smaller peptides that can be metabolised
What happens to APP in AZ?
It gets cleaved by beta secretase
Difference between alpha and beta secretase?
Cleavage position on APP
What forms as a result of beta secretase cleavage of APP?
APP beta, and a larger peptide remnant
What cleaves the larger protein remnant formed by beta secretase cleavage?
Gamma secratase
What forms as a result of gamma secretase cleaving the larger peptide remnant from beta secretase?
Beta amyloid 40 or beta amyloid 42
How is ApoE4 involved in AZ?
It can help beta amyloid 40/42 form plaques
General role of ApoE4?
Helps cholesterol and fat soluble vitamins enter neurons
What can beta amyloid plaques do?
Drive production of phosphorylated Tau
What % of AZ cases are sporadic?
90%
What may cause the formation of amyloid beta 40/42?
Enhancement of beta secretase as a result of environmental/disease/inflammation
Which beta amyloid protein has a more severe effect?
Beta amyloid 42
What does intracellular Tau do?
Causes neuronal cell death
What can beta amyloid plaques form complexes with?
Metal ions–> Cu, Fe etc
What forms as a result of beta amyloid plaques forming complexes with metal ions?
Peroxide is produced
What can peroxide do in neurons?
Peroxidate membrane lipids
Effect of peroxidation on membrane lipids?
Can comprimise their functions–> functions of membrane spanning proteins
Examples of membrane spanning proteins on neurons
All ion channels, all NT receptors etc
What can happen if Ca2+ levels are too high in neurons?
Calcium sets off toxic events
What can calcium cause in neurons that is toxic?
Excitotoxicity, tau phosphorylation
What, other than peroxidation, can beta amyloid plaques cause?
Tau phosphorylation
What can tau phosphorylation (and thus neurofibrillary tangle formation) form?
Disruption of microtubular transport
Main drugs used to treat AZ? symptoms?
Cholinesterase inhibitors, memantine, nootropics,
Examples of cholinesterase inhibitors?
Donepezil, rivastigmine, galangamine
Which type of NT neurons are first affected in AZ?
CHolinergic neurons
Role of Ach in entorhinal cortex and hippocampus?
LTP and normal function
Effect of cholinesterase inhibitors?
ACh stays in synapse for longer so more signalling to postsynaptic neuron
Which drug is given to people in later stage AZ?
Memantine
What is memantine?
Non-competitive NMDA receptor blocker
Why does memantine work as an AZ treatment?
Not known, may be neuroprotective
What a nootropics?
Drugs that are cognitive enhancers
What are AMPAkines?
Positive allosteric modulators at ampa receptor
What is used to treat ADHD?
Methylphenidate (ritalin)
Four drugs used to treat AZ?
Donepezil, rivastigmine, galantamine, memantine
What is most of the research about treating AZ progression aimed at?
The Beta Amyloid hypothesis
Which drugs targeting the beta amyloid hypothesis are in trials?
Beta secretase inhibitors, anti-amyloid beta vaccine/monoclonal antibodies, anti tau vaccine/monoclonal antibodies
How are copper and zinc targeted in possible AZ progression treatment?
With chelators as the metal ions can promote plaque formation
Issues with nerve growth factors for treating AZ?
Would have to be directly infused into brain so cant be used for routine therapy
Effect of statins on AZ?
Cholesterol promotes amyloid deposition
What are donanemab and lecanemab?
Monoclonal antibodies against beta amyloid peptide–> prevent plaque formation by sticking too it
How effective are donanemab and lecanemab?
Delay progression by ~ 4 months
What can be used for early diagnosis?
Beta amyloid plaque formation–> can start to form 5-10 years before symptoms
What could be used to look for AZ biomarkers?
Blood samples, brain scans, spinal fluid draw (last two are difficult)
