bruno (L4-8) Flashcards
organisation of the peripheral nervous system (pns)
- somatic ns (skeletal muscle)
- autonomic ns // sympathetic ns and parasympathetic ns (targets all except skeletal muscles)
- enteric ns (guts)
types of nerve fibres (2)
AFFERENT fibres carry sensory information to the CNS
and
EFFERENT fibres carry signals from the CNS to the periphery
3 types of horns
dorsal horn (sensory inputs, on the back of the spinal cord)
lateral horn (spinal preganglionic neurones of ANS)
ventral horn (somatic motor neurons)
the 5 steps to communication in the CNS/PNS to synaptiic transmission
- Synthesis of neurotransmitter
- Store neurotrans in vesicles - 2 reasons to store (protect neurotrans from enzymes that can metabolise them, package neurotrans at high conc in vesicles so that when released, the conc is much higher than in the synaptic cleft and achieve a burst)
- Release neurotrans - many steps are involved, you have to dock the vesicle with the ??? calcium catalyses the fusion of vesicles and the axon membrane, exocytosis, retrieve the membrane to recycle by endocytosis
- Activation of neurotrans receptors - 2 types (ligand gating receptors with ion channel through them, G protein coupled receptors). Neurotran activates either G protein one only, or both.
- Inactivation - remove neurotrans by 2 mechanisms (enzyme present that metabolises the neuro into inactive components, or remove complete neurotrans or breakdown product of the neurotrans). This is to achieve a phasic fashion for the neurotrans to have a high conc gradient and ensure a high impact.
efferent pathway of somatic nervous system
it consists of a single neurone
cell body of neuron lies in the ventral horn of the spinal cord or nuclei within higher brain centres
motor neuron (efferent) runs directly to the skeletal muscle fibres synapses at a specialised structure (NMJ neuromuscular junction, or endplate)
efferent pathway of somatic nervous system
consists on 2 neurons
- preganglionic neurone
- ganglion
- postganglionic neuron
classification of somatic and autonomic synapses
- somatic motoneurones
1 neuron from cns to skeletal muscle
nAChR - parasympathetic motor neurones
2 neurons from cns to ganglia to eg salivary glands
nAChR pregang / mAChR postgang - sympathetic motor neurons
2 neurons from cns to ganglia to blood vessels
nAChR pre / NA post
OR: 2 neurons from cns to adrenal medulla to all cells
nAChR pre / adrenaline post
OR: 2 neurons from cns to ganglia to sweat glands
nAChR pre / mAChR post
classification of parasympathetic nervous system
LONG PREGANGLIONIC NEURON / SHORT POSTGANGLIONIC NEURON
from brain stem (medulla) to different tissues
-2 neurons (medulla to peripheral ganglion to pupils or salivatory glands)
-2 neurons with vagus (X) nerve as a preganglionic nerve
(medulla to peripheral ganglion to bronchi, heart, gallbladder, gut motility, bladder, genitals)
classification of
sympathetic nervous system
SHORT PREGANGLIONIC NEURON / LONG POSTGANGLIONIC NEURON
from spinal cord to ganglion in sympathetic chain to different tissues
- 2 neurons through sympathetic chain (blood vessels, hari erection, sweat glands)
- 2 neurons through sympathetic chain (pupils, bronchi, heart rate and contractility)
- 2 neurons, ganglia after the sympathetic chain (gut motility, liver, renal)
- 1 neuron to adrenal glands
- 2 neurons through hypogastric ganglion (vas deferens in ejaculation)
Probability of the neurotransmitter releasing
Probability of the neurotransmitter releasing across the synapses is rarely 1, which means that if you send an action potential down a nerve the chances that one of the viral posities will release neurotransmitter is not one so it will not happen every single time
the probability is actually quite low at these varicosities, which is why we have so many vesicles. the probability of releasing something that can be modified can be increased buy the circuits of the brain to ensure that the response will be put into action.
acetylcholine in the parasympathetic NS
ACETYLCHOLINE is the neurotransmitter released from all parasympathetic postganglionic neurones at the neuroeffector junction
how do you classify synapses
Synapses can be classified according to the transmitter released from the presynaptic neurone.
At synapses where the presynaptic neurone synthesises and releases acetylcholine (ACh) transmission is classed as cholinergic. Receptors upon which ACh acts are called cholinoceptors.
Two classes of cholinoceptor in the NS
- nAChR
Nicotinic cholinoceptors
are activated by ACh or the tobacco alkaloid nicotine but not by muscarine.
ALL ARE LIGAND GATED ION CHANNELS - mAChR
Muscarinic cholinoceptors
are activated by ACh or the fungal alkaloid muscarine but not by nicotine.
ALL ARE G PROTEIN COUPLED RECEPTORS
define noradrenergics and name 2 types of their receptors
At synapses where the transmitter is noradrenaline, transmission is described as noradrenergic and the receptors activated are called adrenoceptors.
Two classes of adrenoceptor are found
in the nervous system:
α-adrenoceptors and β-adrenoceptors
molecular structure of nicotinic cholinoceptors (subunits, domains etc)
consists of 5 subunits (αβγαδ) to form a pentameric ligand gated ion channel
Extracellular domain will respond to ach
Transmembrane domains - M2 domain creates the ion channel, M2 determines ion conduction or ion cell activity of the channel.
how do ions flow through the nicotinic cholinoceptors?
the Ach has to bind to the 2 a subunits for the ion channel to open by shape change, ions move down their electrochemical gradient
OR IONS (EG SODIUM)
Sodium ions are repelled from the positive ion dense region at the bottom. Fenestrations are found on the sides of the structure of the channel. They could be roots for ions to flow through.
so the ions flow through the channel from the top and out its sides
g couple protein coupled receptor cycle
by agonist binding, the receptor then becomes occupied and causes a conformational change which allows it to interact with the alpha subunit of the G protein
alpha subunit then loses its affinity to the GDP and its affinity to GTP increases.
Activated the G protein, it goes to interact with its target proteins (activate or inhibit)
To stop the cycle - alpha subunit metabolises the GTP to GDP. GTPase activity switches off the signal. Returns to resting state.
difference in rates of activation between nicotinic receptors and ligand gated channel
Process occurs over a few milliseconds while the activation of a ligand ion gated channel occurs in many seconds so the time scale is very different
this is because nicotinic receptors are found at the skeletal muscles where we need very quick control of activity, whereas in the gut we don’t need quick control so we can use ligand gated channels
Signalling of these 2 processes is very different
process of Botulinum toxin affecting the neuromuscular junction
The fusion of the vesicles to the presynaptic membrane gets interactions of many proteins (snare, syntaxin etc)
They tether the synaptic vesicle to the presynaptic membrane
Ca enters cell, tethers are taken up, take it to close proximity to the membrane, fusion, release of neurotransmitter
B toxin can interfere with one of the proteins (synaptotagmin) to get a complex form
Internalised through endocytosis - bond between HC and LC is broken.
LC cleaves the SNARE proteins
→ PARALYSIS
define mEPP and the result of its summation
Release of a vesicle gives a “quanta” of transmitter
At NMJ each quanta gives rise to a miniature end plate potential (mEPP) via activation of nAChRs
mEPPs summate to give an end plate potential (EPP), which, if large enough, can initiate an action potential (AP) and hence muscular contraction
2 phases of NMJ block
PHASE 1 BLOCK -
persistent activation of endplate nicotinic receptors by suxamethonium
Causing strong depolarization of the muscle which results in inactivation of voltage gated sodium channels (these channels need to rest but as you depolarise the membrane then it tends to deactivate the voltage gated sodium channels). so they become desensitised
PHASE 2 BLOCK - Because nicotinic receptor has been heavily stimulated, so leads to desensitisation of receptors, maintains the blockade of NMJ
ganglionic blockers
ganglion blockers
reduce the actions of both the sympathetic and parasympathetic nervous systems
Both sympathetic and parasympathetic NS have ganglion so blocking ganglia will block the whole autonomic nervous system
difference between the autonomic ganglia and NMJ ganglia
These nicotinic receptors are diff from the ones at the NMJ
Before, they knew this because the drugs used at NMJ don’t work at ganglion. (this is weird because they both respond to nicotine but only one of them response to suxamethonium)
Subunit composition for nicotinic receptors at the ganglia is different
Pharmacology of receptors is diff they have their own antagonists and agonists
muscarinic receptor subtypes
M1 neutral (Autonomic ganglia) - Modulation of ganglionic transmission
M2 cardiac (Cardiac atria and conducting tissue) - Cardiac slowing
↓ force of contraction
M3 glandular (Salivary glands and smooth muscle of gut) - Secretion of saliva and ↑ gut motility
M4 (CNS) - Modulation of synaptic transmission
M5 (CNS, substantia nigra) - Modulation of synaptic transmission
muscarinic receptor / G protein subtype / typical second messengers / physiological response
M1,3,5 / Gαq / Protein Kinase C (PKC) Ca2+ / Excitation, secretion, contraction
M2,4 / Gαi / Reduced cAMP & PKA activity
Gβγ opens K+ channels / Inhibition, reduced force/rate contraction
differences between Gαq and Gαi
Gαq - stimulates phospholipase C β (PLCβ) which breaks down phosphatidylinositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates PKC and IP3 causes the release of Ca2+ from internal Ca2+ stores
Gαi - inhibits adenylate cyclase (AC) which results in a reduction in cAMP, reduced activation of PKA and reduced Ca2+ channel activity. Gβγ activates certain K+ channels that leads to K+ efflux from the cell, membrane hyperpolarisation and reduced excitability
cholinesterases
termination of the effects of acetylcholine by degrading it into acetyl group and choline group
Enzyme works in the active cleft of receptor of the enzyme, there are binding sites for the molecule
Anionic site binds the choline moiety of ACh
Allosteric site binds acetyl end of the molecule
Electrostatic attraction keeps the molecule in the catalytic pocket
Cleaves the bond to release the 2 groups
VERY RAPID, HIGH TURNOVER NMBR
2 types cholinesterases
True acetylcholinesterase (AChE/AChase) // present at cholinergic synapses bound to the postsynaptic membrane in the synaptic cleft
Pseudo-cholinesterase // widely distributed and found in plasma
important in inactivating the depolarising neuromuscular blocker, suxamethonium
–> both true and pseudo cholinesterases are inhibited equally by most clinically-relevant anticholinesterases
cholinergic hypothesis of alzheimer’s disease
Shows reduction of vesicular acetylcholine transporters (that pump acetylcholine into synaptic vesicles)
Reduction correlates with the severity of dementia
You can use acetylcholinesterase inhibitors to reduce the activity of acetylcholinesterase in the brain
Get improvements in cognitive functions
myasthenia gravis
- Auto-immune disease (where the body produces antibodies to the nicotinic receptors
antibodies attach to the receptors and induce a compliment response from the immune systems
called the membrane attack complex) - Loss of NMJ nAChR
- Loss of NMJ structure (Invaginations are lost so membranes of postsynaptic membranes on muscle are not invaginated and are flat and smooth
Reduces surface area for the nicotinic receptors) - Muscular weakness, paralysis
define the alpha2 receptor’s role and the feedback loop of a noradrenergic synapses
alpha2 receptor (alpha2 being the subunit for the alpha receptor type) is found on presynaptic terminals of varicosities - it inhibits the release of noradrenaline Release of noradrenaline is detected by post and presynaptic receptors and switches off calcium channels So these are called inhibitory autoreceptors - senses the release of its own neurotransmitter So that levels of noradrenaline neurotrans dont get too elevated in synaptic cleft → VERY SENSITIVE FEEDBACK LOOP allows synaptic transmission that is finely tuned
2 types of pumps that allow the uptake mechanisms of noradrenaline
Uptake mechanisms of pumps removing noradrenaline from synaptic cleft into pre or postsynaptic cell
2 types of pumps - norepinephrine (high affinity, and target of many drugs) or extraneuronal monoamine transporters (found on a variety of postsynaptic tissues)
enzymes that metabolise noradrenaline and adrenaline
NA and Adr are metabolised by enzymes - MAO (associated with mitochondria) and MAO COMT (degrades NA and Ard)
adrenoceptor diversity and their rank order of potency
α-adrenoceptors (α1 and α2)
β-adrenoceptors (β1, β2 and β3)
the α2 is on presynaptic terminal which inhibits noradrenaline release
ALPHA - very sensitive to noradrenaline, less to adrenaline, not at all to isoprenaline
BETA - very sensitive to isoprenaline, less to adrenaline, not at all to noradrenaline
adrenoceptor subtypes / representative tissue / physiological response
α1 - vascular smooth muscle
vas deferens smooth muscle (inhibits NA release so contracts muscle)
α2 - adrenergic nerve terminals (inhibits NA release)
β1 - cardiac muscle (increases the heart rate and force of contraction)
β2 - cardiac blood vessels
skeletal muscle blood vessels
bronchial smooth muscle (used for treatment of asthma)
β3 - adipose tissue, not found in brain (breakdown of fat)
alpha adrenoceptor subtypes / G protein subtype / typical second messenger / physiological response
α1 / Gαq / Protein Kinase C (PKC) Ca2+ / Contraction of vascular
smooth muscle
α2 / Gαi / Reduced cAMP & PKA activity
Gβγ ↓voltage-gated Ca2+ channels / inhibits noradrenaline and insulin release
beta adrenoceptor subtypes / G protein subtype / typical second messenger / physiological response
all are coupled to Gαs increased cAMP and PKA activity increased cardiac output increased dilation and relaxation lipolysis
drugs acting at the presynaptic terminal and inhibiting noradrenergic transmission
(synthesis of noradrenaline)
L-TYROSINE
tyrosine hydroxylase (inhibited by a-methylparatyrosine)
DOPA
dopa decarboxylase (inhibited by carbidopa, benserazide)
DOPAMINE
dopamine B-hydroxylase (inihibited by disulfiram antabuse)
NORADRENALINE
where do carbidopa and benserazide act in the brain
Carbidopa and benserazide will not enter the brain. Otherwise we will get seizures. It is an antagonist of GABA A receptors
drugs acting at the presynaptic terminal and inhibiting noradrenergic transmission
(storage of noradrenaline)
RESERPINE
Inhibits NA uptake Depletes NA (and DA, 5HT) General decrease in sympathetic function Damages vesicles Decreases HR, BP but…… Postural hypotension Hypothermia Sedation, depression (suicidal at high doses)
α-METHYL DOPA Converted to α-methyl NA Replaces/displaces NA Released instead of NA Less potent than NA at α1 Activates α2 - less NA release Decreases HR, BP
drugs acting at the presynaptic terminal and inhibiting noradrenergic transmission
(release of noradrenaline)
BRETYLIUM
GUANETHIDINE
(noradrenergic neurone blocking drugs, long lasting depletion of NA)
used for ventricular arrhythmia and hypertension
CLONIDINE (alpha 2 agonist so inhibits NA release)
used for hypertension and tourette’s
α Adrenoceptor Antagonists (2)
PRAZOSIN receptor is a1 decreases BP used for hypertension fewer side effects doesn't affect HR
LABETALOL receptor is a/B decreases BP used for hypertension blocks reflex increases HR via B1 block
β Adrenoceptor Antagonists
PROPRANOLOL
receptor is B (non selective)
↓HR, ↓BP, ↓cardiac output, causes hypoglycaemia and cardiac failure
treats angina and dysrhythmias
ATENOLOL
receptor is B (cardioselective)
↓HR, ↓BP, ↓cardiac output (via B1)
treats hypertension
PINDOLOL it's a partial agonist doesn't give max response inhibits action of full agonists treats hypertension
directly acting sympathomimetics
NORADRENALINE
receptor is a and B1
↑ BP due to α1 vasoconstriction
treats shock and cardiac arrest
ADRENALINE receptor is a and B ↑HR (chronotropic) ↑force (ionotropic) bronchodilation treats cardiac arrest, anaphylatic shock and used as local anaesthetics
SALBUTAMOL
receptor is B2
relaxes smooth muscle like bronchodilation
treats asthma and inhibits premature labour
monoamine neurotransmitter 2 types
catecholamines (noradrenaline and dopamine)
tryptamines (serotonin)
define NET
norepinephrine transporter. it takes up noradrenaline from the synaptic cleft
cognitive enhancers - name the psychological effects it was thought to have
- Reduce mental fatigue
- Maintain attention and concentration
- Increase motivation (especially for dull & repetitive tasks – (eg exam revision)
- Alter memory processing (i.e. enhance memory)
- Normalise behavior (eg schizophrenia, autism disorders, addiction)
- Caffeine, modafinil, methyphenidate, ampakines…..
ampakines as cognitive enhancers
Enhance activation of glutamate AMPA receptors
Promote release of brain-derived neurotrophic factor (BDNF)
Show evidence of enhancing cognition in a range of tests
monoamine theory for depression
First proposed by Joe Schildkraut in 1965 based on evidence that drugs that enhance monoamine levels improve mood and symptoms of depression and vice versa (eg reserpine) for drugs lowering monoamine levels.
Other factors may be involved (stress hormone levels, neurogenesis)
name the antidepressant drugs that elevate the monoamine levels
PHENELZINE
monoamine oxidase inhibitors
IMIPRAMINE
monoamine uptake inhibitors (tricyclics)
CITALOPRAM FLUOXETINE, PROZAC
monoamine uptake inhibitors (selective)
REBOXETINE
monoamine uptake inhibitors (selective)
DULOXETINE
monoamine uptake inhibitors (dual action)
positive symptoms of schizophrenia
(over-activity in the mesolimbic dopaminergic pathway activating dopamine D2 receptors)
Delusions/paranoia Hallucinations (voices) Thought disorder Abnormal behaviour (eg stereotyped movements) Catatonia/immobility
negative symptoms of schizophrenia
(symptoms: decreased activity in the mesocortical dopaminergic pathway (D1 receptors))
Social withdrawal
Flattening of emotion
Anhedonia (inability to experience enjoyment)
Apathy (eg for hygiene, routines)
cognitive symptoms of schizophrenia
(attention and memory – mesocortical pathway)
Side Effects of Antipsychotic Drugs
- Motor effects
- Extrapyramidal effects
- D2 receptor antagonism in nigrostriatal pathway
- Involuntary movements / tremor / spasms / rigidity – symptoms of Parkinson’s disease
- Acute dystonias (shortly after treatment onset - reversible)
- Tardive dyskinesia (long after treatment starts - irreversible and progressively worsens)
- Less of a problem with second generation antipsychotics
- Increased prolactin secretion leading to gynecomastia (in men) and galactorrhea
- Weight gain
- Sedation/drowsiness
