Main Chemicals in the Brain Flashcards
Drug targets that may overlap with neurotransmitter’s life cycle:
- AP in pre-synaptic fibre
- synthesis
- storage
- metabolism
- release
- reuptake
- degradation, receptor, receptor induced increase or decrease in ionic conductance, retrograde signalling, second messengers
insert diagram
Neurotransmitter’s:
- endogenous chemical
- released extracellularrly by a neuron
- used to signal to neurons, myocytes, endocrine
- under physiological conditions
How are neurotransmitter’s classified?
- according to chemical class:
- amino acids: glutamate, aspartate,
GABA - monoamine: dopamine, NA, A,
serotonin - acetylcholine, peptides
Life Cycle of Neurotransmitters:
Neurotransmitter Nomenclature:
ach = cholinergic neurons, cholinergic receptors
noradrenaline = noradrenergic neurons, adrenoreceptors
CNS: Amino Acids:
- CNS has high concs of certain amino
acids - inhibitory neurotransmitters
hyperoplarise membranes - excitatory neurotransmitters
depolarise membranes
eg: GABA = inhibitory amino acid
Glutamate = excitatory
Where are neurotransmitters in the CNS located?
Ubiquitous distribution in the brain and produce powerful, readily reversible effects
Glutamate:
- class of neurotransmitter
- source?
- synthesis?
- stored?
- amino acid: primary excitatory in
CNS - mainly dietary amino acid so doesn’t
need synthesis - can be synthesised from alpha-
ketoglutarate or glutamine - sequestered in high cons in synaptic
vesicles by VGLUTs - rreleased in glutamatergic synapses
Glutamate: Action:
- 99.9% transmission is excitatory
- act upon ionotropic (NMDA, AMPA,
Kainate) and metabotropic receptors
(ACPD; mGLU recepptors) - mainly fast transmission, hence
mostly through ionotropic receptors
(fastest)
Ionotropic receptors
ion channels (change in ion movement across the membrane)
Metabotropic receptors are
G protein coupled receptors
Which is the fastest receptor of glutamate?
AMPA receptors
- permeable to Na+, K+ but not Ca2+
NMDA receptors:
- iontropic (four protein subunits)
- permeable to Ca2+, Na+, K+
all have Mg2+ blockade, so cell must
be depolarised by the action of
glutamate on AMPA receptors before
glutamate can open NMDA as a
safety feature - glutamate and glycine must bind,
then strong depolarisation leads to
removal of Mg2+ and rise in
intracellular Ca2+
Long term potentiation/synaptic plasticity
What is excitotoxicity?
Neuronal damage/death causes by excessive cellular excitation
Pathophysiologic mechanism: neurodegenerative syndromes, stroke and trauma, hyperalgesia, epilepsy
What is wind up?
Too much excitation leading to too much Ca2+ influx into cell, which alters mechanisms resulting in altered morphology and cell death
Glutamate: Synaptic Transmission:
AMPA and NMDA are receptors unique to glutamate.
True or False?
False
alcohol etc (many things)
NMDA and AMPA receptors
insert diagram
Glutamate: Signal Termination:
Uptake/Re-uptake:
- Glutamate is sequestered from the
synaptic space by specific transport
molecules located on the
membrane of the pre-synaptic
neurone and neighbouring glial
cells
- glutamate taken back up into
glutametergic neurones (Gt(n)
transporters) and can be used again
after packaging into vesicles
- if re-uptake then in glial cells is
metabolised to glutamine (inactive)
before entering glutamatergic
neurons and then synthesised into
glutamate in the pre-synaptic
membrane of neuron
What is the difference between uptake and re-uptake?
- uptake is removal of
neurotransmitter by a different cell
than what produced/secreted it - re-uptake is removal by the same cell
that produced/secreted it
If only re-uptake of glutamate what is the disadvantage?
Re-uptake is quick and hence if there is depolarisation or continuous stimulation then there will be too much glutamate release and hence excitotoxicity is more likely
Uptake delays and hence acts as a buffer
Glutamate: Signal Termination:
Glutamate: Functional Associations:
- excessive activation of NMDA and
AMPA receptors lead to a significant
influx of Cas2+ - leads to excitotoxic cell death in
stroke and neurodegenerative
diseases - massive release and impaired re-
uptake of glutamate in the synapse - excessive stimulation of glutamate
receptors and neuronal cell death
Glutamate: Pharmacology:
- most drugs seem to modulate
glutamate release - still serious side effects
- eg: anticonvulsants,ALS,
Memantine***
GABA is a primary excitatory neurotransmitter.
True or False?
False
primary inhibitory neurotransmitter
Functional Association of GABA (5):
- attention and arousal
- memory formation
- anxiety
- sleep
- muscle tone
Adverse Effects of drugs that modulate GABA transmission:
- drowsieness
- lacking co-ordination
GABA:
- sources
- synthesis
- synthesised from glutamate within
GABAergic neurones - GABE is sequestered in high concs
into synaptic vesicles via the
vesicular GABA transporter GAT - and is released when an action
potential arrives at the synaptic
bouton
GABA: Action: Receptor types:
- GABA A receptors are ionotropic:
integral Cl- channel and are FAST!! - GABA B receptors are metabotropic:
seven transmembrane domains, G -
protein linked causing opening of K+
channels and are SLOW - GABA C receptors are ionotropic,
transmitter gated Cl- channels - GABA A = ionotropic, influx of Cl-
- GABA B = metabotropic, indirectly results in K+ influx
- GABA C = ionotropic, Cl- influx
- mostly transmission works through
GABA A
GABA: Action:
- predominantly at GABA A receptors
- Cl- enters cell
- increased Cl- conductance in a post-
synaptic neurone - ECl = -70mV
- hence chloride influx will keep the
membrane potential at resting of
-70mV - called hyperpolarisation but not
necessarily for example some cells
will be at -80mV and will depolarise
to -70 - but because so much Cl- enters,
membrane potential sticks to -70mV - hence makes cells less excitable
GABA: Signal Termination:
Uptake and Re-uptake:
- GABA is sequestered from the
synaptic space by specific transport
molecules located on the
membrane of the pre-synaptic
neurone and neighbouring glial
cells
- GABA is taken back up into
GABAergic neurones (GAT-1) and
can be used again after packaged
into vesicles
- GABA taken up by glial cells
(GAT1/2/3) is converted into
glutamate and then glutamine,
before entering GABAergic
neurones and being converted to
glutamate then GABA then
packaged into vesicles
GABA Signal Termination:
Monoamines: Sources and Synthesis:
know the enzymes as well!!
aromatic amino acid decarboxylase
Generally, in the CNS NA or Adr?
NA
Adr is formed in the adrenal medulla
Serotonin is synthesised in a different pathway to adrenaline.
True or False?
True
Serotonin can produce
melatonin which makes you sleepy
Dopamine: Receptors:
- D1-D5 are G-protein coupled
receptors - D1 and D5 belong to D1 family:
increase cAMP through Gs - D3 and D4 belong to D2 family and
decrease cAMP through Gi - D1 and D2 receptors are present
post-synaptically - D2 are also autoreceptors which are
used to control the release - D4 present in the cortex but not the striatum
Dopamine: Functional Associations:
- control of movement = nigrostriatal
dopamine - emotion = mesocorticolimbic
dopamine - reward pathways, addiction = same
as above
Parkinson’s Disease and dopamine:
- dopamine augmentation (increased
synthesis) - agonists of dopamine
- inhibition of dopamine metabolism
Dopamine and Abuse Drugs:
- reward and addiction pathway
- amphetamine increases release
- cocaine blocks re-uptake
Adrenoreceptors:
- alpha one and two
- beta one, two and three
- Gs on beta receptors
- Gq on alpha one
What is the predominant adrenoreceptor in the forebrain?
Beta adrenoreceptors
a lot of presynaptic alpha 2 adrenoreceptors play an important role in modulating NA release and the rate of firing noradrenergic neurones
Drugs that act to increase the concentration of noradrenaline in the brain (almost all antidepressants) cause
downregulation of beta adrenoreceptors in the forebrain
Alpha 2 adrenoreceptor function
autoregulation of neurotransmitter release particularly noradrenaline
Adrenoreceptors are ionotropic or metabotropic?
metabotropic receptors (GPCR)
Phentolamine effect on adrenoreceptors
antagonist
Alpha one adrenoreceptors are found
post-synaptically
Noradrenaline: Functional Associations:
- increased attention
- arousal
- facilitates the responsiveness of
brain regions to other
neurotransmitter systems
Serotonin: Receptors:
- 5-HT receptors: 14 different subtypes
- apart from 5-HT3 subtype, all are G-
protein linked - some 5-HT1 receptor subtypes act as
autoreceptors but most are located
postsynaptically, where they mediate
the diverse effects of serotonergic
neurotransmission
5-HT: Functional Associations:
- brain serotonergic nuclei are in the
brainstem - some cells send descending fibres to
the spinal cord to ***inhibit input
from nociceptive pathways
(descending control of pain) - other cells send fibres in the medial
forebrain bundle to forebrain
structures and cerebral blood vessels - diminishes serotonergic
transmission may lead to depression
Monoamines: Signal Termination:
- majority re-uptake via plasma
membrane transporters - Monoamine Oxidase: MAO-A/B
- Catech-O-methyl transferase (COMT)
- blockade of monoamine transporters and degradative enzymes such as MAO leads to increased concs of the monamines in the synapse of the neurone itself
Monamine: Signal Termination:
insert slide
just the first step
most important because then neurotransmitter conc decreases in the cleft/neuron
Cholinergic Synthesis
- choline + acetyl CoA = acetylcholine
- via choline acetyltransferase
Cholinergic Synapse:
How do we limit the action of acetylcholine?
- no uptake or reuptake of ach
- reuptake of choline
- acetylcholinesterase (AchE)
- butyrlylcholinesterase
What is the rate limiting step of acetylcholine synthesis?
availability of choline (uptake = target)
Where is Acetyl CoA mainly derived from?
Glycolysis
Anti-Cholinergic Side Effects:
- dry mouth
- urinary retention
- constipation
Application of acetylcholine:
