central neurotransmitters Flashcards
Synaptic Transmission
4 steps for synpatic transmission?
- An action potential arrives at the synaptic bouton
- Voltage gated calcium channels open
- ↑[Ca2+]i initiates vesicle fusion with the presynaptic membrane
- Neurotransmitter is released into the synapse, where it interacts with receptors
Synaptic receptors (2)
Ionotropic and metabotropic
Ionotropic receptors
type
speed
Ligand-gated ion channels
FAST synaptic transmission
Metabotrophic
type
speed
GPCRs - G-protein coupled receptors (mostly)
SLOW signal modulation
Synaptic termination
cleared by? (3)
- Neurotransmitter is cleared from the synapse
i. Enzymatic breakdown
ii. Re-uptake into
presynaptic terminal
iii. Diffusion away from
synapse
overview of ap and propagation
how do ap travel?
why is signal transduction fast?
myelin sheaths in pns?cns?
rmp? what is allowed to move out of the cell? what happens with depolarisation? what happens at peak of positivity? how hyperolarised? what returns its back to rmp? what happens when ap gets to synaptic bouton? effect? (2) what is released?
• APs travel along an axon by jumping from node to node
• these nodes have many voltage gated Na+ and K+ channels which open and close as AP
propagates
• Signal transduction is very fast due to the insulation by myelin sheaths
• oligodendrocytes make up myelin sheaths in the CNS
• in the PNS, myelin sheaths are made by schwann cells
• A nerve cell is constantly at a resting membrane potential of -70mV
• K+ membrane channels allow K+ to move outside the cell making the inside of the cell
negative at a PD of -70mV
• as the cell is depolarized, Na+ voltage gated channels open and there is an influx of Na+
making the cell +ve
• at the peak of the positivity, voltage gated K+ channels open and K+ ions leave the cell thus
making the cell -ve in the inside
• excess of K+ exits the cell making it hyperpolarized
• Na+/K+ ATPase pumps then return the cell back to RMP
• At the synaptic bouton, the depolarization leads to
opening of voltage gated Ca2+ channels
• there is an influx of Ca2+ in to the cells
• this leads to an effective release of neurotransmitter
from the presynaptic membrane
• the NT vesicle gets signaled to fuse with the
presynaptic membrane, and release its contents
through exocytosis (neurotransmitter)
• the NT is released into the synapse where it acts on
receptors
• a protein called clathrin binds to the cell membrane
turning it into an endocytotic membrane thus allowing
reuse and recycling of neurotransmitter
Glutamate transmission and termination at synaptic cleft
amino acid transmitter
what converts what to glutamate? how does this enter vesicles?
what is eaat? where does this go? (2)
where are GinT transporters?
Glutaminase converts glutamine to glutamate which gets into vesicles via vGlut channels
Upon AP/activation, glutamate is released in synaptic cleft where it will act on glutamate receptors
EAAT is a glutamate transporter therefore will re-uptake either into neuron where it will be recycled into vesicles OR via an astrocyte it will be converted via glutamine synthase into glutamine and transported back into neuron via GinT transporter.
Why is too much glutamate bad?
can lead to hyper excitability hence cause exocytoxicity and eventually lead to cell death
effect of NMDA antagonist (4)
can be used to treat : glutamate exitotoxicity epilepsy stroke depression
Hypofunction of NMDA
can lead to schitzophrenia
summary of gluatamate
what is it?
receptors abundant where?
what are the 4 receptor subtypes?
NMDA receptors - 2 roles?
NMDA antagonists - 3 reasons
AMPA modulators (AMPAkines)/colocalisation with NMDA - why?
Main excitatory transmitter
Receptors abundant in cortex, basal ganglia, sensory pathways
Four main receptor subtypes
NMDA, AMPA & Kainate (ionotropic) Q. fast or slow?
Metabotropic (G-protein coupled) / modulatory 8 subtypes
(antagonists: potential for PD, addiction, epipepsy)
NMDA receptors (pre- and post synaptic)
Role in synaptic plasticity (hippocampus)
Role in memory, stroke
NMDA antagonists
Epilepsy (lamotrigine)
Stroke – neuronal damage caused by excess glutamate
Schizophrenia, drug abuse
AMPA modulators (AMPAkines)/colocalisation with NMDA Cognitive enhancement
Glutamate/NMDA/glycine
NMDA colocalised with AMPA receptors. Highly permeable to Ca2+ but at resting potential channel blocked with Mg2+, only when cell is depolarised (e.g. activation of AMPA receptor) Mg2+ moves out and allows Ca2+ to flow in. Also needs glycine to bind (glycine thought of as an inhibitory transmitter) therefore glycine antagonists can inhibit glutamate action. Some anaesthetics (ketamine) and psychotomimetics (phencyclidine) block the NMDA channel. Glycine site may be important as may have fewer side effects – results from clinical trials so far have not been conclusive
what is GABA?
speed?
what does it do? where?
highest density where?
Y-aminobutyric acid (GABA) Amino acid transmitter Main inhibitory transmitter in CNS (fast transmitter) Mostly via inhibitory interneurons Highest density in nigrostriatal system
which conditions is GABA important for? (2)
anxiety and insomnia due to reduced GABA
How is GABA synthesised and deactivated?
synthesised from? via?
deactivated - (2)
GABA synthesised from glutamate
Glutamic acid decarboxylase GAD
Deactivation
Re-upatake via GABA receptor
GABA transaminase (GABA-T) will break it down once in neuron/astrocyte
Drug to increase GABA (2)
GABA transaminase inhibitor
GABA reuptake inhibitor
GABAa and GABAb
GABAa receptor? speed? increase this effect? drug that open this channel (2) inhibit GABA transaminase drug?
GABAb receptor? effect?
GABAA receptor – ligand gated Cl- channel
Fast postsynaptic inhibition
Drugs that ncrease GABA or activate of GABAA receptors are used for management of epilepsy (antiepileptic)
Benzodiazepines, barbiturates – facilitate channel opening
Vigabatrin – inhibits GABA transaminase
GABAB receptor (dimer) – G-protein coupled (inhibit Ca++, AC, open K+, inhibit NT release)
Baclofen GABAB activation (inhibit glut, opioid, GABA release)
Baclofen – antispastic effect, drug addiction? (alchohol)
g hydroxybutyrate (GHB): partial agonist of GABAb
What condtions do BZD treat? (4)
treat seizures, anxiety, insomnia and epilepsy
common principles of the Diffuse Modulatory Systems of the Brain
4 key fetaures
Four systems with common principles: Small set of neurons at core Arise from brain stem One neuron influences many others Synapses release transmitter molecules into extracellular fluid
what are the 4 main systems of Diffuse Modulatory Systems of the Brain
Four main systems:
Noradrenergic Locus Coeruleus
Serotonergic Raphe Nuclei
Dopaminergic Substantia Nigra and Ventral tegmental Area
Cholinergic Basal Forebrain and Brain Stem Complexes
Monoamines: Noradrenaline (NA)
main one in which region?
hypothalamus regulates what? (5)
thalamus - what is it?
Locus coeruleus - na in this region does what?
Cell bodies for NAergic neurons – main one in LC (Locus Coeruleus) – gives rise to millions of NAergic nerve terminals throughout the cortex, hippocampus and cerebellum. Release transmitter diffusely (i.e. like an aerosol)
Hypothalamus – hormones, sleep, body temperature, endocrine and autonomic controller)
Thalamus – main relay station for most information going into the brain
Locus coeruleus –known as ‘blue spot’ because of pigmentation. NA in this region makes brain more responsive, increases information processing – LC involved in attention, arousal, anxiety, sleep/wake.
Neurons most active when novel stimuli presented (when animal is vigilant). Low arousal associated with low NA e.g. depressed patients.
Temporal lobe = deep within the temporal lobe = amygdala
Noradrenaline involved in (5)
Arousal Wakefullness Exploration and mood (low NA in depressed) Blood pressure Addiction/gambling
Synthesis of catecholamines
pathway with enzymes
Tyrosine (tyrosine hydroxylase) Dopa (dopa decarboxylase) Dopamine ( dopamine B hydroxylase) Noradrenaline (pheny....) adrenaline
Regulation of NA
post synaptic?
pre synaptic? negtaive feedback? Mao?
Post-synaptic
Carry on the message
Pre-synaptic (autoreceptors)
Usually inhibitory - a2 receptors
Negative feedback mechanism
MAO enzyme breaks down NA when it is re-uptaken
Na regulation drugs
resrpine effect?
amphetamine effect?
cocaine effect?
Reserpine-depletes NA stores by inhibiting vesicular uptake
Amphetamine (indirect sympathomimetic)-enters vesicles displacing NA into cytoplasm, increa NA leakage out of neuron
Cocaine-blocks NA re-uptake
Drugs to increase NA (3)
a2 antagonists
Na Uptake inhibitors
MAO inhibitors
Monoamines: Dopamine (DA)
where?
involved in (4)
diseases (5)
What does dopamine inhibit? how are d1 and d2 receptors split? where are d1 an d2 receptors? where is d3? where is d4?
how to terminate?
Dopaminergic Substantia Nigra and Ventral tegmental Area
Involved in: Movement Reward Inhibition of prolactin release Memory consolidation
Parkinson’s Disease Schizophrenia Addiction Emesis ADHD
Dopamine (DA)
Inhibits central neurons (K+ channels)
D1 (D1 & D5) and D2 (D2, D3, D4) receptors
D1 and D2 receptors in striatum, limbic system, thalamus & hypothalamus
D3 receptors in limbic system NOT striatum
D4 receptors in cortex & limbic system
Termination: MAO, neuronal uptake
Dopamine - main pathways and functions/disorders
mina pathway - parkinson’s? schizophrenia?
function/disorders? (5)
Main pathways
Substantia nigra to basal ganglia (Parkinson’s disease)
Midbrain to limbic cortex (schizophrenia)
Functions / disorders
Movement, addiction, stereotypy, hormone release, vomiting
dopamine receptors
what kind of receptors?
presynaptic?
post synaptic?
dopamine has only metabotropic receptors
D2 - pre synaptic
D1, D2 - post synaptic
dopamine syntheis + termination
synthesis? what enters? what converts it?
autoregulation via what?
what enzyme breaks it down?
L-dopa enters cell
dopa decarboxylase converts to dopamine
dopamine will be released
Termination but auto-regulation via D2 receptors and MAOb enzyme breaks it down to metabolites
serotonin (5-HT) distribution
resembles that of?
where?
Distribution of 5-HT neurons resembles that of NA.
Cell bodies are grouped in the pons and upper medulla, close to the midline (raphe) and are often referred to as raphe nuclei. Projections to the cortex, hippocampus, basal ganglia, limbic system and hypothalamus and the cerebellum, medulla and spinal cord.
serotonin functions + disorders (6)
Function / disorders
Mood (anxiety/depression)
Psychosis (5HT antagonism antipsychotic)
Sleep / wake (5-HT linked to sleep, 5-HT2 antagonists inhibit REM sleep)
Feeding behaviour (5HT2A antagonist increase apetite, weight gain; antidepressants decrease apetite
Pain, migraine (5-HT inhibits pain pathway, synergistic with opioids)
Vomiting
serotonin receptors
what receptors?
5-HT receptors (14 subtypes)all G-protein coupled except 5-HT3
5-HT1 inhibitory, limbic system – mood, migraine
5-HT2 (5-HT2A), excitatory, limbic system & cortex
5-HT3 excitatory, medulla – vomiting
5-HT4 presynaptic facilitation (ACh) – cognitive enhancement
5-HT6 and 5-HT7 – novel targets, cognition, sleep
serotonin synthesis + termination
how does it terminate? (2)
auto regulation via what?
5-HT released
terminate via 5-HT transporters re-uptaking it and MAO enzyme breaking it down
5HT1d auto regulation
Autoreceptors
5-HT, dopamine, Na - cell body? terminal?
inhibit cell firing and transmitter release at the terminal regions
transmitter cell body terminal
5-HT 5-HT1A 5-HT1D (5-HT1B)
dopamine D2 or D3 D2 or D3
noradrenaline α2 α2
Transporters usually take the neurotransmitter back up into the pre-synaptic terminal
dopamine 5-HT NA glutamate dopamine
reuptake site?
transmitter Reuptake site dopamine DAT (on dopamine neurons) 5-HT SERT (on 5-HT neurons) NA NET (on noradrenaline neurons) glutamate EAAT1 (mostly on astrocytes) dopamine vMAT2 (into vesicles)
ach pathways
Two main diffuse modulatory cholinergic systems – basal forebrain complex / septohippocampal pathway and nucleus basalis (cognitive function / Alzheimer’s disease) and motor control (striatal)
Ach receptors, termination
Ach abundant where? (3)
terminate how?
different receptors?
Acetylcholine (ACh)
Abundant in basal forebrain, hippocampus and striatum
Termination – acetylcholinesterase (AChE)
ACh excitatory neurotransmitter
Nicotinic (ionotropic / fast)
Muscarinic (G-protein coupled / slow)
M1 excitatory ( M1 receptors in dementia)
M2 presynaptic inhibition (inhibit Ach release)
M3 excitatory glandular/smooth muscle effects (side effects)
M4 and M5 function not well known
Ach function (5)
Functions:
Arousal
Epilepsy (mutations of nAChR genes)
Learning and memory (KO mice)
Motor control (M receptors inhibit DA), pain, addiction
Involved in schizophrenia, ADHD, depression, anxiety, Alzheimers
Other Transmitter / Modulator Substances
histamine - receptor and fucntions?
purines - example and functions?
opiod peptides - functions?
Histamine
H1 (arousal) and H3 (presynaptic / constitutively active)
Functions: sleep / wake, vomiting
Purines
Adenosine (A1, A2A/2B) and ATP (P2X)
Functions: sleep, pain, neuroprotection, addiction, seizures, ischaemia, anticonvulsant
Neuropeptides
Opioid peptides
u, o, k
Functions: pain
Neuropeptides that control the pituitary (5)
CRH TRH GnRH GHRH Somatostatin
Peptide Synthesis is a complex process
synthesised where? transported to?
derived from?
These are large protein neurotransmitters
• They are synthesized in the cell body and then transported into the nerve terminals
derived from genes and then transcribed nd translated to proteins
Opioid peptides and opioid receptors ( 4 families?)
4 families B-endrophin to MOP and DOP enkephalins to DOP dynorphins to KOP nociceptin to NOP
Other Transmitter / Modulator Substances
Lipid mediators
- Products of conversion of eicosanoids to endocanabinoids
- act on CB1 (inhibit GABA, glutamate release)
- involved in vomiting (CB1 agonist block it, MS, pain, anxiety, weight loss/rimonabant CB1 antogonist)
recap of everything
RECAP
GABA is a major inhibitory NT in CNS, some long projecting pathways, many short interneurons. GABA-A and GABA-B receptors. Action is terminated by re-uptake.
Benzodiazepines are clinically important modulators at GABAA receptors (e.g. against anxiety). Baclofen, a GABAB agonist used to treat muscle spasticity.
DA has 3 major pathways, its action is terminated by reuptake, there are 5 receptor sub-types (D1-D5). Implicated in PD/schizophrenia/drug abuse. DA agonists are used in PD (D1/D2), DA antagonists used in Sz (D2)
Excitatory amino acids include glutamate and aspartate. These are major excitatory NTs in CNS. High synaptic concentrations are associated with neurotoxicity, implicated in ischaemic damage, stroke and epilepsy. Action is terminated by re-uptake. There are no agonists/antagonists in clinical use.
Ach has both excitatory (mostly) and inhibitory effects. There are well documented pathways, there are nicotinic and muscarinic receptors. They are involved in arousal and memory. Ach neurones degenerate in Alzheimer’s disease. Inhibitors of aceytlcholinesterases used in treatment of Alzheimer’s disease.
