Neurotransmission Flashcards
List the types of neurotransmitters in the CNS
Amino acids (glutamate, GABA, glycine)
Gaseous molecules (NO, CO)
Miscellaneous (purines, endocannabinoids)
Monoamines: Catecholamines (noradrenaline, dopamine), Indoleamines (5-hydroxtryptamine/ 5-HT), Others (melatonin, histamine)
Acetylcholine
Peptides:
Hypothalamic releasing factors (eg. somatostatin), Tachykinins (eg. Substance P), Opioids (eg. enkephalins), Others (eg. CCK, NPY, orexin)
What are the types of monoamines?
Catecholamines (noradrenaline, dopamine), Indoleamines (5-hydroxtryptamine/ 5-HT), Others (melatonin, histamine)
What signalling predominates in the cortex?
Interlaminar glutamate or GABA neurons, Local circuit GABA, gaseous or peptide
Cortico-cortical glutamate neurons
Cortico-subcortical glutamate neurons
What signalling predominates in the brain stem?
Monoamine/ACh projecting to higher centers
What signalling predominates in the subcortical regions (cerebellum, striatum, thalamus and spinal cord)?
Local circuit neurons GABA and peptides
Projecting GABA and peptide neurons
What are the criteria to localize a neurotransmitter to a neuron?
Neuronal localization: the neurotransmitter must be localized in the neuron including; the transmitter candidate itself, biosynthetic/metabolic enzymes, reuptake mechanisms and appropriate receptors
Synaptic mimicry: must be proven to occur by a different exogenous transmitter or receptor agonist, compare responses.
Neurotransmitter versus neuromodulator: must be understood if it transmits or just modulates
Neuronal release: must be evidence of release from neuron (sample supernatant produced)
What is an EPSP and an IPSP?
Excitatory post synaptic potential (depolarization) and inhibitory post synaptic potential (hyperpolerization)
What is pre-synaptic inhibition?
Presynaptic inhibition is an inhibitory input to a neuron to make it less likely to fire an action potential
GABA receptors are activated, it causes a chloride influx, which hyperpolarizes the cell
What are excitatory amino acids?
Glutamate
aspartate
Where are glutamate neurotransmitters located?
Cortico-cortical and cortico-subcortical neurons
How is glutamate synthesised?
De novo synthesis from glucose and from glutamine supplied by glial cells.
What packages glutamate into vesicles?
Vesicular glutamate transporters (vGluTs)
What receptors does glutamate bind to?
Ionotropic (ligand-gated ion channels) AMPA, NMDA, Kainate
(evoke fast EPSPs)
Metabotropic (G-protein coupled receptors) (mGlu1-8)
What does the NMDA receptor allow through?
Na+, Ca2+
What is the action of ketamine?
NMDA blocking drug
How is glutamate cleared from the synapse?
Excitatory amino acid transporters (EAATs) on neighbouring glial cells (EAAT1 and EAAT2).
What happens to glutamate within the glial cell?
Glutamate is converted to glutamine by glutamine synthetase
Glutamine is subsequently released by System N transporters and taken up by neurons through System A sodium-coupled amino acid transporters to complete the glutamate–glutamine cycle.
What are the functions of glutamate?
Memory: long term potentiation (LTP) is mediated by glutamate.
Describe excitotoxicity
Ischemia (hypoxia/hypoglycemia) leads to excess release of glutamate overstimulation of NMDA receptors - excessive Ca2+ entry into neurons - cell death.
NMDA receptor antagonists reduce cell death
What are the inhibitory amino acids?
GABA and glycine
What neurons release GABA/glycine?
Cortical interneurons, sub-cortical neurons (eg. basal ganglia).
Glycine in spinal cord interneurons
How is GABA synthesised?
From glutamate (Glu) by glutamate decarboxylase (GAD)
What are the GABA receptors?
GABAa receptor (Cl- channel) (Ionotropic GABAA receptors evoke fast inhibitory postsynaptic potentials (IPSPs))
GABAb (Gi-protein coupled)
Describe the GABAa channel
Ligand-gated ion channel (Cl-)
Pentameric structure
What role do GABAa blocking drugs have?
Channel blocking agents are convulsant agents.
How is GABA neurotransmission terminated?
Uptake of GABA by GABA transporter 2/3 (GAT 2/3) into astrocytes
What happens to GABA in astrocytes?
GABA transaminase (GABAT) converts it into succinic semialdehyde (SSA).
SSA is then oxidized by SSADH to succinate and serves as a substrate within the tricarboxylic acid (TCA) cycle.
What is the role of GABA?
Movement control: GABA is a major transmitter in the basal ganglia.
What disease affecting movement is due to loss of GABAergic neurons?
Huntington’s disease due to loss of GABA-containing long projection neurones (striatopallidal) leads to uncontrolled movement.
What do many anti-epileptic drugs target?
Anticonvulsants increase GABA transmission by facilitating GABAA receptor function (eg. benzodiazepines, barbiturates)
Inhibiting GABA metabolism (valproate) or uptake (tiagabine).
Where are CNS ACh receptors located?
ACh neurons located in basal forebrain, septum and striatum.
What are the ACh receptor subtypes?
Muscarinic (metabotropic)
Nicotinic (ionotropic)
What are the CNS functions of acetylcholine?
Movement control: muscarinic antagonists (benzatropine) helpful in relief of tremor in Parkinson’s disease.
Reward and motivation: addiction to nicotine related to ACh interaction with midbrain dopamine (mesolimbic) pathways.
Memory: lesion of cholinergic pathways and muscarinic antagonists induce amnesia.
What are peptide neurotransmitters stored in?
Dense cored vesicle, released by exocytosis
What are tachykinins?
Substance P and the Neurokinins
What are tachykinin receptors?
Slow excitatory responses via G-protein coupled receptors (NK1-3).
Where is substance P localised to?
Primary sensory afferents (pain pathways), medulla (vomiting centre) and limbic system (anxiety pathways).
What is the role of substance P?
Emesis, pain processes, and behavioural response to anxiety & stress.
What are the opioid receptors?
µ, d, k: inhibitory, G-protein coupled.
CNS effects mainly mediated by inhibitory µ receptors.
Role of opioid receptors
Pain transmission: opiate analgesics (eg. morphine) act on µ receptors in the spinal cord to relieve pain (also limbic system & brainstem).
Reward and motivation: morphine euphoria & addiction linked to opioid interaction with midbrain dopamine (mesolimbic) pathways.
Chemistry of monoamine transmitters?
Contain one amino group connected to an aromatic ring by a two-carbon chain.
Where do dopamine neurons innervate mainly?
Basal ganglia (striatum)
Where is there a large amount of dopaminergic neurons?
Substantia nigra compacta
Locus coeruleus (NA)
Reticular formation
Nucleus raphe (5HT)
Describe the firing of monoamine neurons, what does this mean?
Fire spontaneously and rhythmically, this provides a constant level of tone at the neuronal target - making modulation especially important.
Function of monoamine neurons
Global arousal pathways (5HT)
Reward and behaviour (dopamine)
How is noradrenalin transported from cytosol to vesicle?
Vesicular monoamine transporter (VMAT)
How is noradrenaline removed from the synapse?
UT1 mechanism via NET transporter into cytosol, broken down by MAO or repackaged.
UT2 into postsynapse, digested by COMT
Therapeutic uses of drugs targeting noradrenaline synapses
Anxiety: b-adrenoceptor antagonists (propranolol) are anxiolytic
Attention hyperactivity deficit disorder: Noradrenaline-releasing agents (ritalin and amphetamine) are therapeutically useful in ADHD
Depression: Noradrenaline reuptake inhibitors (reboxetine) and MAO inhibitors (phenelzine) are antidepressant.
How is dopamine transported from the cytosol into synaptic vesicles?
Vesicular monoamine transporter, VMAT2
What are the dopamine receptors?
Postsynaptic dopamine receptors, located on dendrites (the postsynaptic neuron), or presynaptic autoreceptors ( D2 and presynaptic D3 receptors),
Therapeutic uses of drugs targeting dopamine synapses
Parkinsons disease: L-DOPA, dopamine agonists (ropinerole), COMT inhibitors (tolcapone) are used in the treatment of Parkinson’s disease.
Schizophrenia: Dopamine receptor antagonists (haloperidol) are antipsychotic.
Addiction: Partial dopamine receptor agonists (buproprion) help manage relapse to tobacco smoking.
Bipolar depression: Dopamine receptor antagonists (haloperidol) are anti-manic agent
Describe the serotonin receptors
Except for the 5-HT3 receptor, a ligand-gated ion channel, all other 5-HT receptors are G-protein-coupled receptors
Therapeutic uses of drugs targeting 5-HT synapses
Depression: Selective 5-HT (serotonin) reuptake inhibitors (fluoxetine) are antidepressant
Schizophrenia: Non-selective 5-HT2 receptor antagonists (risperidone) are antipsychotic.
Migraine: 5-HT1B/D agonists (sumatriptan)
Nausea and vomiting: 5-HT3 receptor antagonists (ondansetron) are antiemetic
What is the underlying cause of epilepsy?
Excessive and abnormal neuronal activity in the cortex of the brain.
What can a hyperexcitable state arise from (epilepsy)?
Increased excitatory synaptic neurotransmission,
Decreased inhibitory neurotransmission,
An alteration in voltage-gated ion channels,
An alteration of intra- or extra-cellular ion concentrations in favour of membrane depolarization.
How can epilepsy be treated by antagonising excitable neurotransmission?
NMDA, AMPA, Kainate antagonists
How can epilepsy be treated with agonising inhibitory neurotransmission?
GABAa agonists,
Barbiturates and benzodiazepines act by positive modulation
Vigabatrin acts by inhibiting GABA metabolism
Tiagabine, an inhibitor of the high-affinity GABA transporter GAT1.
How can epilepsy be treated through modulation of voltage gated sodium and calcium channels?
Sodium channel-blocking AEDs, phenytoin, carbamazepine and lamotrigine. Inhibit high-frequency repetitive spike firing during seizure spread
Gabapentin binds to calcium channel subunits Might inhibit calcium currents, resulting in reduced excitatory neurotransmission.
Ethosuximide inhibits T-type calcium channels
The receptor involved in hippocampal long term potentiation
NMDA
Which neurotransmitter is released from retinal photoreceptors?
Glutamate
A neuropeptide involved in suppressing nociceptive transmission
Neuropeptide Y
NMDA receptors
Excitatory/ionotropic/Bind glutamate/require depolarisation to remove Mg2+ before channel can open/important in LTP
Neurotransmitter released from granule cells in the cerebellum is
Glutamate
