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YEAR 2 - The Nervous System > 19. Principles of Neuronal Function (2) > Flashcards

19. Principles of Neuronal Function (2) Flashcards

1
Q

Summarise the evolution and ultimate function of the brain.

A
  • Nervous systems evolved to allow predictive interactions between mobile animals and their environment.
  • To move around safely, an animal must anticipate the outcome of each movement on the basis of incoming sensory data.
  • Prediction may thus be the ultimate function of the brain.
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2
Q

Who discovered chemical transmission at synapses?

A

Henry Dale and Otto Loewi

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3
Q

Give some experimental evidence for chemical transmission at a synapse.

[EXTRA]

A

Dale and Loewi’s experiment:

  • Stimulation of a heart by the vagus caused it to contract more slowly
  • When the fluid medium from the first heart was transferred to a different heart, this one also slowed down
  • This suggested that there was some substance secreted by the vagus nerve (in this case, ACh)
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4
Q

How many synapses are there in the brain?

A

1-5 x 1014

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5
Q

What are some common disorders due to abnormal functioning of synaptic transmission in the CNS?

A
  • Anxiety
  • Depression
  • Schizophrenia
  • Epilepsy
  • Alzheimer’s disease
  • Parkinson’s disease
  • Huntington’s disease
  • Migraine
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6
Q

What are the main classes of neurotransmitter in the CNS?

A
  • Amino acids
  • Acetylcholine
  • Monoamines
  • Peptides [EXTRA]
  • Gaseous [EXTRA]
  • Miscellaneous [EXTRA]
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7
Q

What are some examples of amino acid neurotransmitters in the CNS?

A
  • GABA
  • Glutamate
  • Glycine
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8
Q

What are some examples of monoamines neurotransmitters in the CNS?

A
  • Catecholamines (noradrenaline, dopamine)
  • Indoleamines (5-hydroxtryptamine a.k.a. serotonin)
  • Others (melatonin, histamine)
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9
Q

What are some examples of peptide neurotransmitters in the CNS? [EXTRA]

A
  • Hypothalamic releasing factors (eg. somatostatin)
  • Tachykinins (eg. Substance P)
  • Opioids (eg. enkephalins)
  • Others (eg. CCK, NPY, orexin)
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10
Q

What are some examples of gaseous neurotransmitters in the CNS? [EXTRA]

A
  • NO
  • CO
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11
Q

What are some examples of miscellaneous neurotransmitters in the CNS? [EXTRA]

A
  • Purines
  • Endocannabinoids
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12
Q

Describe the different types of neurons in the cerebral cortex.

A
  • Interlaminar neurons (glutamate or GABA) -> These span between the layers of the cortex
  • Local circuit neurons (GABA, peptides or gaseous) -> These are interneurons that have a limited sphere of influence
  • Cortico-cortical neurons (glutamate) -> Connect different parts of the cortex
  • Cortico-subcortical neurons (glutamate) -> Provide all output from the brain to the subcortical regions

Also:

  • Receive fibres from neurons in the brainstem (monoamine and ACh)
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13
Q

Describe the different types of neurons in the subcortical regions of the brain (cerebellum, striatum, thalamus, spinal cord).

A
  • Local circuit neurons (GABA and peptides) -> These are interneurons that have a limited sphere of influence
  • Projecting neurons (GABA and peptides) -> These project out of the brain to more distant regions of the CNS

Also:

  • Receive fibres from neurons in the brainstem (monoamine and ACh)
  • Receive fibres from cortico-subcortical neurons in the cerebral cortex (glutamate)
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14
Q

Describe the different types of neurons in the brainstem.

A
  • Neurons that output to the cerebral cortex and subcortical regions (monoamine and ACh)
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15
Q

Approximately what percentage of neurons in the brain are utilising these neurotransmitters:

  • Glutamate
  • GABA
  • Other
A
  • Glutamate -> 60%
  • GABA -> 30%
  • Other -> 10%
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16
Q

What are some criteria for proving that something is a neurotransmitter in a neuron?

[IMPORTANT]

A
  • Neuronal localisation
  • Neuronal release
  • Synaptic mimicry

It is also important to distinguish between whether it is a neurotransmitter or neuromodulator.

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17
Q

How can neuronal localisation be used to show that something is a neurotransmitter in a neuron?

A
  • Should be able to find one or more of these within or near the neuron:
    • NT itself
    • Enzymes used to make it
    • Reuptake mechanisms
    • Receptors for it
  • These can be tested for using immunocytochemistry
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18
Q

How can neuronal release be used to show that something is a neurotransmitter in a neuron?

A
  • The neuron itself should release the neurotransmitter
  • This can be done by incubating the neuron is a medium and then sampling the supernatant for neurotransmitter levels
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19
Q

How can synaptic mimicry be used to show that something is a neurotransmitter in a neuron?

A

If exogenous neurotransmitter or an agonist of its receptor are applied to the target neuron, you should see the same physiological response as with stimulation by the pre-synaptic neuron.

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20
Q

Compare a neurotransmitter and neuromodulator.

[EXTRA]

A

Neurotransmitter:

  • Acts directly on a postsynaptic neuron to cause a change in its membrane potential, although it may sometimes act through second messengers.

Neuromodulator:

  • Affects groups of neurons, or effector cells that have the appropriate receptors.
  • It may not be released at synaptic sites
  • Often acts through second messengers and can produce long-lasting effects.
  • Does not necessarily carry excitation of inhibition from one neuron to another, but instead alters either the cellular or synaptic properties of certain neurons so that neurotransmission between them is changed
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21
Q

What are some techniques that are used to understand the function of a neurotransmitter?

A
  • Transmitter pathway mapping
    • Localisation of where the NT is found
    • Pathway tracing of where the neurons are positioned
  • Transmitter pathway lesion (in a test animal)
    • Mechanically or electrolytic lesion
    • Neurotoxin lesion against specific types of neurons
  • Pharmacological manipulation
    • Use of agonists that increase the NT function
    • Use of antagonists that decrease the NT function
  • Genetic manipulation
    • Gene KO in test animals
    • Overexpress the NT gene
  • Transmission pathway stimulation
    • Electrical stimulation
    • Optogenetic -> Insert a light-sensitive channel into animal neurons by a vector, then stimulate them using light
    • Chemogenetic -> Insert a drug-sensitive channel into animal neurons by a vector, then stimulate them using the drug
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22
Q

What are the 8 key events that occur during chemical transmission at a synapse that can be mediated?

A
  1. Precursor supply
  2. Synthesis
  3. Storage
  4. Release
  5. Receptor activation
  6. Reuptake
  7. Metabolism
  8. Autoreceptor activation
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23
Q

How is a neurotransmitter precursor delivered to the axons at the synapse?

A

It is either:

  • Synthesised in the cell body and transported to the terminal via vesicles
  • Supplied in the diet, entering the blood and then crossing the BBB using transporters, and then getting into the neuron
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24
Q

How is neurotransmitter packaged into vesicles at the nerve terminal?

A

Using specific vesicular transporters.

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25
Q

What leads to release of neurotransmitter at a synapse?

A
  • The action potential travels down the neuron, depolarising the membrane and causing calcium channels to open.
  • The influx of calcium causes vesicles to fuse with the membrane and release the NT into the synapse.
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26
Q

Compare the effects of NT binding to ionotropic and metabotropic receptors.

A
  • Ionotropic receptors produce fast excitatory or inhibitory effects
  • Metabotropic receptors produce more long-lasting effects
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27
Q

What is the function of autoreceptors on the pre-synaptic neurons?

A

They act to produce negative feedback of release of the neurotransmitter.

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28
Q

Does each neurotransmitter only have one type of receptor in the nervous system? What is the consequence of this?

A
  • No, they may have different types and subtypes.
  • This diversity allows for the targeting of specific receptors with drugs.
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29
Q

What are the main forms of excitatory and inhibitory neurotransmission in the CNS?

A

Excitatory:

  • Glutamate

Inhibitory:

  • GABA
  • Glycine
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30
Q

Is glutamate excitatory or inhibitory as a neurotransmitter?

A

Excitatory (it is the main excitatory NT in the CNS)

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31
Q

What neurons use glutamate as a neurotransmitter?

A
  • Cortico-cortical neurons
  • Cortico-subcortical neurons
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32
Q

Summarise the synthesis, release, reuptake and recycling of glutamate at a synapse.

A
  • Synthesis starts with glutamine, which is converted to glutamate by glutaminase
  • VGLUT1 or 2 or 3 is the transporter that packages the glutamate into vesicles (in exchange for H+)
  • Upon an action potential, the calcium flux causes release of the vesicle contents into the synapse
  • Na+-dependent transporters reuptake the glutamate into the pre-synaptic neuron and other cells (such as glial cells)
  • In glial cells, glutamine synthase is used to produce glutamine again, which is shuttled back to the pre-synaptic neuron using glutamine transporters (SN1/SN2 and then SATs)
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33
Q

What are the different types of glutamate receptor?

[IMPORTANT]

A

Ionotropic:

  • AMPA (use Na+ currents)
  • NMDA (use Ca2+/Na+ currents)
  • Kainate (use Na+ currents)

Metabotropic:

  • mGluR1-8 (lead to rise in IP3)
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34
Q

What is the effect of stimulating ionotropic glutamate receptors?

A

They trigger a mixed fast EPSPs:

  • First, AMPA receptors trigger a fast-onset depolarisation
  • This depolarisation releases a voltage-dependent Mg2+ block on the NMDA, which allows further depolarisation
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35
Q

What is the effect of stimulating metabotropic glutamate receptors?

A

There are 8 different types of mGluR:

  • Some lead to slow excitatory effects
  • Some lead to slow inhibitory effects

Therefore, the effect depends on the particular synapse.

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36
Q

Describe the structure and binding sites of the NMDA glutamate receptor. How can this be exploited pharmacologically?

[EXTRA?]

A
  • Ligand-gated ion channel (Ca2+/Na+)
  • Tetrameric protein

Receptor site:

  • Glutamate -> Inhibited by ketamine

Modulatory sites:

  • Glycine (+) -> Inhibited by glycine antagonists
  • Polyamine (+) -> Inhibited by polyamine antagonists
  • Magnesium (-)
  • Calcium-blocking drugs can also inhibit the receptor
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37
Q

What is the clinical importance of ketamine?

[EXTRA]

A
  • It is a blocker of the glutamate NMDA receptor
  • It has anaesthetic and analgesic properties
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38
Q

What are some putative functions of glutamate as a NT in the brain?

[IMPORTANT]

A

It is the main excitatory NT in the CNS:

  • Memory -> Mediates LPT (long term potentiation: a persistent increase in synaptic strength following high-frequency stimulation of a chemical synapse)
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39
Q

What is long-term potentiation (LTP)?

A
  • The persistent strengthening of synapses based on recent patterns of activity.
  • In other words, it is the way in which high frequency stimulation at synpases in the brain leads to stronger EPSPs being evoked the next time transmission happens.
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40
Q

What are some problems associated with glutamate in the CNS?

A

Excitotoxicity:

  • Cerebral ischaemia leads to excessive release of glutamate
  • This leads to excessive NMDA receptor stimulation, which leads to increased calcium influx
  • This causes cell death

Pathogenesis of epilepsy:

  • Too much excitation (or too little inhbition) of glutamate neurons can cause epileptic attacks [CHECK]
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41
Q

How can the brain be protected from excitotoxicity in an ischaemic episode?

A
  • NMDA receptor antagonists reduce the excitotoxic effects of excessive glutamate release during cerebral ischaemia.
  • They are effective even after the ischaemic episode is over.
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42
Q

How can epilepsy be treated, in relation to glutamate?

A

Lamotrigine -> It’s anticonvulsant action includes decreased glutamate release.

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43
Q

Is GABA excitatory or inhibitory as a neurotransmitter?

A

Inhibitory -> It is the main inhbitory NT in the CNS

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44
Q

Is glycine excitatory or inhibitory as a neurotransmitter?

A

Inhibitory

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45
Q

What neurons use GABA as a neurotransmitter?

A
  • Local circuit interneurons in the cerebral cortex
  • Sub-cortical neurons
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46
Q

What neurons use glycine as a neurotransmitter?

A

Interneurons in the spinal cord

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47
Q

Summarise the synthesis, release, reuptake and recycling of GABA at a synapse.

A
  • Synthesis starts with glutamine, which is converted to glutamate by glutaminase
  • Glutamate is then converted to GABA by glutamate decarboxylase
  • VGAT is the transporter that packages the GABA into vesicles (in exchange for H+)
  • Upon an action potential, the calcium flux causes release of the vesicle contents into the synapse
  • Na+-dependent transporters reuptake the glutamate into the pre-synaptic neuron and other cells (such as glial cells) -> GAT1 pre-synaptically and GAT3 on glial cells
  • In glial cells, GABA transaminase is used to produce glutamate again, which is converted to glutamine by glutamine synthase
  • Glutamine is shuttled back to the pre-synaptic neuron using glutamine transporters (SN1/SN2 and then SATs)
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48
Q

What are the different types of GABA receptor?

[IMPORTANT]

A
  • GABAA -> Ionotropic, Cl- channel
  • GABAB -> Metabotropic, Gi-coupled
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49
Q

What is the effect of stimulating ionotropic and metabotropic GABA receptors?

[IMPORTANT]

A
  • Ionotropic GABAA receptors evoke fast inhibitory postsynaptic potentials (IPSPs) -> Due to influx of chloride.
  • After this, there is a slower, longer-lasting hyperpolarisation due to the metabotropic GABAB receptors -> Due to the opening of potassium channels.
  • The metabotropic GABAB receptor also lead to decreased calcium influx (due to closing of calcium channels) and decreased intracellular cAMP
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50
Q

Describe the structure and binding sites of the GABAA receptor. How can this be exploited pharmacologically?

[EXTRA?]

A
  • Ligand-gated ion channel (Cl-)
  • Pentameric structure with multiple chemical binding sites

Receptor site:

  • GABA -> Inhibited by GABA antagonists

Modulatory sites:

  • Benzodiazapine binding site -> Benzodiazapine (+), Benzodiazapine antagonists and inverse agonists (-)
  • Channel modulators (+) -> Including arbiturates & steroidal anaesthetics
  • Channel-blocking drugs (-) -> These are convulsant agents (thus they are not used therapeutically)
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51
Q

Give an example of a benzodiazapine and what its effect is on the GABAA receptor.

[IMPORTANT]

A
  • Valium is an example
  • Benzodiazapines have neuromodulatory action
  • They increase the affinity of the receptor for GABA and increase the probability that GABA will open the channel
  • Thus, this leads to increased CNS inhibition
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52
Q

What are some putative functions of GABA as a NT in the brain?

[IMPORTANT]

A

It is the major inhbitory NT involved in:

  • Movement control -> In the basal ganglia
  • Downregulation of anxiety and epilepsy
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53
Q

What are some pathologies associated with GABA in the CNS?

A
  • Anxiety -> Reduced GABA signalling
  • Epilepsy -> Reduced GABA signalling
  • Huntington’s disease -> Loss of GABA-containing long projection neurones leads to uncontrolled movement.
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54
Q

How can anxiety be treated, with relation to GABA?

A

Benzodiazepine agonists (eg. diazepam) relieve anxiety by facilitating GABAA receptor function.

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55
Q

How can epilepsy be treated, with relation to GABA?

A

Major classes of anticonvulsants:

  • Increase GABA transmission by facilitating GABAA receptor function (eg. benzodiazepines, barbiturates)
  • Inhibit GABA metabolism (valproate)
  • Inhibit uptake (tiagabine)
56
Q

What are some examples of drugs that:

  • Inhibit GABA breakdown
  • Mimick GABA actions

[IMPORTANT]

A
  • Inhibit GABA breakdown -> Valproate [IMPORTANT]
  • Mimick GABA actions -> Benzodiazepines, Barbiturates (Note that these are not GABA receptor agonists, but neuromodulators that sensitise the receptor to GABA)
57
Q

What neurons use GABA as a neurotransmitter?

A
  • Brainstem neurons -> Basal forebrain, septum and striatum
  • Peripheral neurons
58
Q

Summarise the synthesis, release, reuptake and recycling of ACh at a synapse.

A
  • Synthesis starts with choline, which is combined with acetate by a choline acetyl transferase (CAT)
  • VAChT is the transporter that packages the ACh into vesicles (in exchange for H+)
  • Upon an action potential, the calcium flux causes release of the vesicle contents into the synapse
  • There is no specific transporter for ACh, so it is broken down on the post-synaptic cell membrane by acetylcholinesterase (AChE)
  • Na+-dependent transporters reuptake the choline into the pre-synaptic neuron
59
Q

What enzymes are used to synthesise and breakdown ACh?

A
  • Synthesis -> Choline acetyl transferase (CAT)
  • Breakdown -> Acetylcholinesterase
60
Q

What are the different types of ACh receptor?

[IMPORTANT]

A
  • Muscarinic (metabotropic) -> Gq/i-coupled
  • Nicotinic (ionotropic) -> Na+ channels

Both are found in the CNS and periphery.

61
Q

What are some putative functions of ACh as a NT in the CNS?

[IMPORTANT]

A

Cholinergic neurons rich in basal forebrain (nucleus basalis), septo-hippocampal pathway, and striatum:

  • Memory
  • Movement
  • Reward and motivation
62
Q

What are some pathologies associated with ACh in the CNS?

A
  • Amnesia -> Lesions of cholinergic pathways and muscarinic antagonists lead to memory loss
  • Alzheimer’s disease -> Loss of cholinergic neurons
  • Nicotine addiction -> Related to ACh interaction with midbrain dopamine (mesolimbic) pathways.
63
Q

How can Alzheimer’s disease be treated, with relation to ACh?

A

Cholinesterase inhibitors (tacrine) have some therapeutic benefit.

64
Q

How can Parkinson’s disease be treated, with relation to ACh?

A

Muscarinic antagonists (benzatropine) are helpful in treating tremor.

65
Q

What are the 3 monoamine neurotransmitters you need to know about?

A
  • Dopamine
  • Noradrenaline
  • Serotonin (5-HT)
66
Q

What neurons use monoamines as a neurotransmitter?

A

Neurons that arise from the midbrain.

67
Q

What are monoamine NTs synthesised from?

A

Tryptophan or tyrosine

68
Q

Summarise the synthesis, release, reuptake and recycling of monoamine NTs at a synapse.

A

NOTE: This should be covered more in a later lecture. If not, add flashcards.

69
Q

What are the different types of monoamine receptor?

[IMPORTANT]

A

They are all GPCRs, except 5-HT3.

NOTE: This should be covered more in a later lecture. If not, add flashcards.

70
Q

How many different peptides are used as NTs in the CNS?

[EXTRA]

A

More than 50

71
Q

Where do peptides act as neurotransmitters?

A

Both in the CNS and periphery.

72
Q

For peptide neurotransmitters, summarise:

  • Synthesis
  • Storage
  • Release
  • Metabolism
  • Receptors

[EXTRA]

A
73
Q

What do peptide neurotransmitters co-localise with?

A

Small molecular weight neurotransmitters (e.g. substance P or 5-HT)

74
Q

Name two example classes of peptide neurotransmitters.

A
  • Tachykinins
  • Opioids
75
Q

For substance P, state:

  • Class
  • Receptors
  • Localisation
  • Function

[EXTRA]

A
  • Class: Tachykinins (peptide neurotransmitters)
  • Receptors: Slow excitatory responses via G-protein coupled receptors (NK1-3)
  • Localisation: Primary sensory afferents (pain pathways), medulla (vomiting centre) and limbic system (anxiety pathways).
  • Function: Involved in emesis, pain processes, and behavioural response to anxiety & stress (via NK1 receptors)
76
Q

How can the actions of substance P be modulated pharmacologically?

A

NK1 (the receptor for substance P) antagonists have antiemetic, analgesic and anxiolytic & antidepressant properties.

77
Q

What are some examples of opioid peptide neurotransmitters?

[EXTRA]

A
  • Enkephalins
  • Endorphin
  • Dynorphin
  • Endomorphin
78
Q

For opioid peptide neurotransmitters, state:

  • Receptors
  • Function

[EXTRA]

A
  • Receptors: Inhibitory, G-protein coupled. CNS effects mainly mediated by inhibitory µ receptors.
  • Function:
    • Mediation of 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.
79
Q

For NO neurotransmitters, state:

  • Synthesis
  • Cellular effects
  • Function

[EXTRA]

A
  • Synthesis: Nitric oxide synthase found in many CNS neurons
  • Cellular effects: NO diffuses from neurons to increase cGMP and regulate intracellular Ca2+
  • Function: Possible role in learning & memory -> NO facilitates LTP (long-term potentiation) by diffusing from postsynaptic neuron to facilitate release of glutamate (‘retrograde’ transmission)
80
Q

What are the dangers of NO?

[EXTRA]

A

Excessive NO is neurotoxic.

81
Q

How can the action of NO as a neurotransmitter be manipulated pharmacologically?

A

NOS inhibitors

82
Q

Summarise the history of monoamines as CNS neurotransmitters.

[EXTRA]

A
83
Q

Where in the CNS are monoamine neurons found?

A

They are all found in the brainstem. They make up less than 1% of the neurons in the brain, but they are functionally very important.

84
Q

Monoamine neurons make up less than 1% of the neurons in the brain. What makes them so functionally important?

A
  • They are globally distributed throughout the brain
  • A single monoamine neuron can have multiple targets
  • Monoamine neurotrasmitters are released at varicosities
85
Q

Describe the distribution of noradrenergic neurons in the CNS. Where do they go?

[IMPORTANT]

A
  • They are found in the locus coeruleus (a nucleus in the pons of the brainstem)
  • The supply the forebrain, cerebellum and also go down the spinal cord
86
Q

Describe the distribution of dopaminergic neurons in the CNS. Where do they go?

[IMPORTANT]

A
  • They are found in the:
    • Substania nigra pars compacta (a basal ganglia structure in the midbrain of the brainstem)
    • Ventral tegmental area (just next to the substantia nigra in the midbrain of the brainstem)
  • The supply the forebrain

(Note: There is also a small area near the hypothalamus)

87
Q

Describe the distribution of 5-HT neurons in the CNS. Where do they go?

[IMPORTANT]

A
  • They are found in the aphe nuclei (along the midline of the brainstem, as part of the reticular formation?)
  • The supply the forebrain, cerebellum and also go down via the spinal cord
88
Q

Give some experimental evidence for the fact that a single monoamine neuron can innervate more than one target.

[EXTRA]

A

(Matsuda, 2009):

  • Reconstructed the axon of a single dopamine neuron that sent axons to the striatum
  • This axon occupied 6% of the volume of the striatum, meaning that it had many targets within the striatum
89
Q

Are monoamine neurotransmitters released at synapses?

A

They are mostly released at en passant varicosities, which means that the NTs act on more than one target.

90
Q

Add some flashcards on the synthesis, etc. of monoamine NTs.

A

Do it!

91
Q

Describe the firing of monamine neurons in the CNS.

A

Spontaneous, rhythmical firing provides constant tone at neuronal targets.

92
Q

What is the function of monoamine neurons in the brain?

A
  • Sleep-wake cycle and maintaining arousal (i.e. a waking state)
  • Encode specific behavioural events:
    • Dopaminergic neurons are involved in learning to associate a stimulus with a reward
    • 5-HT neurons are involved in learning to associate a stimulus with a punishment (maybe)
  • Mood regulation
  • Anxiety and fear mechanisms
  • Cognition and attention
  • Motor function
  • Prolactin secretion
  • Nausea and vomiting
  • Feeding

(Note that not all of these are due to each type of monoamine. There are flashcards later that break this down into noradrenaline, dopamine and 5-HT.)

93
Q

What is some experimental evidence for the importance of monoamine systems in the CNS in maintaining arousal?

[EXTRA]

A

(Moruzzi, 1949)

  • Inducing a lesion at the medulla-spinal cord level has no effect on wakefulness (as shown by the EEG)
  • Inducing a lesion in the midbrain causes a sleep-like state (as shown by the EEG)
  • Therefore, somewhere between these two points must be the neurons responsible for wakefulness, which are the monoamine neurons

(Jacobs, 1976)

  • Found that raphe nuclei cells fired more during wakefulness than during sleep
94
Q

What is some experimental evidence for the importance of monoamine systems in encoding specific behavioural events?

[EXTRA]

A

(Schultz, 1997):

  • In animals that were not conditioned to associate a stimulus with a reward, the firing of dopamine neurons in the midbrain was shown to increase after the reward (shown by the R line on the diagram)
  • In animals that were conditioned to associate a stimulus with a reward, the firing of dopamine neurons in the midbrain was shown to increase after the stimulus (shown by the CS line on the diagram) -> If no reward occured, then there was a decrease in firing when the reward should’ve been
95
Q

Draw out the noradrenaline synthesis pathway, including enzymes.

A
96
Q

Summarise the synthesis, release, reuptake and recycling of noradrenaline at a synapse.

A
  • Starting point for synthesis is tyrosine, which is taken in via the diet, then transported across the BBB by an amino acid transporter
  • Tyrosine is converted to L-DOPA by tyrosine hydroxylase
  • L-DOPA is converted to dopamine by DOPA decarboxylase
  • Dopamine is transported into vesicles by VMAT (vesicular monoamine transporter)
  • Inside the vesicles, dopamine is converted to noradrenaline by dopamine beta-hydroxylase
  • Noradrenaline is released upon an action potential, due to depolarisation of the membrane leading to an influx of calcium
  • It can bind to alpha-1/2 or beta-1/2 receptors on the postsynaptic membrane, and alpha-2 autoreceptors on the presynaptic membrane
  • Reuptake into the presynatic terminal occurs via NET (norepinephrine transporter) and into the postsynaptic terminal via ENT (extraneuronal uptake)
  • Noradrenaline can then be reused or broken down
  • Break down occurs by:
    • Mostly via MAO (monoamine oxidase) in the presynaptic terminal
    • COMT (catechol-O-methyltransferase) on the postsynaptic membrane (although we don’t fully know the location)
97
Q

At a noradrenergic synapse in the CNS, describe the roles of the different receptors.

[IMPORTANT]

A
  • α1
    • ​Excitatory?, Gq-coupled
    • Leads to an increase in PLC activity, so that IP3 and DAG are increased, mobilising Ca2+
    • [ADD MORE]
  • α2
    • ​Inhibitory, G<span>i</span>-coupled
    • Leads to a decrease in cAMP
    • On pre-synaptic membrane (autoreceptor) AND post-synaptic membrane
  • β1 and β2
    • ​Excitatory, Gs-coupled
    • Leads to an increase in cAMP
98
Q

What are the different sites of action of drugs that can be used to increase or decrease noradrenergic transmission at a synapse?

[IMPORTANT]

A

Decrease transmission:

  • Inhibit synthesis -> e.g. α-methyl-p-tyrosine inhibits tyrosine hydroxylase
  • Inhibit VMAT -> e.g. Reserpine
  • Inhibit adrenoceptors -> e.g. Propranolol is a beta antagonist, Prazosin is an α1 antagonist
  • Stimulate inhibitory adrenoceptors -> e.g. Clonidine is an α2 agonist [CHECK]

Increase transmission:

  • Stimulate exocytosis -> e.g. Ritalin or amphetamine
  • Inhibit reuptake -> e.g. Reboxetine inhibits NET
  • Inhibit metabolism -> e.g. Phenelzine inhibits MAO, Tolcapone inhibits COMT
99
Q

What are the drugs that modulate transmission at a noradrenergic synapse that you need to know?

A
  • Prazosin -> α1 antagonist
  • Phenelzine -> MAO inhibitor
  • Propranolol -> β antagonist
100
Q

What are some drugs that inhibit noradrenaline synthesis?

[EXTRA]

A

α-methyl-p-tyrosine inhibits tyrosine hydroxylase. This is not selective for NA though.

101
Q

What are some drugs that inhibit VMAT?

[EXTRA]

A

Reserpine -> Used to treat hypertension

102
Q

What are some drugs that inhibit alpha-1 adrenoceptors?

A

Prazosin -> Used to treat hypertension and PTSD symptoms

103
Q

What are some drugs that stimulate alpha-2 adrenoceptors?

[EXTRA]

A

Clonidine -> Used to treat hypertension, ADHD and drug withdrawal.

104
Q

What are some drugs that stimulate exocytosis of noradrenaline vesicles?

[EXTRA]

A

Ritalin or amphetamine -> Ritalin is used to treat ADHD.

105
Q

What are some drugs that inhibit reuptake of catecholamines from the synapse?

[EXTRA]

A

Reboxetine inhibits NET -> Used as an antidepressant.

106
Q

What are some drugs that inhbit the metabolism of catecholamines?

A
  • Phenelzine inhibits MAO -> Used as an antidepressant
  • Tolcapone inhibits COMT -> Used to treat Parkinson’s disease
107
Q

Summarise the functions of noradrenergic neurons in the CNS.

A
  • Sleep-wake cycle
  • Arousal
  • Mood regulation
  • Anxiety & fear mechanisms
  • Cognition (such as attention)
108
Q

What are some therapeutic uses of drugs targeting noradrenergic synapses?

A
109
Q

Summarise the synthesis, release, reuptake and recycling of dopamine at a synapse.

A
  • Starting point for synthesis is tyrosine, which is taken in via the diet, then transported across the BBB by an amino acid transporter
  • Tyrosine is converted to L-DOPA by tyrosine hydroxylase
  • L-DOPA is converted to dopamine by DOPA decarboxylase
  • Dopamine is transported into vesicles by VMAT (vesicular monoamine transporter)
  • There is no dopamine beta-hydroxylase enzyme, so it is not converted to noradrenaline
  • Dopamine is released upon an action potential, due to depolarisation of the membrane leading to an influx of calcium
  • It can bind to D1-5 receptors on the postsynaptic membrane, and D2-3 autoreceptors on the presynaptic membrane
  • Reuptake into the presynatic terminal occurs via the dopamine transporter (homologous to the norepinephrine transporter)
  • Doapmine can then be reused or broken down
  • Break down occurs by:
  • Mostly via MAO (monoamine oxidase) in the presynaptic terminal
  • COMT (catechol-O-methyltransferase) on the postsynaptic membrane (although we don’t fully know the location)
110
Q

At a dopaminergic synapse in the CNS, describe the roles of the different receptors.

[IMPORTANT]

A

D1 receptors (D1, D5):

  • Gs-coupled, Stimulate adenylate cyclase to increase cAMP

D2 receptors (D2, D3, D4)

  • Gi-coupled, Inhibit adenylate cyclase to decrease cAMP
  • D2 and D3 are also on the pre-synaptic membrane
111
Q

Are all of the types of dopamine receptor expressed on each neuron in the striatum?

A

Some neurons express the D1 family (D1 and D5), while others express the D2 family (D2-4).

112
Q

What are the different sites of action of drugs that can be used to increase or decrease dopaminergic transmission at a synapse?

[IMPORTANT]

A

Decrease transmission:

  • Inhibit synthesis -> e.g. α-methyl-p-tyrosine inhibits tyrosine hydroxylase
  • Inhibit VMAT -> e.g. Reserpine
  • Inhibit receptors -> e.g. Haloperidol is a D2 antagonist

Increase transmission:

  • Stimulate exocytosis -> e.g. Amphetamine
  • Inhibit reuptake -> e.g. Cocaine inhibits the dopamine transporter
  • Inhibit metabolism -> e.g. Selegiline inhibits MAOB, Tolcapone inhibits COMT
  • Stimulate receptors -> e.g. Ropinerole is a D2 agonist
113
Q

What are the drugs that modulate transmission at a dopaminergic synapse that you need to know?

A
  • Haloperidol -> D2 receptor antagonist
114
Q

What are some drugs that are D2 receptor antagonists and agonists?

A
  • Haloperidol is a D2 antagonist -> Antipsychotic medication [IMPORTANT]
  • Ropinerole is a D2 agonist -> Used to treat Parkinson’s disease
115
Q

What are some drugs that inhbit the dopamine transporter (in reuptake of dopamine)?

[EXTRA]

A

Cocaine

116
Q

What are some drugs that selectively inhibit dopamine metabolism?

[EXTRA]

A

Selegiline inhibits MAOB -> Used to treat Parkinson’s and depression

117
Q

Summarise the functions of dopaminergic neurons in the CNS.

A
  • Motor function
  • Reward and motivation
  • Cognition
  • Prolactin secretion
118
Q

What are the main dopaminergic pathways in the brain and what is the function of each?

A
  • From substantia nigra to striatum -> Nigrostriatal
    • Motor function
  • From ventral tegmental area to nucleus accumbens -> Mesolimbic
    • Reward and motivation
  • From ventral tegmental area to prefrontal cortex -> Mesocortical
    • Cognition
  • From hypothalamus to median eminence -> Tuberoinfundibular
    • Prolactin secretion
119
Q

What are some therapeutic uses of drugs targeting dopaminergic synapses?

A
120
Q

Summarise the synthesis, release, reuptake and recycling of 5-HT at a synapse.

A
  • Starting point for synthesis is tryptophan, which is taken in via the diet, then transported across the BBB by an amino acid transporter
  • Tryptophan is converted to 5-HTP by tryptophan hydroxylase
  • 5-HTP is converted to 5-HT by 5-HTP decarboxylase
  • 5-HT is transported into vesicles by VMAT (vesicular monoamine transporter)
  • 5-HT is released upon an action potential, due to depolarisation of the membrane leading to an influx of calcium
  • It can bind to 5HT1-7 receptors post-synaptically, and some autoreceptors on the pre-synaptic membrane (CHECK what types)
  • Reuptake into the presynatic terminal occurs via the serotonin transporter (homologous to the norepinephrine transporter)
  • 5-HT can then be reused or broken down
  • Break down occurs by:
  • Mostly via MAO (monoamine oxidase) in the presynaptic terminal
121
Q

At a 5-HT synapse in the CNS, describe the roles of the different receptors.

A

5-HT receptors are very complex (there are 14 types) and you probably don’t need to know all of the details:

  • Some are Gq-coupled -> Such as 5-HT2A, 2C
  • Some are Gi-coupled -> Such as 5-HT1A
  • Some are Gs-coupled -> Such as 5-HT4, 6, 7
  • 5-HT3 is the only ionotropic receptor, allowing sodium in

There are also presynaptic receptors (autoreceptors).

122
Q

What are the different sites of action of drugs that can be used to increase or decrease 5-HT transmission at a synapse?

[IMPORTANT]

A

Decrease transmission:

  • Inhibit synthesis -> e.g. PCPA inhibits tryptophan hydroxylase
  • Inhibit VMAT -> e.g. Reserpine
  • Inhibit receptors -> e.g. Risperidone is a 5-HT2 antagonist, Ondansetron is a 5-HT3 antagonist,

Increase transmission:

  • Inhibit reuptake -> e.g. Fluoxetine inhibits the serotonin transporter
  • Inhibit metabolism -> e.g. Phenelzine is a MAO inhibitor
  • Stimulate receptors -> e.g. Triptans are agonists at 5-HT1 receptors, Buspirone is a partial agonist at 5-HT1A receptors
123
Q

What are the drugs that modulate transmission at a 5-HT synapse that you need to know?

A
  • Fluoxetine
  • Ondansetron
  • Phenelzine
  • Buspirone
124
Q

What are some drugs that inhibit 5-HT synthesis?

[EXTRA]

A

PCPA inhibits tryptophan hydroxylase

125
Q

What are some drugs that inhibit and stimulate 5-HT receptors?

A
  • Risperidone is a 5-HT2 antagonist -> Used as an antipsychotic
  • Ondansetron is a 5-HT3 antagonist [IMPORTANT] -> Used to prevent nausea and vomiting
  • Triptans are agonists at 5-HT1 receptors -> Used to treat migraines and headaches
  • Buspirone is a partial agonist at 5-HT1A receptors [IMPORTANT] -> Used to treat anxiety
126
Q

What are some drugs used to inhibit the serotonin transporter (in 5-HT reuptake)?

A

Fluoxetine inhibits the serotonin transporter -> Used as an antidepressant

127
Q

What are some drugs used to inhibit 5-HT metabolism?

A

Phenelzine is a MAO inhibitor -> Used as an antidepressant

128
Q

Give some experimental evidence for the importance of 5-HT neurons.

[EXTRA]

A

(Smith, 1997):

  • Patients who had recovered from depression and were now stable were given an amino acid mixture, either containing tryptophan or not
  • In the group containing tryptophan, no return of depressive symptoms was seen
  • In the group without tryptophan, the depressive symptoms returned after several hours -> This suggested the importance of 5-HT in mood control (since tryptophan is a precursor of 5-HT)
129
Q

Summarise the functions of 5-HT neurons in the CNS.

A
  • Sleep-wake cycle
  • Mood regulation
  • Anxiety & fear mechanisms
  • Cognition (eg. impulse control)
  • Nausea and vomiting
  • Feeding
130
Q

What are some therapeutic uses of drugs targeting 5-HT synapses?

A
131
Q

How can monoamines be imaged in the brain?

A

PET (positron emission tomography)

132
Q

Are monoamines released from neurons with any co-transmitters?

A

Yes, they are released with co-transmitters, such as with glutamate.

133
Q

What is optogenetics?

[EXTRA?]

A
134
Q

What is epilepsy?

A

Uncontrolled excessive synchronisation of CNS activity

135
Q

What drugs are used to treat epilepsy acutely and chronically?

A
  • Status epilepticus (acute): Benzodiazepine, phenytoin.
  • Management of chronic epilepsy: Valproate, carbamazepine
136
Q
A

YEAR 2 - The Nervous System (18 decks)

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