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Neurology > Neurotransmitters Systems III: Monoamines > Flashcards

Neurotransmitters Systems III: Monoamines Flashcards

1
Q

What CNS Systems are in place to control behaviour?

A
  • Autonomic nervous system
  • Hypothalamic-pituitary neurohormones
  • Diffuse monoamine system
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2
Q

What are the roles of the CNS?

A

> the sympathetic nervous system is body activation
parasympathetic nervous system is relaxation and
recovery

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3
Q

What is the significance of monoamines?

A

The diffuse modulatory systems of the brain

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4
Q

What are the four main monoamine systems?

A
  • Noradrenergic Locus Coeruleus
  • Serotonergic Raphe Nuclei
  • Dopaminergic Substantia Nigra and Ventral tegmental
    Area
  • Cholinergic Basal Forebrain and Brain Stem Complexes
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5
Q

Describe the fast point-to-point signalling neurotransmission across the CNS

A
  • Neurotransmitters producing excitatory or inhibitory
    potentials
  • Ligand-gated ion channels
  • Glutamate, GABA, ACh
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6
Q

Describe the slow transmission that occurs in the CNS

A
  • Neurotransmitters and neuromodulators
  • G-protein coupled receptors
  • Monoamines, peptides, ACh
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7
Q

Name the metabotropic receptors of the CNS

A 
5-HT1				Inhibits AC
5-HT2 				Stimulates PLC
Dopamine D1 		Stimulates AC
Dopamine D2 		Inhibits AC
Noradrenaline β		Stimulates AC
Noradrenaline α1		Stimulates PLC
Noradrenaline α2		Inhibits AC
  • AC = adenylyl cyclase
  • *PLC = phospholipase C
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8
Q

What are the functions of noradrenaline?

A
  • Arousal, wakefullness, exploration and mood (low NA in
    depressed patients)
  • Blood pressure regulation, (antihypertensive e.g.
    clonidine α2)
  • (Addiction/gambling)
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9
Q

Describe the effects of the drug reserpine on the noradrenergic receptors

A

Reserpine depletes NA stores by inhibiting vesicular uptake

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10
Q

Describe the effects of amphetamine on noradrenergic receptors

A

Amphetamine (indirect sympathomimetic)-enters vesicles displacing NA into cytoplasm, increases NA leakage out of neuron

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11
Q

Describe how cocaine effects noradrenaline receptors

A

Cocaine-blocks NA re-uptake

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12
Q

What are the main actions of noradrenaline receptors?

A 
Main action inhibitory (β) 
Also excitatory (⍺ / β)
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13
Q

How are noradrenergic synaptic transmission terminated?

A

Termination of noradrenaline occurs via neuronal uptake and monoamine oxidase

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14
Q

Where are noradrenergic receptors mainly located?

A

Main cell body in locus coeruleus

  • NAergic neurons active when ‘awake’
  • Amphetamine - ↑ alertness and exploratory behaviour

High density in brainstem, hypothalamus & medial temporal lobe

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15
Q

What are the 2 receptor locations and their functions?

A

Post-synaptic
- Carry on the message

Pre-synaptic (autoreceptors)

  • Usually inhibitory
  • Negative feedback mechanism
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16
Q

What is the function of autoreceptors?

A

Inhibit cell firing and transmitter release at the terminal region

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17
Q

Where are autoreceptors found?

A

Presynaptically
Note that these receptors can also be found post-synaptically
– but they are not autoreceptors if they are post-synaptic

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18
Q

What is the role of neurotransmitter transporters?

A

Usually take the neurotransmitter back up into the presynaptic terminal

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19
Q

Describe the structure of monoamine transporters

A

12 Transmembrane Domains
Both ends intracellular
Pump monoamines in neuron
Function: DA, NA, 5HT transporters back into neurones

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20
Q

What is the role of dopamine?

A

Inhibits central neurons (K+ channels)

Binds to D1 (D1 & D5) and D2 (D2, D3, D4) receptors

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21
Q

How is dopamine acitvity regulated?

A

Termination by Monoamine Oxidase B, neuronal uptake

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22
Q

What are the physiological functions of dopamine?

A

Functions / disorders

  • Movement
  • addiction
  • stereotypy
  • hormone release
  • vomiting
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23
Q

What are the main brain pathways dopamine works across?

A

Tubero-hypophyseal pathway
Main pathways: Substantia nigra to basal ganglia (Parkinson’s disease)
Midbrain to limbic cortex (schizophrenia)

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24
Q

Explain how dopamine exerts its effects?

A

Dopamine released in the hypothalamus in the portal capillary system connecting the hypothalamus to the pituitary gland.
When bound to dopamine receptors in the pituitary, dopamine inhibits the release of Prolactin (PL)

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25
Q

Which pathologies is dopamine involved in?

A

Involved in:
PD, Schizophrenia, Addiction, Emesis and ADHD
Too much dopamine in the synaptic cleft leads to addiction

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26
Q

Outline the synthesis of catecholamines

A

Tyrosine produced in the neuron and converted to DOPA by tyrosine hydroxylase and then to dopamine by DOPA decarboxylase
Dopamine gets metabolised to noradrenaline by Dopamine-𝜷-hydroxylase
Noradrenaline can get metabolised further to Adrenaline

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27
Q

How do neurons decide to release (nor)adrenaline or dopamine?

A

Neurons with Dopamine-𝜷-hydroxylase in excess release noradrenaline, those without are dopaminergic

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28
Q

Where is dopamine produced?

A

Produced from precursor L-DOPA at the dopaminergic end terminus

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29
Q

How is dopamine transported ready for release?

A

When the neurone is activated dopamine is released in the synaptic milia

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30
Q

What are the 2 types of dopamine receptors and their location?

A

D1 are postsynaptic receptors

D2 autoreceptors are pre and postsynaptic

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31
Q

Explain the effects of dopamine binding to its D2 receptors

A

Dopamine binds to its receptors

When bound to its autoreceptor (D2) it inhibits the release of dopamine → regulatory control

32
Q

How is dopamine release mediated?

A

Control of dopamine levels in the synaptic cleft are vital for normal physiological functions of the brain
This is done in the same way noradrenaline is mediated

Excess dopamine is taken into the neuron via dopamine transporter and broken down into metabolites by monoamine oxidase B

33
Q

How do Parkinson’s disease targeting drugs alter dopamine effects?

A

Drugs targeting Parkinson’s disease inhibit monoamine oxidase B to increase dopamine

34
Q

What are the 2 types of dopamine receptors?

A

There are 2 types of dopamine receptors:
D1-like receptors (D1 & D5)
D2-like receptors (D2,3 & 4)

35
Q

Where are the different dopamine receptors found?

A

D1 and D2 receptors in striatum, limbic system, thalamus & hypothalamus
D3 receptors in limbic system NOT striatum
D4 receptors in cortex & limbic system

36
Q

Describe the structure of dopamine receptors

A

These are GPCRS with 7 transmembrane domains. Each is coupled to different G proteins

37
Q

Which G protein are D1 receptors coupled to?

A

D1 receptors activate the Gs pathway stimulating AC → cAMP increasing PKA and induces phosphorylation for secondary messenger signalling

38
Q

Outline the D2 receptors G protein coupled signalling

A

D2 are coupled to the Gi protein. This causes the inhibition of AC → cAMP (inhibitory)

39
Q

What is serotonin?

A

A monoamine released from serotonergic neurons projecting from the Raphe nucleus

40
Q

What is the role of serotonergic neurons?

A

Serotonergic neurons project to various brain regions including the cerebellum, cortex, striatum, hippocampus and spinal cord

41
Q

What effect does serotonin have in the brain cortex?

A

When serotonin is released into the brain cortex (top) it binds to its receptors to induce heightened perceptions - cognitive effect

42
Q

What effect does serotonin produce in the hypothalamus?

A

In the hypothalamus serotonin reduces appetite when bound to its receptors

43
Q

Describe the effects of serotonin in the amygdala

A

When released and bound to its receptors in the amygdala, serotonin elevates the mood - antidepressants commonly increase serotonin levels

44
Q

What other physiological functions is serotonin heavily involved in?

A

Serotonin is also involved in sleep, vomiting (antiemetic effect)

45
Q

Outline the synthesis of serotonin

A

Tryptophan (a.a) is the precursor molecule of serotonin
It is metabolised by tryptophan hydroxylase into 5-hydroxytryptophan which is metabolised further by L-aromatic acid decarboxylase into serotonin 5-HT

5-HT can be further metabolised by monoamine oxidase into 5-hydroxy acetaldehyde and then aldehyde dehydrogenase converts it into 5-hydroxyindoleacetic acid (5-HIAA)

46
Q

How is serotonin transported to the synaptic cleft?

A

Serotonin carried in vesicles and released across synaptic cleft when the neurone is activated
There are ~10 subtypes of 5-HT receptors

47
Q

Which serotonin receptor mediates the release of serotonin release?

A

5HT₁D is an autoreceptor (presynaptic) inhibiting serotonin release

48
Q

How do 5HT₁D receptors regulate serotonin release?

A

Excess serotonin is transported back into the neuron via serotonin transporter where it is metabolised and broken down via monoamine oxidase

49
Q

As depression is associated with decreased serotonin levels, what is the required mechanism of antidepressants?

A

Drug needs to increase serotonin levels -

block transporter or inhibit monoamine oxidase

50
Q

Describe the serotonin receptors

A

5-HT receptors (14 subtypes) all G-protein coupled except 5-HT3

51
Q

Outline the role and location of the different serotonin receptors

A

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

52
Q

How is serotonin release stopped?

A

Termination – MAO, neuronal uptake

53
Q

What are the functions/disorders associated with serotonin?

A

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 appetite

Pain, migraine (5-HT inhibits pain pathway, synergistic with opioids)

Vomiting

54
Q

How does LSD effect serotonin levels?

A

LSD: Hallucinogenic drug - 5HT antagonism

Heightened perception, Stimulation, Reduced appetite, Elevated mood

55
Q

Where is Ach most commonly found?

A

Abundant in basal forebrain, hippocampus and striatum regions of the brain.
Cholinergic neurons specifically release Ach

56
Q

What is the major cholinergic pathway in the brain?

A

There are various cholinergic pathways in the brain

One of the main ones project from the nucleus basalis onto the cortex where ACh is released

57
Q

What are the other brain pathways involved in cholinergic signalling?

A

Smaller interneurons found in the striatum also release Ach
Other cholinergic neurones release Ach projecting from the septum (emotional behaviour and stress regulation) to the hippocampus (learning & memory)
Cholinergic neurons also project from the substantia nigra to the thalamus
These neurons play a vital cognitive role and are significant in memory and learning

58
Q

How is ACh signalling terminated?

A

Termination via acetylcholinesterase (AChE) hydrolyses Ach

59
Q

How is Ach produced?

A

ACh excitatory neurotransmitter formed from a choline and an acetyl group
It is transported in cholinergic vesicles and released into the synaptic cleft

60
Q

What are the 2 types of receptors Ach binds to?

A

Nicotinic (ionotropic / fast)

Muscarinic (G-protein coupled / slow)

61
Q

Outline the 4 muscarinic Ach receptors and their roles

A

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

62
Q

What are the functions of Ach?

A

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

63
Q

What is the role and action of histamine?

A

Histamine
- H1 (arousal) and H3 (presynaptic / constitutively active)

Functions: sleep / wake, vomiting

64
Q

What are the effects of Purine modulatory substances?

A

Purines
- Adenosine (A1, A2A/2B) and ATP (P2X)

Functions: sleep, pain, neuroprotection, addiction, seizures, ischaemia, anticonvulsant

65
Q

What are the effects of neuropeptides?

A

Neuropeptides:
- Opioid peptides
μ, δ, κ

  • Tachykinins (Substance P, neurokinin A & neurokinin B)
    NK1 (Substance P), NK2 (neurokinin A), NK3 (neurokinin
    B)

Functions: pain

66
Q

Why are opioid peptides associated with addiction?

A

Fast synaptic transmission – neurotransmitters producing rapid excitatory or inhibitory potentials

67
Q

Where are opioid peptides released from?

A

Neuromodulators released from glial cells (particularly astrocytes).

Glial cells known as inexcitable neurons.
Glutamate acts via ligand gated receptors and also through G protein receptors

68
Q

How does opioid neurotransmission differ from the CNS?

A

Although transmission principles are the same as in the periphery CNS is made more complex because of the interconnections between neurons and also the fact that other cells e.g. glial cells also release mediators.
Also longer term changes affect the balance between these systems

Many subtypes: improves selectivity CNS complex, connectivity

69
Q

Describe the synthesis and release of neuropeptides

A

Genes give rise to POMC (opioids) mRNA which is packaged to undergo modifications via the golgi apparatus.

POMC undergoes proteolytic cleavage into smaller / modified proteins e.g. beta-endorphins etc. which are transported into vesicles to be released across the synaptic cleft

70
Q

Describe the effects of lipid mediators in the body

A

Lipid mediators
-Products of conversion of eicosanoids to
endocannabinoids
-act on CB1 (inhibit GABA, glutamate release)
-involved in vomiting (CB1 agonist block it, MS, pain,
anxiety, weight loss/rimonabant CB1 antagonist)

71
Q

Describe the effects of melatonin

A

Melatonin
-MT1, MT2 receptors
- involved in sleep regulation, circadian rhythmicity,
agonists for jet lag and insomnia

72
Q

What are the pharamacological effects of psychostimulants like amphetamine?

A

↑ alertness and locomotor stimulation (↑ aggression)
Euphoria / excitement
Stereotyped behaviour
Anorexia
↓ physical and mental fatigue (improves monotonous tasks)
Peripheral sympathomimetic actions (↑ blood pressure & ↓ gastric motility)
Confidence improves/lack of tiredness

73
Q

What are the therapeutic uses of psychostimulants?

A

ADHD (methylphenidate), appetite suppressants, narcolepsy

74
Q

Why are psychostimulants involved in addictive disroders?

A

Amphetamine-like drugs (methylphenidate & MDMA) release cytosolic monoamines (DA)
Prolonged use neurotoxic
Degeneration of amine-containing nerve terminals, cell death

75
Q

Explain the effects of central stimulants like cocaine

A

Blocks catecholamine reuptake

↑ DA, stimulant effect

76
Q

What are the pharmacological effects of cocaine?

A

Euphoria
Locomotor stimulation
Fewer stereotyped behaviours than amphetamine
Heightened pleasure
Lower tendency for delusions, hallucinations and paranoia

77
Q

Explain the pharmacokinetics of cocaine use

A

HCl salt, inhaled and i.v. administration
- Nasal inhalation less intense, leads to necrosis of nasal
mucosa
Freebase form (‘crack’), smoked, as intense as i.v route

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