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Physiology 2: Sem 3 > NEURO: Neurotransmitter Systems III: Monoamines > Flashcards

NEURO: Neurotransmitter Systems III: Monoamines Flashcards

1
Q

What are the three CNS systems that control behaviour?

A

Autonomic Nervous System
Hypothalamic-Pituitary Neurohormones
Diffuse Monoamine Modulatory System

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2
Q

What are the four main systems we talk about when discussing the diffuse monoamine system?

A
  • Noradrenaline: Noradrenergic Locus Coeruleus
  • Serotonin (5-HT): Serotonergic Raphe Nuclei
  • Dopamine: Dopaminergic Substantia Nigra and Ventral Tegmental Area
  • Acetylcholine: Cholinergic Basal Forebrain and Brain Stem Complexes
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3
Q

What are some principles that the 4 monoamine systems have in common?

A

Ø Released from neurones which arise from the brain stem
Ø Neurones project from the central core where cell bodies are located to many different regions of the brain where the neurotransmitter gets released
Ø One neurone influences many others
Ø Synapses release transmitter molecules into the extracellular fluid

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4
Q

What type of receptors are monoamine receptors?

Describe the structure of monoamine transporters.

A

G-protein coupled receptors

They have 12 transmembrane domains, of which both ends are intracellular.
They pump monoamines in neurones.

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5
Q

Noradrenergic modulatory pathway

A

noradrenergic neurones project from the central core called Locus Coerulus to different brain regions:

  • the cortex
  • the amygdala
  • the hypothalamus
  • the spinal cord
  • the cerebellum
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6
Q

Give some examples of metabotropic receptors and their consequent actions upon stimulation.

A
  • 5-HT1: inhibits Adenylate Cyclase (AC)
  • 5-HT2: stimulate PhosphoLipase C (PLC)
  • Dopamine D1: stimulates AC
  • Dopamine D2: inhibits AC
  • Noradrenaline β: stimulates AC
  • Noradrenaline α1: stimulates PLC
  • Noradrenaline α2: inhibits AC
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7
Q

Effects of increased noradrenaline

Effects of decreased noradrenaline

A
  • Cardiovascular effects (tachycardia, high blood pressure)
  • Addictive-like behaviour (gambling)
  • Hyperarousal
  • Depression
  • Parkinson’s disease
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8
Q

Noradrenaline Regulation: Reuptake mechanism

A

noradrenaline transporters on pre-synaptic membrane reuptake excess noradrenaline from synapse

once inside the synapse, noradrenaline is metabolised and broken down by monoamine oxidase (MAO), terminating its action

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9
Q

Noradrenaline receptors

A

G-protein coupled receptors:

  • Alpha 1 (Gq)
  • Alpha 2 (Gi)- autoreceptors
  • Beta (Gs)
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10
Q

The action of drugs in depression treatment

A

Drugs to increase noradrenaline:

  • block monoamine oxidase (MOA)
  • block noradrenaline transporters
  • block serotonin transporters
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11
Q

Signalling in the nervous system can be fast or slow.

Describe the fast and slow signalling.

A

FAST point-to-point signalling:

  • neurotransmitters producing excitatory or inhibitory potentials
  • ligand-gated ion channels
  • glutamate, GABA, ACh

SLOW transmission:

  • neurotransmitters and neuromodulators
  • G-protein coupled receptors
  • monoamines, peptides, ACh
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12
Q

List some drugs and their effect on noradrenaline levels.

A
  • Reserpine: depleted NA stores by inhibiting vesicular uptake
  • Amphetamine (indirect sympathomimetic): enters vesicles, displacing NA into the cytoplasm, increasing NA leakage out of the neuron
  • Cocaine: blocks NA reuptake
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13
Q

Dopaminergic Modulatory Pathways

A

Nigrostriatal Pathway

Mesolimbic Pathway

Mesocortical Pathway

Tubero-hypophyseal Pathway

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14
Q

Nigrostriatal pathway

A

dopaminergic neurones project from substantia nigra (SN), where cell bodies are found, to the striatum where dopamine is released to induce MOVEMENT

*degeneration of these neurones decreasing dopmaine levels in the striatum, causing Parkinson’s disease (suppressed movement)

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15
Q

Mesolimbic pathway

A

dopaminergic neurones project from the ventral tegmental area (VTA) to the amygdala, hippocampus and nuclear accumbens, where dopamine is released to induce REWARD (e.g. food, sex)

  • Abused drugs over-stimulate this pathway, increasing pleasure/reward, leading to addiction
  • Hyperactivity of this system causes psychotic episodes in schizophrenics
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16
Q

Mesocortical pathway

A

dopaminergic neurones project from ventral tegmental area (VTA) to the cortex, where dopamine is released

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17
Q

Tubero-hypophyseal pathway

A

dopaminergic neurones project from the hypothalamus to the portal capillary system in the median eminence where dopamine is released, binding to receptors in the anterior pituitary and inhibiting the release of prolactin

*prolactin responsible for mammary gland enlargement and milk production

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18
Q

Synthesis of Catecholamines

A

Dopamine is synthesised from tyrosine.

1) Tyrosine is converted to DOPA by tyrosine hydroxylase
2) DOPA is converted to dopamine via DOPA decarboxylase
3) Dopamine is then metabolised to noradrenaline via Dopamine-β hydroxylase
4) Noradrenaline can then further be metabolised to adrenaline

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19
Q

Dopamine involved in…

Dopamine associated with…

A 
addiction (gambling)
emesis
ADHD
Schizophrenia (hyperactivity of mesolimbic pathway)
Parkinson's disease (lack of dopamine)
movement
addiction
stereotypy
hormone release
vomiting
20
Q

What determines whether a neurone is dopaminergic or noradrenergic?

A

The presence of Dopamine-β hydroxylase in excess makes neurones dopaminergic

Neurones without this enzyme are noradrenergic

21
Q

Effects of increased dopamine

Effects of decreased dopamine

A

addiction
psychosis

Parkinson’s disease

22
Q

Dopamine Regulation: Reuptake Mechanism

A

dopamine transporters on pre-synaptic membrane reuptake excess dopamine from synapse

once inside the neurone, dopamine is metabolised and broken down by monoamine oxidase b (MOAb), terminating its action

23
Q

Actions of drugs in Parkinson’s treatment

A

Drugs to increase dopamine:

  • block monoamine oxidase b (MOAb)
  • block dopamine reuptake transporters
24
Q

What are some ways in which we could increase the amount of dopamine in the synaptic cleft?

A

We could inhibit the dopamine reuptake transporter on the pre-synaptic neurone, meaning there is more dopamine available to act.

We could also inhibit monoamine oxidase B activity, thus reducing the breakdown of dopamine.

Lastly, we could also introduce a dopamine precursor to increase the production of dopamine.

25
Q

Describe dopamine receptors.

A

There are two kinds of dopamine receptors (and 5 receptor subtypes):

  • D1-LIKE RECEPTORS: D1, D5
  • D2-LIKE RECEPTORS: D2, D3, D4

The receptor is a G protein-coupled receptor with 7 transmembrane domains, with N terminals found extracellular and C terminals found intracellularly.

D1 receptors are linked to αGs subunits, and thus are excitatory. D2 receptors are linked to αGi subunits, and thus are inhibitory.

26
Q

Where are dopamine receptors are found?

A
  • Post-synaptic D1 and D2 receptors
  • Pre-synaptic D2 or D3 auto-receptors

· D1 and D2 receptors are found in the striatum, limbic system, thalamus and hypothalamus
· D3 receptors are found in the limbic system
· D4 receptors are found in the cortex and limbic system

27
Q

Describe the serotonergic monoamine system.

A

Serotonin is released from serotonergic neurones which project on this important nucleus called the raphe nucleus. This is where the cell bodies are found.

They project to different areas of the brain, such as:

  • the cortex
  • the cerebellum
  • the amygdala
  • the hypothalamus
  • the hippocampus
  • the striatum
28
Q

Briefly mention some actions of serotonin on the body.

A
  • increased 5-HT in your cortex causes heightened perceptions
  • increased 5-HT in your hypothalamus causes reduced appetite
  • increased 5-HT in your amygdala causes elevated mood
29
Q

How is serotonin synthesised?

A

Tryptophan is the precursor of serotonin. It can only be obtained from food as the body cannot manufacture it.

Precursor of serotonin is the amino acid tryptophan:

1) Tryptophan is metabolised by tryptophan hydroxylase to 5-hydroxytryptophan
2) 5-hydroxytryptophan is metabolised by L-Aromatic acid decarboxylase to serotonin (5-HT)
3) 5-HT can be metabolised further by monoamine oxidase to 5-hydroxyindoleacetylaldehyde
4) This metabolite can be further metabolised to 5-HIAA (5-hydroxyindoleacetic acid) by aldehyde dehydrogenase

30
Q

What kind of drugs would be used to treat depression?

A

Drugs that block serotonin reuptake transporters would be used. Drugs that inhibit monoaminoxidase could also be used.

Both of these mechanisms ensure that there is more serotonin in the synaptic cleft.

31
Q

Effect of serotonin

A

Different effects in different brain regions:

· Binds to receptors in the cortex and causes heightened perceptions
· Binds to receptors in the hypothalamus and reduces appetite
· Binds to receptors in the amygdala and causes elevated mood

Other effects:

  • sleep/wake cycle
  • vomiting
  • psychosis
  • reducing pain, migraine
32
Q

Serotonin Regulation: Reuptake Mechanism

A

Serotonin transporters on pre-synaptic membranes reuptake excess serotonin from the synapse

once inside the neurone, the serotonin is metabolised and broken down by monoamine oxidase (MOA), terminating its action

33
Q

List the transmitter and the corresponding autoreceptor.

A

5-HT: 5-HT1A

dopamine: D2 or D3
noradrenaline: α2

34
Q

List the transmitter and the corresponding reuptake transport.

A 
dopamine: DAT (on dopamine neurones)
5-HT: SERT (on 5-HT neurones)
NA: NET (on noradrenaline neurones)
glutamate: EAAT1 (mostly on astrocytes)
dopamine: vMAT2 (into vesicles)
35
Q

Describe the different acetylcholine pathways in the brain.

A

Septohippocampal Pathway
-cholinergic neurones project from the septum to the hippocampus, where acetylcholine is released

Nucleus Basalis
-cholinergic neurones project from the nucleus basalis to the cortex where acetylcholine is released

Striatal Interneurons
-small cholinergic neurones called striatal interneurons found within the striatum release acetylcholine.

Substantia Nigra
-cholinergic neurones project from the substantia nigra to the thalamus, where acetylcholine is released.

36
Q

Describe the synthesis and action of acetylcholine.

A

Acetyl CoA and choline are combined to form acetylcholine, which is packaged into vesicles and released. When released, they act on their receptors.
There are two kinds of receptors:
- muscarinic (G protein-coupled): M1,3,5 excitatory, M2&4 inhibitory
- nicotinic (ionotropic)

37
Q

What are cholinergic neurones involved in?

Acetylcholine involved in…

A

cognition, learning, memory

arousal
epilepsy (mutations of nAChR genes)
learning and memory
motor control, pain, addiction
schizophrenia
ADHD
depression
anxiety
Alzheimer's
38
Q

How do we regulate the amount of acetylcholine in the synapse?

A

We can regulate the number of acetylcholinesterases, which break down acetylcholine into acetate and choline (the choline is reabsorbed and recycled).

To increase the amount/activity of ACh, we would use an acetylcholinesterase inhibitor, which will mean less ACh is being broken down.

39
Q

What does the degeneration of cholinergic neurones cause?

A

dementia and Alzheimer’s, causing cognitive symptoms such as memory loss

Drugs increase acetylcholine levels:
-inhibit the acetylcholinesterase enzyme

40
Q

List some other transmitters/modulator substances.

A

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 (μ, δ, κ)
  • tachykinins (substance P [NK1], neurokinin A [NK2] and neurokinin B [NK3])
  • functions: pain

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)

MELATONIN:

  • MT1, MT2 receptors
  • involved in sleep regulation, circadian rhythmicity, agonists for jet lag and insomnia
41
Q

What are opioid peptides (neuropeptides) derived from?

A

a bigger protein e.g. β endorphin is derived from pro-opiomelanocortin (POMC)

once the peptide is released from the neurone it acts on receptors

42
Q

How are neuropeptides synthesized?

A
  • Encoded by DNA
  • Gene modified in rER and Golgi
  • Proteolytic cleavage in Golgi breaks down big proteins into many different peptides e.g. β endorphin, which is stored in synaptic vesicles for release upon stimulation
43
Q

Which drugs interact with the diffuse system?

A

Amphetamine (psychostimulant)

Cocaine (central stimulant)

44
Q

Describe amphetamine and its actions.

A

methylphenidate & MDMA:

  • release cytosolic monoamines
  • prolonged use causes degeneration of nerves and death (neurotoxic)

Pharmacological effects

  • increased alertness and locomotor stimulation (increased aggression)
  • stereotyped behaviour
  • anorexia
  • less physical and mental fatigue
  • increased blood pressure
  • decrease gastric motility
  • improved confidence/lack of tiredness

Therapeutic uses:

  • ADHD (methylphenidate)
  • Appetite suppressants
  • Narcolepsy
45
Q

Describe cocaine and its actions.

A

Cocaine blocks catecholamine reuptake. It increases dopamine and has a stimulant effect.

Pharmacological effects:

  • euphoria
  • locomotor stimulation (fewer stereotypes behaviours than amphetamine)
  • heightened pleasure (the lower tendency for delusions, hallucinations and paranoia)

Pharmacokinetics:

  • HCl salt, inhaled and i.v. administration (nasal inhalation is less intense, but leads to the necrosis of nasal mucosa)
  • Freebase form (‘crack’) is smoked and can be as intense as the i.v. route

Physiology 2: Sem 3 (39 decks)

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