Neuro: Neurotransmitter Systems III: Monoamines Flashcards

1
Q

Why is the monoamine system important?

A
  • Involved in behavioural effects e.g. motivation, reward, pleasure, movement, learning, cognition, arousal, mood etc.
  • Dysregulation or disruption of this monoamine system is well known to lead to various psychiatric conditions.
  • Important to study the different disruptions that take place in these conditions so that you can develop appropriate pharmacotherapy to manage some of the symptoms.
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2
Q

What are the three CNS systems that control behaviour?

A

Autonomic nervous system - hypothalamus is responsible for the control of the automatic nervous system. The autonomic nervous system is not under voluntary control.

Hypothalamic-pituitary neurohormones - pituitary and hypothalamus release neurohormones which affect behaviour (e.g. HPA)

Diffuse monoamine system

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3
Q

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

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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4
Q

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

A
  • they have a small set of neurons at their core
  • they arise from the brain stem
  • one neuron influences many others
  • synapses release transmitter molecules into the extracellular fluid
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5
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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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 (Gs coupled, increase cAMP)
  • Noradrenaline α1: stimulates PLC (Gq coupled, create IP3)
  • Noradrenaline α2: inhibits AC (Gi coupled, decrease cAMP)
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7
Q

Describe the noradrenergic monoamine system.

A

It consists of noradrenergic neurons which project from the central core, the locus coeruleus (LC).

They project to several areas of the brain, including:

  • the cortex
  • the amygdala
  • the hypothalamus
  • the spinal cord
  • the cerebellum
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8
Q

Briefly mention some actions of noradrenaline on the body.

A

Noradrenaline is very important in brain arousal enabling us to think and take action fast.

It also affects our cardiovascular system by increasing our heart rate and blood pressure, etc. It does this not only by acting on the heart muscle directly but also by acting on the cardiovascular systems in the brain.

When gambling/etc., we get a noradrenergic surge, which plays a role in addiction.

It is also involved in exploration and mood (low NA involved in depression)

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9
Q

How is noradrenaline synthesised?

A
  • Tyrosine is acted upon by the enzyme tyrosine hydroxylase, making DOPA
  • DOPA is then acted upon by DOPA decarboxylase, making dopamine
  • Dopamine is metabolised into noradrenaline via the enzyme Dopamine beta-hydroxylase
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10
Q

How is noradrenaline regulated?

A

If there is an excess of release of NA, it get re-uptaken back inside the neurone via the noradrenaline transporter. Once NA is inside the neurone it gets broken down and metabolised by an enzyme called monoamine oxidase. This allows the termination of NA action.

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11
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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12
Q

How can you increase levels of noradrenaline inside the synaptic media?

A
  • Low NA associated with depression
  • Can block the noradrenaline transporter - NA wont be able to get back inside the neurone
  • Inhibit the monoamine oxidase, increasing NA levels in the synaptic cleft, causing it to leak out
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13
Q

List the different dopaminergic pathways.

A
  • Dopaminergic neurones which project from the Substantia nigra (SN) go to the striatum where dopamine gets released. Involved in movement. Parkinson’s disease is due to neurodegeneration of the striatum neurones.
  • Mesolimbic pathway. Dopaminergic neurones project from ventral tegmental area (VTA) to various regions. The nucleus accumbens (Ac) - region involved in reward, pleasure. The amygdala (Am) - region of the brain involved in emotionality. The hippocampus - involved in memory and learning. Hyperactivity of the mesolimbic dopaminergic system associated with schizophrenia.
  • Mesocortical dopaminergic system. Dopaminergic neurones which project from the VTA directly to the frontal cortex. This is involved in executive function.
  • Tubero-hypophyseal pathway. Dopamine released by the hypothalamus in portal system and is transported via blood circulation to the pituitary. Causes activation of the dopamine D2 receptor in pituitary - inhibits release of hormone prolactin. Regulates prolactin function.
  • Dopamine receptors in chemoreceptor trigger zone (CTZ) have an important function in inducing emesis. So activation of the D2 receptor by dopamine induces vomiting.
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14
Q

How is dopamine synthesised?

A
  • Tyrosine is acted upon by the enzyme tyrosine hydroxylase, making DOPA
  • DOPA is then acted upon by DOPA decarboxylase, making dopamine
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15
Q

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

A
  • Inhibit the dopamine reuptake transporter on the pre-synaptic neurone, meaning there is more dopamine available
  • Inhibit monoamine oxidase B activity, reducing the breakdown of dopamine e.g. selegiline.
  • Introduce a dopamine precursor e.g. L-dopa to increase the production of dopamine.
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16
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, so are excitatory. D2 receptors are linked to αGi subunits so are inhibitory.

17
Q

Describe the serotonergic monoamine system.

A

Serotonin is released from serotonergic neurones which project from 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
  • the thalamus
  • the spinal cord
18
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
  • increased 5-HT in the spinal cord will suppress pain
19
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.

Tryptophan is acted upon by tryptophan hydroxylase, making it 5-hydroxytryptophan. This is then acted upon by dopa decarboxylase, making it 5-hydroxytryptamine, or serotonin.

20
Q

Describe the serotonin receptor subtypes.

A
  • Most of them are G-protein coupled receptors - except for 5HT3 which is the only ion channel receptor.
  • Serotonin receptors are predominantly found postsynaptically. However there is also the 5HT1D auto-receptor and is located presynaptically. Activation of the 5HT1D receptor results in inhibition of serotonin in the synaptic media.
21
Q

How is serotonin regulated?

A
  • Activation of the 5HT1D auto-receptor by serotonin results in inhibition of serotonin in the synaptic cleft
  • Excess of serotonin is mopped up via serotonin transporters and enters back inside the pre-synaptic neurone. Once it is inside it is metabolised and broken down by the enzyme monoamine oxidase (MAO). Therefore this re-uptake terminates the action of serotonin.
  • You can increase serotonin levels in the synaptic cleft by blocking the serotonin transporter. If this is blocked then the serotonin cant go back inside the pre-synaptic neurone. This is how some antidepressants work such as the SSRIs such as Prozac, Citalopram etc.
  • Another way to increase serotonin in the synaptic media is to inhibit the enzyme monoamine oxidase. This inhibits the breakdown of serotonin resulting in an accumulation of serotonin in the synaptic bouton. This will leak out into the synaptic media, inducing a surge of serotonin.
22
Q

List the neurotransmitter and the corresponding autoreceptor.

A

5-HT: 5-HT1A

dopamine: D2 or D3
noradrenaline: α2

23
Q

List the neurotransmitter 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)

24
Q

Describe the structure of monoamine transporters.

A
  • They have 12 transmembrane domains, of which both ends are intracellular.
  • They pump monoamines in neurones.
  • Examples would be DA, NA and 5HT transporters.
25
Q

Describe the different acetylcholine pathways in the brain.

A
  • Cholinergic neurones project from the nucleus basalis where the cell body is found to the cortex.
  • Others project from the septum to the hippocampus.
  • Others project from the substantia nigra to the thalamus.
  • There are also a lot of cholinergic interneurones which are found in the striatum.
26
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)
  • nicotinic (ionotropic)
27
Q

What does acetylcholine do to the brain?

A
  • Involved in memory and learning - neurodegeneration of cholinergic neurones is associated with cognitive decline such as in Alzheimer’s and dementia.
  • Acetylcholine is also involved in motor control. The striatum plays an important role in this.
  • Also involved in reward. Acetylcholine binds and acts on nicotinic receptors - main target of the rewarding drug nicotine.
  • Involved in arousal
  • Plays a role in the modulation of pain
  • Involved in addiction
  • Involved in epilepsy
  • Schizophrenia
  • ADHD
  • Depression
  • Anxiety
28
Q

How is acetylcholine regulated?

A
  • Auto-receptors
  • Acetylcholinesterase breaks acetylcholine into choline. Choline gets back inside the pre-synaptic neurone via a transporter called the choline carrier so that choline can get recycled.
  • Can increase acetylcholine in the brain by inhibiting the acetylcholinesterase enzymes. This is one of the drugs available for the management of Alzheimer’s disorder e.g. neostigmine
29
Q

List some other transmitters/modulator substances.

A

Histamine

  • H1 receptor (arousal) and H3 receptor (presynaptic / constitutively active)
  • Blockade of the H1 receptor via antihistamines is involved in sedation and can induce sleep
  • Functions: sleep/wake cycle, vomiting

Purines

  • Adenosine (act on adenosine receptors such as A1, A2A/2B) and ATP (acts on P2X)
  • The breakdown product of ATP is adenosine
  • Functions: sleep, pain, neuroprotection, addiction, seizures, ischaemia, anticonvulsant
  • E.g. caffeine can induce stimulatory effect by blocking adenosine A2A/2B

Neuropeptides

  • Opioid peptides
  • μ , δ, κ
  • Tachykinins (Substance P, neurokinin A & neurokinin B)
  • NK1 (Substance P), NK2 (neurokinin A), NK3 (neurokinin B)
  • Functions: pain

Lipid mediators:

  • Products of conversion of eicosanoids to endocanabinoids (lipid mediators)
  • act on CB1 receptors (canabinoid recepors) - 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
30
Q

List the opioid peptide families and the opioid receptors they act on.

A

Proopioimelanocortin (gives rise to β-endorphins) acts on MOP (μ) and DOP (δ).

Proenkephalin (giving rise to at least 4 enkephalins) acts on DOP (δ).

Prodynorphin (giving rise to two dynorphins and two neo-endorphins) acts on KOP (κ).

Pronociceptin (giving rise to nociceptin and OFQ) acts on NOP (ORL 1).

31
Q

How do the psychoactive drugs induce the rewarding effect?

A

All drugs of abuse including nicotine, cannabis, heroin, cocaine, amphetamine, alcohol, ecstasy etc all induce the hedonic effect by activating the mesolimbic dopaminergic system.

Activate reward system in the brain, increasing dopamine responsible for the rewarding and pleasurable effect following administration of drug.

32
Q

Describe amphetamine and its actions.

A

Examples of amphetamine-like drugs that are used recreationally are methylphenidate and MDMA. They release cystolic monoamines (DA) by displacing them. Their prolonged use can be neurotoxic. It causes the degeneration of amine-containing nerve terminals and cell death.

Pharmacological effects:

  • increased alertness and locomotor stimulation (increased aggression)
  • euphoria/excitement
  • sterotyped behaviour
  • anorexia
  • decreased physical and mental fatigue (improves monotonous tasks)
  • peripheral sympathomimetic actions (increased BP and decreased gastric mobility)
  • confidence improves/lack of tiredness

It can be used therapeutically to treat ADHD (methylphenidate), as appetite suppressants and to treat narcolepsy.

33
Q

Describe cocaine and its actions.

A

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

Pharmacological effects:

  • euphoria
  • locomotor stimulation (fewer sterotypes behaviours than amphetamine)
  • heightened pleasure (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
34
Q

Besides from the dopaminergic system what other systems can drugs effect?

A

MDMA (ecstasy):
- Induces effects by inhibiting monoamine transporters (mainly 5-HT)
- Large increase in 5-HT (serotonin) in brain (followed by depletion)
- Increased 5-HT linked to psychotomimetic effects
- Increased dopamine linked to euphoria
(followed by rebound dysphoria)

LSD, Psylocybin:

  • These are not necessarily drugs of abuse
  • They have a hallucinogenic effect by acting on 5HT2 receptors - Psylocybin activates an agonist on those receptors

Psychostimulants (including amphetamine and cocaine):

  • Increases dopamine in the nucleus accumbens
  • Also increase 5HT (serotonin) and NA (noradrenaline) in the brain
  • Cocaine block DAT, NET, SERT