NEURO: Neurotransmitter Systems III: Monoamines

Question 1

What are the three CNS systems that control behaviour?

Answer 1

• the autonomic nervous system
• hypothalamic-pituitary neurohormones
• diffuse monoamine system

Question 2

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

Answer 2

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

Question 3

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

Answer 3

• 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

Question 4

Signalling in the nervous system can be fast or slow.

Describe the fast and slow signalling.

Answer 4

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

Question 5

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

Answer 5

• 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

Question 6

Describe the noradrenergic monoamine system.

Answer 6

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

They project to several areas of the brain, including:

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

Question 7

Briefly mention some actions of noradrenaline on the body.

Answer 7

Noradrenaline is very important in brain arousal (via the LC) enabling us to think and take action fast.

It also affects our cardiovascular system by increasing our heart rate, increasing our 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.

Question 8

List some drugs and their effect on noradrenaline levels.

Answer 8

• 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

Question 9

How is dopamine synthesised?

Answer 9

Dopamine is synthesised from tyrosine.

Tyrosine is acted upon by the enzyme tyrosine hydroxylase, making DOPA. DOPA is then acted upon by DOPA decarboxylase, making dopamine.

Question 10

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

Answer 10

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.

Question 11

Describe dopamine receptors.

Answer 11

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.

Question 12

Describe the serotonergic monoamine system.

Answer 12

Serotonin is released from serotonergic neurones which project on this important nucleus called 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

Question 13

Briefly mention some actions of serotonin on the body.

Answer 13

• 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

Question 14

How is serotonin synthesised?

Answer 14

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.

Question 15

What kind of drugs would be used to treat depression?

Answer 15

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.

Question 16

List the transmitter and the corresponding autoreceptor.

Answer 16

5-HT: 5-HT1A

dopamine: D2 or D3
noradrenaline: α2

Question 17

List the transmitter and the corresponding reuptake transport.

Answer 17

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)

Question 18

Describe the structure of monoamine transporters.

Answer 18

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

Examples would be DA, NA and 5HT transporters.

Question 19

Describe the different acetylcholine pathways in the brain.

Answer 19

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 interneurones which are found in the striatum.

Question 20

Describe the synthesis and action of acetylcholine.

Answer 20

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)

Question 21

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

Answer 21

We can regulate the amount 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.

Question 22

List some other transmitters/modulator substances.

Answer 22

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 endocanabinoids
• act on CB1 (inhibit GABA, glutamate release)
• involved in vomiting (CB1 agonist block it, MS, pain, anxiety, weight loss/rimonoabant CB1 antagonist)

MELATONIN:

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

Question 23

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

Answer 23

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).

Question 24

Describe amphetamine and its actions.

Answer 24

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, ultimately, 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 therapeuticaly to treat ADHD (methylphenidate), as appetite suppressants and to treat narcolepsy.

Question 25

Describe cocaine and its actions.

Answer 25

Cocaine blocks catecholamine 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