PCOL3022 Lecture 6: Monoamines

What are Monoamines?

- Subclass of neurotransmitters within the class of biogenic amines
- Contains 1 aromatic ring connected to an amino group by a 2-carbon chain

- Regulate cognitive processes like emotions, arousal, and certain types of memory
- Drugs that alter monoamine transmission are used to treat psychiatric and neurological disorders (depression, anxiety, schizophrenia, Parkinson's)

What are the subclasses and neurotransmitters under Biogenic amines?

1. Catecholamines
- NAd
- Ad
- DA

2. Indoleamines
- 5-HT

3. Imidazoleamines
- Histamine

What are the key features of Monoamine Neurotransmitters?

- Synthesised from decarboxylated amino acids
- Synthesis mainly by cytosolic enzymes
- Mainly activate GPCRs
- Characteristic anatomical distribution: synthesis is limited to a few subcortical or brainstem regions, which project to multiple cortical and limbic target regions

How are Catechcholamines synthesised?

- Precursors: L-tyrosine --> L-DOPA --> dopamine --> noradrenaline --> adrenaline
- Enzymes: Tyrosine dehydroxylase (rate-limiting step) --> aromatic L-amino acid decarboxylase --> dopamine B-hydroxylase --> phenylethanolamine N-methyl transferase

How are Indoleamines synthesised?

- Precursors: L-tryptophan (essential amino acid - from diet) --> 5-HPT --> 5-HT
- Enzymes: Tryptophan hydroxylase (rate-limiting step) --> aromatic L-amino acid decarboxylase

- While L-Try and 5-HTP can cross the BBB, 5-HT cannot. This helps to maintain appropriate concentrations in the PNS/CNS

Examples of Drugs that Target Synthesis

- Dietary tryptophan (supplements) can increase 5-HT synthesis
- 5-HTP is used (as self-medication) to treat depression, anxiety, and insomnia -- Using the intermediate, instead of the precursor, means the rate-limiting step is avoided)
- L-DOPA used to increase DA synthesis in substantia nigra (Parkinson's)

How are monoamines stored?

- Transported into vesicles by VMAT (vesicular monoamine transporter)
- Stored as complex -- bound with ATP, protein, Ca2+, Mg2+

How are monoamines released?

- Influx of Ca2+ causes release from vesicles
- Released when action potential occurs

5-HT and NAd Storage and Release

- Released from varicosities and synapses
- Large amounts of NAd/5-HT released from varicosities into extracellular space
- Concentration gradients in projection areas of varicosities

Examples of Drugs that Target Storage and Release

- Amphetamine (and its derivatives) are nonselective VMAT substrates
= Same for MDMA, dexamphetamine, methamphetamine
= Compete with endogenous monoamines for vesicular storage
= Increased concentration for cystosolic monoamine increases spontaneous leakage into synapse
= Used therapeutically: Adderall treats ADHD, narcolepsy

- Reserpine
= Disrupts storage of noradrenaline in the vesicular monoamine transporter by disruption the H gradient
= A range of areas where noradrenaline is stored and released to affect mood, blood pressure regulation, etc

Receptor Activation: Dopamine

- All receptors are GPCRs

- D1-like (D1 and D5 receptors) - Gs protein-coupled - Excitatory
- D2-like (D2, D3, and D4 receptors) Gi protein-coupled - Inhibitory

Receptor Activation: Adrenoreceptors

- a1-adrenoreceptors - Gq protein-coupled - Excitatory
- a2-adrenoreceptors - Gi protein-coupled - Inhibitory
- B-adrenoreceptors (1,2,3) - Gs protein-coupled - Excitatory

- Ad affinity: B2 > B1/B3 > a
- NAd affinity: a > B2 >> B2

Receptor Activation: Serotonin

- 5-HT1 (1A, 1B, 1D, 1E, 1F, 1-like) - Gi protein-coupled - Inhibitory
- 5-HT2 (2A, 2B, 2C) - Gq protein-coupled - Excitatory
- 5-HT3 - Ligand-gated ion channel (Na+) - Excitatory
- 5-HT4 - Gs protein-coupled - Excitatory
- Also 5-HT5, 5-HT6, 5-HT7 - Various g protein-coupled - Excitatory

Inactivation

- Main mechanism for terminating action:

Reuptake via high-affinity Na+ dependent membrane transporter proteins (DAT, NET, SERT)

Examples of Drugs that Target Transport: Cocaine

Cocaine blocks DAT, NET, SERT to prevent dopamine re-uptake so it prolongs dopamine action in the synapse

Area: Dopamine mesolimbic pathway

Examples of Drugs that Target Transport: Amitriptyline

Amitriptyline blocks noradrenaline and serotonin transporters to prevent dopamine re-uptake so prolongs dopamine action in the synapse

Area: Wherever noradrenaline and serotonin are stored and released

Examples of Drugs that Target Transport: Bupropion

- Antidepressant
- Anti-nicotinic

Bupropion blocks the dopamine transporter to prevent dopamine re-uptake so prolongs dopamine action in the synapse

Area: Dopamine mesolimbic pathway

Drugs Targeting Reuptake: Antidepressants

- TCAs block NAT and/or SERT > DAT
- NRIs block NAT
- SNRIs block NAT, SERT
- SSRIs block SERT

Degradation

- Breakdown of the transmitter

- By MAO (monoamine oxidase)
= Bound to neuronal and non-neuronal mitochondria
= Has two isoforms: (a) MAO-A: non-selective, degrades all monoamines; (b) MAO-B: degrades DA only

= Used clinically for depression (both selective and non-selective)
= Used for Parkinson's (MAO-B selective inhibitors only)

- By COMT
= Specific for catecholamines
= In extraneuronal locations (outside)

CNS Dysfunctions and Diseases: Dopamine

- Mood
- Schizophrenia and psychosis
- Regulation of hormone release
- Reward and drug abuse
- Movement disorders

- DAT not considered a good target because often associated with addiction

CNS Dysfunctions and Diseases: Noradrenaline

- Mood
- Anxiety
- Regulation of autonomic function
- Pain

CNS Dysfunctions and Diseases: Serotonin

- Mood
- Anxiety
- Regulation of autonomic function
- Regulation of hormone release
- Pain

Dopamine pathways: Synthesis

- VTA
- Substantia nigra
- Hypothalamus

Dopamine pathways: Projects to...

- Mesolimbic pathwat
- Amygdala
- Hippocampus
- Mesocortical pathway
- Nucleus accumbens
- Cortex
- Straitum
- Nigro-striatal pathway
- Tubero-infundibular pathway

Noradrenaline pathways: Synthesis

- Locus coeruleus
- Reticular formation

Noradrenaline pathways: Projects to...

- Spinal cord
- Cerebellum
- Amygdala
- Hypothalamus
- Cortex
- Thalamus
- Septum

Serotonin pathways: Synthesis

- Raphe nuclei

Serotonin pathways: Projects to...

- Spinal cord
- Cerebellum
- Amygdala
- Hippocampus
- Septum
- Striatum
- Cortex
- Thalamus