catecholamines

Catecholamine synthesis

Derived from tyrosine (amino acid)

Pathway:

• Tyrosine → (tyrosine hydroxylase) → L-DOPA

• L-DOPA → (aromatic L-amino acid decarboxylase) → Dopamine

• Dopamine → (dopamine β-hydroxylase) → Norepinephrine

• Norepinephrine → (PNMT enzyme) → epinephrine

Catechol ring = benzene with two hydroxyl groups; gives name “catecholamine”

Dopamine: pathways and functions

Origin: ventral tegmental area (VTA), substantia nigra

Pathways:

• Mesolimbic: VTA → nucleus accumbens (reward, euphoria)

• Mesocortical: VTA → prefrontal cortex (executive function, cognition)

• Nigrostriatal: substantia nigra → striatum (motor control, PD)

• Tuberoinfundibular: hypothalamus → pituitary (inhibits prolactin)

Roles: reward, motivation, motor control, endocrine regulation

Dopamine synapse

1. Tyrosine (AA precursor) enters the presynaptic neuron

2. Tyrosine hydroxylase (TH) converts tyrosine → L-DOPA

3. Aromatic L-amino acid decarboxylase converts L-DOPA → Dopamine

4. Dopamine is transported into synaptic vesicles by VMAT2 (vesicular monoamine transporter 2)

5. This protects dopamine from breakdown and stores it for release

6. AP → Ca influx →vesicles fuse with presynaptic membrane

7. Dopamine is released into the synaptic cleft

8. Rebinds postsynaptic receptors (DRs) → generates signal in postsynaptic membrane

9. Reuptake by DAT (dopamine transporter) → recycled back into presynaptic neuron

10. Metabolism by MAO (monoamine oxidase, in mitochondria) → broken down into inactive metabolites

Tonic transmission

• Baseline, low-frequency firing of presynaptic release

• Produces steady, low-level dopamine release

• Important for reward prediction and motivation signal

Phasic transmission

• Occurs in bursts of action potentials

• Produces large, high-concentration dopamine release

• Important for reward prediction and motivation signals

Dopamine fate after release:

• Reuptake into presynaptic terminal

• Repackaged into vesicles or broken down

• Enzyme degradation: monoamine oxidase (MAO)

Dopamine receptors

• All GPCRs 

• D1-D5

D1 family

D1 and D5

• Couple with Gs (excitatory)

• Located on postsynaptic neurons

• Lower affinity for dopamine (may require phasic transmission)

D2 family

D2, D3, D4

• Couple with Gi (inhibitory)

• Located on presynaptic and/or postsynaptic neurons

• Greater affinity for dopamine (may mediate tonic transmission)

Dopamine and schizophrenia

Schizophrenia symptoms

• Positive: hallucinations, delusions

• Negative: flat affect, lack of motivation

• Cognitive: impaired memory, executive function

Pathology: impaired memory, executive function

Treatment:

• Typical (1st gen) antipsychotics: ex. Haloperidol. Strong D2 antagonists, but high risk of extrapyramidal side effects (movement disorders)

• Atypical (2nd gen) antipsychotics: ex. Olanzapine. Block both DA and 5-ht receptors, lower risk of motor side effects

Dopamine and PD

• Progressive neurodegeneration of substantia nigra  →loss of dopamine in striatum  → motor dysfunction 

• Treatments: 

  • Levodopa (L-DOPA): precursor to dopamine; often co-administered with carbidopa (aromatic L-amino acid decarboxylase inhibitor) to prevent peripheral conversion 

  • Dopamine agonists: ex. Pramipexole, ropinirole (D2, D3, D4 agonists). Side effects: nausea, hallucinations

Dopamine and ADHD

• ADHD treatments enhance DA and NE neurotransmission by blocking reuptake 

• Methylphenidate (ritalin): norepinephrine-dopmine reuptake inhibitor (NDRI), high affinity for dopamine transporters 

• Atomoxetine (Strattera): reuptake inhibitor for NE > serotonin > dopamine 

• Non-stimulant ADHD drug

Norepinephrine (noradrenaline) pathways

• Locus coeruleus (pons) 

• Roles: attention, arousal, stress response 

• Receptors (all GPCRs):

  • α1 (Gq): excitatory (smooth muscle contraction, vigilance).

  • α2 (Gi): inhibitory autoreceptor (reduces NE release).

  • β1 (Gs): excitatory (↑ heart rate, alertness).

• Synthesized from dopamine by dopamine β-hydroxylase

Norepinephrine as a modulatory N

• Widespread projections throughout CNS 

• Modulates overall brain state (similar to ACh)

• Roles: arousal, attention, mood regulation, pain modulation 

• Dopamine → converted by dopamine β-hydroxylase → norepinephrine (noradrenaline)

• NE is loaded into synaptic vesicles 

• An AP triggers vesicle fusion → NE released into synaptic cleft 

• NE binds to adrenergic receptors on the postsynaptic cell

• NET (norepinephrine transporter): recycles NE back into presynaptic terminal 

• Degradation: MAO (inside presynaptic neuron and synapse); COMT (extracellular enzyme, degrades NE in cleft)

Norepinephrine and ADHD

• Same drugs as dopamine 

  • Methylphenidate (ritalin): blocks NE and DA reuptake 

  • Atomoxetine (Strattera): blocks NE > 5-HT > DA reuptake

Norepinephrine and antidepressants

• SNRIs boost both serotonin and norepinephrine 

• Ex: Venlafaxine (Effexor) – 1990s, Duloxetine (Cymbalta) – 2000s