Monoamine Neurotransmitters

Question 1

Monoamine synapse – common features:

Answer 1

1. Monoamine are concentrated in vesicles by VMAT – requires energy
2. Auto receptors located presynaptically – used to inhibit further NT release
3. Presynaptic reuptake transporters (DAT, NET and SERT)
4. Specificity between types of monoamine synapse include location of synapse and expressed receptors

Question 2

Serotonin (5-HT)

Answer 2

Tryptophan is the precursor of serotonin

Tryptophan is actively transported across the BBB and is enzymatically converted to 5-HT in serotonergic neurons

Metabolism of 5-HT:

Enzymatic breakdown by monoamine oxidase (MAO) then conversion to 5-HIAA which is actively transported out of the CNS for excretion in the urine

Question 3

NA and DA

Answer 3

*Tyrosine is the precursor of NA and DA

*MAO and COMT used in the metabolism of NA and DA

DA synthesis:

*Tyrosine converted to L-DOPA which is then converted to DA via DOPA decarboxylase

*NA synthesised from DA via Dopamine B-hydroxylase

Question 4

NA in the CNS

Answer 4

Binding of NA to reuptake transporters = 3 Na+ in and 2 K+ out and 1 Cl- in

Noradrenergic pathways contain cell bodies in pons and medulla – extensive projections into the neural cortex

All adrenergic receptors present in CNS – are all GPCR

Alpha 1 in CNS = motor control, fear and cognition

Alpha 2 in CNS = BP control, sedation and analgesia

Beta 1 in CNS = in higher brain (hippocampus)

Beta 2 in CNS = in cerebellum

Question 5

5-HT in the CNS

Answer 5

5-HT is placed into vesicles by VMAT2 and is cleared by SERT in the presynaptic membrane

7 families of 5-HT receptors and 14 subtypes – sum of receptor activation = physiological activity

Serotonergic pathway in CNS resembles the pattern of noradrenergic neurons

Cell bodies groups in pons and upper medulla

5-HT loss is correlated with: mood, aggression, appetite and migraines

Question 6

DA pathways in the brain

Answer 6

1. Mesocorticol – from DA neurons in ventral tegmental area (middle) to cortex
   - Mediates cognitive
2. Mesolimbic – from VTA to nucleus accumbens
   - Reward centre
3. Nigrostriatal – from substantia nigra to the striatum
   - Controls motor function
4. Tuberoinfundibular – from hypothalamic nuclei to the pituitary
   - Inhibits prolactin synthesis via DA release
5. DA reuptake transporters (DAT) – same MOA as NA reuptake transporters

2 types of receptor structures:

D1:
Activation of Gs = stimulation = increase cAMP and activate protein kinase A
- postsynaptic

D2 – have shorter terminal tail and longer intracellular loop

Activation of Gi = inhibition = decrease cAMP and inhibit Ca channels

Pre and post synaptic

Emesis is a common AE of dopamine agonists – hence DA antagonist a have antiemetic activity

Decrease in DA is associated with Parkinson’s, Depression and ADHD

Question 7

Amphetamine

Answer 7

Results in euphoria due to DA effects

Anxiety due to NA effects

MOA: competitively inhibits DAT and once in neuron it interferes with VMAT to impede with filling of synaptic vesicles = vesicles are depleted and cytoplasmic DA increases —> can lead to DAT reversing direction and non-vesicular release of DA = increases extracellular DA

 

Question 8

Methamphetamine

Answer 8

Made from amphetamine but differs in that much greater concentrations cross the BBB, making it a more powerful stimulant = longer effect

Question 9

Cocaine:

Answer 9

Cocaine crosses BBB and blocks reuptake transporters (of DA, NA and 5-HT)

Increased NA levels = vasoconstriction = heart arrhythmias, stroke and seizures

Increased DA levels = dependence