serotonin pathway

Why is acetylcholine not classified as a monoamine?

• it has a single amine group

• but is not derived from amino acid precursors

What are the monoamines?

• dopamine

• noradrenaline

• serotonin

• histamine

• melatonin

typical monoamine synapse

• neurotransmitter is packaged into vesicles by VMAT

• released in a quantal, calcium dependent manner

• postsynaptic receptors detect the signal, presynaptic receptors provide feedback

What are the 3 specific uptake systems?

• SERT: serotonin reuptake transporter

• NET: norepinephrine transporter

• DAT: dopamine transporter

uptake 2

• primary astrocyte monoamine transporter

• high capacity

• low affinity

Dopamine and noradrenaline metabolism

• occurs within synaptic environment

• via catechol-O-methyltransferase COMT

• expressed in surrounding cells such as astrocytes and postsynaptic neurons

monoamine oxidase

• located in OMM, abundant inside presynaptic terminals

  • regulates the releasable pool of monoamines

monoamine circuit

• transmitter en passant

• no specialised nerve terminal, ends at final varicosity instead

which transmission systems have varicosities

• noradrenergic and serotonergic

• dopaminergic - more spatially precise, and more typical

which amino acid is serotonin derived from

• tryptophan

What functions does serotonin contribute to?

• sleep

• appetite

• thermoregulation

• pain

• mood, anxiety and stress

• sexual behaviour

• motor tone

biosynthesis of serotonin

• hydroxylation of tryptophan to yield 5-hydroxytryptophan via tryptophan hydroxylase 2

• decarboxylation to yield serotonin via DOPA decarboxylase

uptake of serotonin

• uptake is SERT

  • located on presynaptic terminals

  • cleared via uptake 2 in surrounding glial cells

primary target of SSRIs

SERT

degradation of serotonin in the presynaptic terminal

• monoamine oxidase A and aldehyde dehydrogenase

• produces major serotonin metabolite 5-hydroxyinhdolecatic acid 5-HIAA

Where do the major serotonergic pathways originate?

• raphe nuclei

• cell groups located along the midline of the brainstem

Where do the serotonergic neurons project to?

• to higher brain regions eg cortex, hippocampus, basal ganglia and hypothalamus

• descending projections to the cerebellum, medulla and spinal cord

serotonergic receptors diversity

• 7 major classes

• 14 total subtypes, encoded by distinct gene

• most belong to class A GPCR

  • except 5-HT3 - ligand gated ion channel

class GPCR serotonergic receptors

• 5‑HT1 and 5‑HT2 families

•  5‑HT4, 5‑HT5, 5‑HT6, and 5‑HT7 receptors

How does 5-HT3 allow excitatory signalling?

5-HT3 ligand gated ion channel mediates excitatory signalling by directly allowing cation influx

Why are allosteric modulators useful drug targets?

• under less evolutionary constraint than the orthosteric agonist sites

• provide opportunities for more selective drug action

which serotonergic receptors are gi coupled

• 5-HT1A-F

• 5-HT5A,B

which serotonergic receptors are gs coupled

• 5HT4

• 5HT6

• 5HT7

which serotonergic receptors are gq coupled

• 5-HT2A

• 5-HT2B

• 5-HT2C

5-HT1 receptor roles

• anxiety

• aggression

• mood

• addiction

• pain

5-HT2 roles

• addiction

• anxiety

• appetite

• mood

• GI

• respiration

• pain

5-HT3 roles

• addiction

• anxiety

• vomiting

• pain

• learning and memory

5-HT4 roles

• anxiety

• gi

• learning

• memory

• mood

5-HT5 role

• sleep

• locomotion

5-HT6 role

• anxiety

• cognition

• learning

• memory

• mood

5-HT7 role

• anxiety

• cognition

• learning

• memory

• mood

• respiration

• thermoregulation

• vasoconstriction

• pain

isoprenaline

synthetic derivative of noradrenaline and pharmacological tool

Where is the highest concentration of 5-HT found?

• wall of the intestine - enterochromaffin cells

• in blood - platelets

  • platelets and neurons have a high affinity uptake mechanism

• in the cns

Actions and function of 5-HT

• increased gastrointestinal motility (direct excitation of smooth muscle and indirect action via enteric neurons)

• contraction of other smooth muscle (bronchi, uterus)

• mixture of vascular constriction (direct and via sympathetic innervation) and dilatation (endothelium dependent)

• platelet aggregation

• stimulation of peripheral nociceptive nerve endings

• excitation/inhibition of CNS neurons.