Drugs 3 - Catecholamines Flashcards
Noradrenaline cell bodies:
around 10,000 in the medulla and pons. mainly the locus coreleus but also solitary nucleus and lateral tegmental area
Noradrenaline projections
LTA and SN to the spinal cord. locus coreleus to the amygdala, hypothalamus and thalamus cerebellum and cortex
Noradrenaline transmission
almost paracrine from noradrenergic viscosities rather than nerve terminals. occur along the length of a population of neurons effecting all cells they pass.SYNAPSES EN PASSANT
Noradrenaline reuptake
both synaptic degradation (MAO and COMT) and transporters (NET)
Noradrenaline receptors
a1/2 b1/2/3
Noradrenaline a1
cAMP (-)
Noradrenalinea2
autorecptor IP3 (+)
Noradrenaline B1
cAMP (+)
Noradrenaline B2
cAMP (+)
Noradrenaline B3
cAMP(+) periphery only
functions of Noradrenaline receptors
autonomic function (HR, blood pressure and motor) and cognitive function (mood, fear, attention) TPJ = circuit breaker
Drug targets:
–synthesis –reuptake (NET) –a2 –a/1b1/2/3 –MAO –vesicular packaging and release (reserpine)
what is responsible for Noradrenaline vesicular packaging and release
reserpine
what is NA synthesised from
tyrosine
Dopamine is synthesised in
cells in the Substantia nigra and ventral tegmentum
how do dopaminergic cells differ from adrenergic ones
they don’t contain phenylethanolamine N-methyltransferase
dopaminergic pathways
meso limbic
meso cortical
nigrostriatal
tuberohypophoseal
mesocortical pathway
from VTA to frontal lobe -the reward pathway. when we plan an action and its successful we reward ourselves with dopamine
mesolimbic pathway
VTA to the amygdala and nucleus accumbens
tuberophypophoseal
VTA to the pituitary, median eminence, hippocampus, hypothalamus - very short
Nigrostriatal
SN to BG - movement, 75% of dopaminergic cells. 1 SN cell has 500,000 striatal synapses
Dopamine functions
reward, movement, cognitive functions and modulation of other modulators (NA by locus coreleus and ACh) attention
Dopamine modulation of ACh
Acts in the prabrachium presnaptically to increase ACh release (cog enhancement - attention and arousal)
Dopamine receptors
Genreally post synaptic. D1 and D2 change levels of cAMP which acts with PKA to convert darpp to phospho darpp. phosphodarpp inhibits protein phophotase 1. PP1 strips other proteins and phosphotase enzymes to decrease activity.
This process is amplified so a little receptor inout has a big effect.
d1 and 2 generally found on different cells
D1
excitatory. D1, D5. increase cAMP
D2
inhibitiory, decrease cAMP,
d2,3,4
Seratonin synthesised
from tryptophan (diet) in the raphe nuclei (medula and pons)
serotonin projections
project back to spine medulla and cerebellum. Mainly forward to cortices and to hippocmapus, striatum, thalamus, hypothalamus, amygdala through same bundle as NA.
serotonin metabolism
broken down by MAO to aldehydes then to v. soluble easily removable substrate by aldehyde dehydroxylase. No COMT involvement because its not a catecholamine
serotonin receptors
all GPCRS except 5HTR-3. 1-7. Huge diversity is very good for drug targets.
5HTR-1
presynaptic autoinhibitor
5HTR-2
pre and post synaptic in cortex
5HTR-3
ligand gated in cortex
5HTR-4
limbic system and basal ganglia. also increases presynaptically increases ACh release so cog enhancement
5HTR-5
No one knows!
5HTR-6
hippocampus, cortex, limbic system
5HTR-7
hippocampus, cortex, amygdala and thalamus - also GABA modulation
Dopamine metabolism
MAO –> aldehyde
Aldehyde dehydroxylase + COMT –> HVA (verysoluble and easy to remove)
serotonin dopamine and ach receptors also found
on the area postremma for vomiting
