Dopaminergic neurotransmission Flashcards
DA synthesis
L-tyrosine -> L-DOPA -> Dopamine.
Tyrosine -> L-DOPA catalysed by tyrosine hydroxylase (with tetrohydrobiopterin as an essential co-factor)
L-DOPA -> dopamine catalysed by DOPA decarboxylase
DA transporters
DAT is reuptake for dopamine.
VMAT-2 packs DA into vesicles (or VMAT-1 in adrenal chromaffin cells)
what does 6-hydroxydopamine do
It is a selective neurotoxin. It is a substrate for DAT, which allows it to enter neurons. It autoxidises to become a ROS, which causes mitochondrial dysfunction and consequent apoptosis. The oxidative stress of the mitochondria releases cytochrome c -> cell death
DA metabolism
MAO found on the inner mitochondrial membrane of cells. COMT is cytosolic and membrane bound.
MAO metabolises DA to form DOPAC, which is then metabolised by COMT to form HVA.
COMT metabolises dopamine to produce 3-MT, which is then metabolised by MAO to also produce HVA.
Autoreceptors
D2/3 can be found in the presynaptic terminals and act as negative feedback loops.
NA and adrenaline formation
NA neurones contain all of the above, as well as dopamine beta-hydroxylate which converts DA to NA.
Adrenergic neurones further contain PNMT which converts the NA to adrenaline
DA receptors subtypes, location, and Ga-coupled
D1 - post synaptic
D2 - pre and post synaptic (lots in striatum)
D3 - pre and post synaptic
D4 - pre and post synaptic
D5 - post synaptic
D1/5 classified as D1-like - increase cAMP (Gas)
D2/3/4 classified as D2-like - decrease cAMP (Gai)
Dopamine receptor signalling
All GPCRs
D1/5 (Gas) increase cAMP and PIP2 hydrolysis, thus activating PKC and producing IP3. Ca mobilised.
D2/3/4 (Gai) decrease cAMP, open K+ channels, and decrease opening of Ca channels.
DA imaging
Exposure to formaldehyde produces the fluorescent isoquinoline, which can be seen under microscope.
antibodies against tyrosine hydroxylase used to visualise the dopaminergic neurones in the 1980s
Nigrostriatal pathway
Substantia nigra innervates the basal ganglia to control planning and execution of voluntary movements.
degenerated in Parkinson’s.
Mesolimbic pathway
The midbrain ventral tegmental area (VTA) innervates the nucleus accumbens to control emotion, pleasure, reward, and goal-directed behaviour.
Overactivity leads to psychosis/hallucinations. Positive symptoms of schizophrenia
Mesocortical pathway
The VTA innervates the frontal cortex and controls emotion and motivation.
mesocortiyal under activity associated with negative symptoms of schizophrenia
