Lecture 12- Dopamine Flashcards
What is a neurotransmitter?
- A substance that is released by a neuron and that affects a specific target in a specific manner
What is the time scale of neurotransmitter and receptor interaction and the resulting change?
- Interaction between neurotransmitter and receptor are transient (m/s to min), however the resultant action can result in long term changes in the target (hrs todays)
What neurotransmitter family does dopamine belong to?
- Dopamine belongs to the monoamine family, which includes 3 catecholamines
- together with norepinephrine and epinephrine, histamine and serotonin (either depolarise or hyperpolarise the postsynaptic cell)
What is dopamine biosynthesis like?
- starts with an amino acid Tyrosine that is readily available in the body and can cross the blood-brain barrier
- Tyrosine is made into L-dopa via Tyrosine hydroxylase
- L-dopa is made into dopamine within the nerve terminal via DOPA decarboxylase or Aromatic L-amino acid decarboxylase
- dopamine can be further utilised to make noradrenaline or adrenaline
How is dopamine stored, released and re-uptaken into the nerve terminal?
- dopamine is packaged into vesicles by vesicular monoamine transporter
- vesicles fuse with the membrane upon calcium release (triggered by AP) -the vesicles release dopamine via exocytosis
- dopamine then interacts with the receptors on the postsynaptic membrane and is then taken back into the presynaptic terminal (via DAT, dopamine transporter) and is recycled can be used in vesicles again, or into an astrocyte where it can be degraded
How can dopamine be degraded after release?
-
What types of dopamine receptors are there?
- 7 transmembrane G-protein coupled receptors
- 5 main dopamine receptors
- 2 families
- within a nerve terminal all 5 may be present
- excitatory D1-like receptor family: D1, D5
- inhibitory D2-like receptor family: D2, D3, D4
What do the D1 and D2 do?
- excitatory is the D1= coupled to excitatory G proteins= activation of adenylyl cyclase
- D2 etc. inactivates adenylyl cyclase via inhibitory G protein
What are presynaptic dopamine receptors for?
- another isoform of two receptors= pre synaptic D2 and D3 they create a crtitical feedback loop telling the cell about the levels of dopamin (autoreceptors) influence the firing of APs and they inhibit calcium and potassium channels within the presynapatic terminal
- if too much dopamine can make the decision to retract the axonal arbor so less contact with the other neuron= so important regulatory function
What is the dopamine receptor expression like across the brain?
- D1 and D2 in caudate nucleus and putamen a lot
- some also in the midbrain 400 000 dopamine neurons in the adult brain
What are the 4 main populations of dopamine receptors separated into?
- 3 systems
1. the ultrashort (within the retina the amacrine cells), amacrine cells and periglomural cells(olfactory)
2. intermediate= regulate prolactin secretion and production, hypothalamus-> pituitary gland
3. Long: ventral midbrain ->striatum, cortex, nigra-striatal pathway and the mesolimbic pathway, reward and motivation
What are the two main dopamine midbrain pathways? (the motor plus reward dopamine aspects that we focus on)
- The nigrostriatal pathway from the substantia nigra pars compacta to the dorsal striatum= motor function, originate in the midbrain, regulation of movement 4 cm long axons
- The mesolimbic / mesocortical pathway from the ventral tegmental area to the limbic system via the nucleus accumbens (ventral striatum) and prefrontal cortex = reward, part of the limbic system, main role is reward and motivation, length up to 7 cm per axon
What is the basal ganglia circuitry like and what is it important for?
• The basal ganglia provides refinement of information that is received by the cortex
– Direct pathway: D1R, initiating motor function (+)
– Indirect pathway: D2R, inhibiting unwanted movement (-)
• Interconnected subcortical nuclei - Striatum (caudate, putamen, nucleus accumbens), - Globus pallidus (GP) - Substantia Nigra (SN) - Subthalamic nuclei (STN) - (Thalamus)
What is the direct pathway?
- start in the frontal lobe of the brain, decide to move and sends excitatory signal to the striatum
- at the same time the substantia nigra pars compacta is dopaminergic projection into the striatum, the dopamine on the D1R is to modulate the signal coming from the motor cortex
- striatum increases its inhibition of the globus pallidus GPi
- globus pallidus internal segment and subtantia nigra pars reticulata inhibit thalamus normally but now this is inhibited and so teh thalamus is more active so the excitatory input into the motor cortex
What is the indirect pathway?
- motor cortex excites the striatum and in this case the Substantia nigra pars compacta is releasing the dopamine onto D2 so inhibitory
- striatum inhibits GPe and that usually inhibits the STN so now less inhibition and the STN is now more active
- STN excites GPi and SNpr increased stimulation which increases inhibition of the thalamus= reduces the thalamic input from the thalamus
What is Parkinson’s disease?
- what happens when issue with the dopamine in the nigrostriatal pathway
- Progressive neurodegereration of DA neurons in the SNpc=nigrostriatal pathway
- 1% of population >65 yrs old
- 10% inherited, 90% idiopathic
- Symptoms only show when: >80% DA loss due to compensation
- second most common neurodegenerative disorder
- trauma can increase the susceptibility
- must have 80% of dopamine neurons lost until you show symptoms, before then all good due to compensatory mechanism (make more connections per neuron to compensate)
What happens in Parkinson’s to the nigrostriatal pathway?
-loss in control of movement, and loss of control of unwanted movement too
How does addiction work?
-cocaine: blocks the dopamine transporter, so the reuptake doesn’t occur and more dopamine in the cleft for longer and increase stimulation of postsynaptic neuron
-amphetamine: promotes, causes the fusion of vesicles and release of dopamine into the synaptic cleft and also inhibits the degradation of dopamine (inhibits MAO)
-withdrawal: largely driven by the D2 receptors,
