Lecture 12: Neurotransmitters in SZ Flashcards
Name the 4 pathways of the dopamine system
1) Mesolimbic VTA → nucleus accumbens, amygdala & hippocampus
2) Mesocortical VTA → frontal lobe (and the rest of the brain)
3) Mesostriatal SN → striatum (basal ganglia) → motor cortex
4) Frontal lobe inhibitory projection → VTA
What are the Ventral tegmental area (VTA) and Substantia nigra (SN)?
- Brainstem nuclei that are the sources of the dopamine (DA) system
- Excess DA in both systems
What is the The dopamine hypothesis of sz?
There is an over-activation in the dopamine system causes SZ
Explain how the dopamine hypothesis of sz came about.
- It was an Accident
– chlorpromazine was an anesthetic used as a sedative to treat severe agitation in SZ - Found to reduce psychotic symptoms, not just sedate
How did Chlorpromazine reduce psychotic symptoms?
- Chlorpromazine was found to block dopamine (DA) receptors
- Specifically D2 receptors
- D2 receptors found through-out the system; but most common in the meso-striatal system
What are two other pieces of evidence for involvement of DA in SZ are:
1) Stimulant drugs (cocaine, amphetamines) stimulate DA
- High doses of stimulants can mimic psychosis
2) Side effects of antipsychotics look like the motor deficits seen in Parkinson’s disease
- Parkinson’s disease is known to be related to decreased DA in the striatal motor system
- So, antipsychotics may be reducing DA in the motor system
Post-mortem studies show __________of people with SZ
reduced D2 receptors in the basal ganglia
What are the three components (claims) of the DA hypothesis?
- Overactive DA in VTA/SN
- Overactivity in all pathways
- Antipsychotics are effective because they block DA
Give reasons as to why the (simple) DA hypothesis doesn’t work
- Even when antipsychotic drugs improve positive symptoms, negative symptoms and cognitive deficits do not improve
- These deficits related to frontal lobe function
- Can appear before symptom onset, in high-risk groups and in 1st degree relatives
What would hint that D1 receptors are also involved?
- Typical (1st generation) antipsychotics mostly block D2 receptors
- Frontal cortex has mostly D1 receptors.
- DA important for frontal lobe function
What is the revised DA hypothesis?
↓ DA in frontal → ↓ inhibition on VTA
↓ DA in frontal → Negative symptoms
↑ DA in mesostriatal
↑ DA in mesolimbic
↑ DA in mesolimbic → Positive symptoms
According to the revised DA hypothesis, what are the two forms of DA dysfunction in SZ?
1) Decreased DA in frontal lobe
2) Increased DA in VTA/SN
The study on the Relationship of meso-striatal dopamine pathway found a relationship to symptoms of SZ. (Laruelle, 1999). What was this relationship?
Increases in DA are related to:
Increases in DA related to:
- increases in positive symptoms
- decreases in negative symptoms
What were the findings of the Relationship of meso-striatal DA to symptoms (Abi-Dargham, 2000 study)?
Methodolody:
- People with SZ given small doses of amphetamine
- Measured increases in DA (reactivity of the system)
- Gave 6 weeks of antipsychotic treatment (DA receptor blocker)
- Those with greater reactivity _____________
showed greater decreases in positive symptoms after treatment
In conclusion what are the evidence for Evidence for Da dysregulation in frontal cortex?
1) Studies showing increased D1 receptor binding in frontal cortex
- ↑ binding = more receptors = ↓ DA [need more receptors])
2) Decreases in D1 receptors in people abusing drugs that block NMDA receptors (PCP)
- NMDA regulates DA in frontal cortex
- NMDA disregulation decreases performance on frontal tasks
3) No antipsychotic that selectively target D1 receptors, so direct evidence limited
