Schizophrenia 2 Flashcards
Describe how PFC DA effects working memory?
MONKEYS: Using a delayed response task, if you lesion DA with 6OHDA its the same reduction as removing the PFC itself, this is similar to schiz patients.
SCHIZ PATIENTS: using oculomotor delayed response, people with schiz are worst at this, similar to the DA depleted monkeys
Describe the inverted U shape of Dopamine and working memory. Which receptor does it act on?
D1 receptors
Too low: impairments
Too high: impairments
Only D1, not D2, tested using radial maze
- if you block D1 receptors (SCH 233) animals suck at radial maze, but not if you block D2 (sulpiride). Measured by times going into an unrewarded arm
How is D1 receptor stimulation dependent on baseline levels of performance on working memory task?
If you increase D1 you get worse working memory when you have good baseline performance (only a 30 minute delay) but after a 12 hour delay you’ll have shitty performance and a D1 agonist would actually improve performance on working memory task
How does PFC DA D1 activity affect attention? What’s a commonly used attention task?
If you have good attention (taken from rats who were naturally good or bad): extra D1 stimulation impairs
If you have bad attention: extra D1 stimulation improves
5 choice serial reaction time task: light comes on and touch nose to it
How does PFC DA affect cognitive flexibility?
Block D1 PFC , disrupt cognitive flexibility
Makes you bad at “set-shifting” or changing rules of something
RATS: usually can change behavior (on turning left task then turning to visual cue)
2 kinds of errors:
perseverative - doing the old behavior
non-perseverative - trying to figure out new rules, not really making sense.
If you BLOCK D1 receptor activity when learning 1st rule, no impairment, but if you block D1 during the shift, you see both types of errors made.
HUMANS
Same for Wisconsin card sorting errors in humans with schizophrenia for set shifting
How do D2 and D4 receptors work in PFC?
Not always U shaped
Blocking D1 and D2 impairs cognitive flexibility (set shifting) .
Overstimulation of D1 and D2 receptors doesnt affect cognitivie flexibility (but this impaired working memory and attention!)
Block D4: improved set shifting
Excessive D4: worse set shifting
- S shaped function
How does DA metabolism and polymorphisms work for schizophrenia?
Less PFC activity contributes to negative schiz symptoms
- via clearance from PFC
- cleared through COMT transporter (and NE)
- polymorphisms
1. MET/MET: slow acting metabolism, more PFC DA, optimal DA levels
2. VAL/VAL: fast acting metabolism, less PFC DA, poorer cognition/flexibility
Different baseline levels!
How does having VAL/VAL affect cognitive flexibility?
Always have lower performance thatn VAL/MET or MET/MET, but doesn’t mean you alsways have schizophrenia. may exacerbate cognitive dysfunciton in schizophrenia tho!
What is the glutamate hypothesis of schizophrenia? Describe.
Schizophrenia is caused by decreased glutamate transmission.
- If you give people a drug that reduces glut (non competitive NMDA antagonists like PCP or ketamine) it induces cognitive deficits, psychotic symptoms in healthy people and makes schizophrenic patients even worse. Perfect model of schizophrenia when given.
- People with schizophrenia have degenerated glutamatergic PFC and hippocampal neurons (leading to disfunction and less trnaamsission)
What do studies that use acute or repeated PCP treatment show?
- Decreases levels of DA in PFC
- Cognitive deficits on PFC dependent tasks
(multiple components of the disorder)
- Decrease in DA activity in PFC
- Imbalance of DA transmission in PFC (too little) and striatum (too much)
Describe the anatomy of the PFC, NAC and VTA.
VTA sends mesocortical DA to PFC and mesolimbic DA to NAC
PFC sends GLUT signals back to VTA, 1 to teh mesocortical DA pathway and 1 a GABA interneuron leading to mesolimbic DA pathway.
What does reduced Glutamate transmission in PFC do to dopamine?
Reduce firing of mesocortical DA (leading to less DA in PFC) but DISINHIBIT mesolimbic DA (leading to DA increase in striatum)
- negative vs positive symptoms of schizophrenia.
- reduce in one and increase in another.
Connecting all the dots!
What happens when you give a LOW DOSE NMDA antagonist (PCP or Ketamine) to gaba interneurons and pyramidal cells? What is the differences in baseline firing?
GABA internuron: baseline firing high
PFC pyramidal cell: baseline firing low.
NMDA antagonist causes GABA interneuron to decrease firing, and increase firing of PFC pyramidal cell (through disinhibition)
Produces noisy cortex, hyperactivity in cortex due to GABA
Dose must be LOW because that’s what induces the schizophrenic like symptoms, higher doses cause a reduction in all firing.
Describe the anatomy of GABA internurons and pyramidal PFC cells CLOSE UP. Also what happens when you give low dose PCP and ketamine
NMDA receptors on pyramidal cells and GABA internruons (fast firing). GABA interneurons synapse at haxon hillock to keep pyramidal cells at bay with inhibitory influence.
Low dose PCP has a greater effect on GABA cells, causing disinhibitory increase on PFC pyramidal cells and just degrades the signal on NMDA receptor pyramidal cells from other areas.
DISRUPTS INHIBITORY/EXCITATORY BALANCE.
- reduced signal combined with noise
- mechanism related to ketamine’s antidepressant effects, resetting the system?
What are the animal models of schizophrenia?
- PCP/Ketamine
- High dose amphetamine,
- gets paranoid schizophenia (stereotypes behaviors and compulsive shit) but you don’t always see negative/cognitive symtpoms. - Neurodevelopmental
- early insults (poor diet, virus, stressors, hypoxia) to pregnant rodent or young pups - Neonatal ventral hippocampal lesion: 7 day old puppo produces abnormalities in adulthood (from 1 extitotoxis lesion)
- negative symptoms appear early and positive ones around adolescence/adulthood, initiated by stress
