The Dopamine Hypothesis Flashcards
What is this?
Believes that schizophrenia is caused by abnormalities in DA functioning in the brain
overactivity of DA in the mesolimic system = positive symptoms
underactivty of DA in the mesocortical system = negative and cognitive symptoms
What is going wrong with dopamine?
overactivity of DA in the mesolimic system = positive symptoms
underactivty of DA in the mesocortical system = negative and cognitive symptoms
How are the positive symptoms caused?
By overactivity of dopamine in the mesolimbic system
How are the negative symptoms caused?
By underactivity of dopamine in the mesocortiyal system
Where is there normal activity?
In other systems such as nigrostriatal pathway and the tuberoinfundibulnar pathway
What do DA agonist do?
Increase the amount of dopamine - these produce the symptoms the resemble the positive symptoms of schizophrenia
Examples of DA agonists
Amphetamine
Cocaine
Methylphenidate
L dopa
How can they symptoms that DA create by alleviated?
With antipsychotic drugs - which block DA receptors
What else do DA agonists do?
They can treat Parkinson’s as well - too much L dopa can cause the positive symptoms so need to be careful with dosage
How were DA antagonists discovered?
A French surgeon discovered a drug used for surgical shock also reduced anxiety - a related compound called chlorpromazine was developed which had dramatic effects on schizophrenia
What was the first DA antagonist / first antipsychotic?
Chlorpromazine (CPZ)
What are typical antipsychotics?
Many drugs have been discovered since CPZ which treat schizophrenia - they eliminate or diminish the positive symptoms - but 20-30% of people don’t respond, treatment resistant. They don’t treat the negative symptoms. They all have in common: block D2 receptors
What are the types of DA receptors?
D1 type family - GS coupled - D1 and D5
D2 type family - Gi coupled - D2, D3, D4 (inhibit)
What does affinity mean?
How well the drugs bind to the receptor
What is the relationship between effective doses and D2 receptor binding affinity?
Strong negative correlation between affinity and average clinical dose
the higher the affinity - the less of the drug you need to give
low affinity - increase the dose of the drug
What is IBZM?
A D2 receptor reversible ligand - this means it will bind to D2 but when dopamine is on board, it will compete with DA for binding to that receptor
Is IBZM involved?
Pet study using it
Measured displacement (being moved) after treating with amphetamine in striatum
More displacement of IBZM means that there is DA activty
More DA activity in striatum correlated with positive symptoms
before amphetamine - IBZM binds to the D2 receptor
When given amphetamine (promotes dopamine) - there is a decrease in the signal of IBZM, kicked out
more displacement = more DA = worse positive symptoms
What are the consequences of long term drug treatment?
Antipsychotic drugs cause symptoms resembling those in Parkinson’s disease - slowness in movement, lack of facial expression, general weakness - because they don’t just target one receptor
More serious: affects 1/3 of all patients who take the drug - tardive dyskinesia - inability to stop movements
What is tar dive dyskinesia?
Inability to stop movements - happens when people take antipsychotics for a long period of time
What are atypical antipsychotics?
These are newer drugs which work in treatment resistant patients
What is good about atypical antipsychotics?
They do not have the extra side effects - Parkinson’s side effects - due to the fact they have lower affinity to D2 receptor
they improve both positive and negative symptoms
and they improve the performance in neuropsychological tests - not the case for typical antipsychotics
What was the first atypical antipsychotic drug?
Clozapine - followed by risperidone, olazapine etc
What is clozapine?
The first atypical drug which was discovered - the king of atypical ones
lower affinity for D2 and higher affinity for other DA receptors (D3, D3 and even serotonin). Mystery how it works
It is highly effective, but not very used - treats positive and negative symptoms
It is the only antipsychotic to reduce suicide rates n schizophenics
But still tricky: weight gain, sedation, hypersalivation, hypotension, neutropenia etc - immune system hyper functioning
Is suicide problematic in patents?
Yes, the rate is 13 times higher than the general population