The Dopamine Hypothesis

Question 1

What is this?

Answer 1

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

Question 2

What is going wrong with dopamine?

Answer 2

overactivity of DA in the mesolimic system = positive symptoms
underactivty of DA in the mesocortical system = negative and cognitive symptoms

Question 3

How are the positive symptoms caused?

Answer 3

By overactivity of dopamine in the mesolimbic system

Question 4

How are the negative symptoms caused?

Answer 4

By underactivity of dopamine in the mesocortiyal system

Question 5

Where is there normal activity?

Answer 5

In other systems such as nigrostriatal pathway and the tuberoinfundibulnar pathway

Question 6

What do DA agonist do?

Answer 6

Increase the amount of dopamine - these produce the symptoms the resemble the positive symptoms of schizophrenia

Question 7

Examples of DA agonists

Answer 7

Amphetamine
Cocaine
Methylphenidate
L dopa

Question 8

How can they symptoms that DA create by alleviated?

Answer 8

With antipsychotic drugs - which block DA receptors

Question 9

What else do DA agonists do?

Answer 9

They can treat Parkinson’s as well - too much L dopa can cause the positive symptoms so need to be careful with dosage

Question 10

How were DA antagonists discovered?

Answer 10

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

Question 11

What was the first DA antagonist / first antipsychotic?

Answer 11

Chlorpromazine (CPZ)

Question 12

What are typical antipsychotics?

Answer 12

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

Question 13

What are the types of DA receptors?

Answer 13

D1 type family - GS coupled - D1 and D5

D2 type family - Gi coupled - D2, D3, D4 (inhibit)

Question 14

What does affinity mean?

Answer 14

How well the drugs bind to the receptor

Question 15

What is the relationship between effective doses and D2 receptor binding affinity?

Answer 15

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

Question 16

What is IBZM?

Answer 16

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

Question 17

Is IBZM involved?

Answer 17

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

Question 18

What are the consequences of long term drug treatment?

Answer 18

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

Question 19

What is tar dive dyskinesia?

Answer 19

Inability to stop movements - happens when people take antipsychotics for a long period of time

Question 20

What are atypical antipsychotics?

Answer 20

These are newer drugs which work in treatment resistant patients

Question 21

What is good about atypical antipsychotics?

Answer 21

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

Question 22

What was the first atypical antipsychotic drug?

Answer 22

Clozapine - followed by risperidone, olazapine etc

Question 23

What is clozapine?

Answer 23

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

Question 24

Is suicide problematic in patents?

Answer 24

Yes, the rate is 13 times higher than the general population

Question 25

What are the problems with the dopamine hypothesis?

Answer 25

It only explains a part of schizophrenia - positive
Atypical antipsychotic drugs. Clozapine are better, but have less specific effect on dopamine, so maybe it isn’t dopamine which is involved
Negative symptoms caused by underactivity in mesocortiyal dopamine - how can we explain that is is under activity and over activity