1. Dopamine Theory of Schizophrenia
Schizophrenia is caused by too much dopamine (DA)
DA antagonists are effective neuroleptics (antischizoprenic drugs)
Chlorpromazine
Reserpine
Evidence
Neuroleptics take 2-3 weeks to work
Parkinson’s disease (PD) side effects
PD = reduced DA in striatum
Schizophrenia = too much DA
Cocaine/amphetamine increase DA levels and induce schizophrenia type symptoms (stereotype behavior)

2. Problems with DA Theory
Different drug mechanisms
Reserpine depletes DA
By breaking down synaptic vesicles
Chlorpromazine does not deplete DA
DA levels are normal
Increased levels of DA metabolites
Is a receptor blocker

5. Revised DA Theory
Increased DA receptor activation, rather than DA levels per se
Explains both clorpromazine and reserpine
Other drugs reveal a positive relationship between
affinity to bind to DA receptors
and antischizophrenic potency
However…

6. Revised DA Theory - D2 receptors
Some drugs such as haloperidol
Are potent neuroleptics
But initially showed low affinity for DA receptors
However…
There are 5 subtypes of DA receptors
Haloperidol is a D2 receptor antagonist
The relationship between receptor affinity and neuroleptic potency is better for D2 receptors

8. D2 receptor theory Is not a perfect explanation
30% of patients do not respond to D2 receptor antagonists
Atypical neuroleptics such as clozapine bind D1, D4 and several 5-HT receptors (low affinity for D2)
Neuroanatomical findings
Widespread brain damage
…not evenly distributed (prefrontal, cingulate and hippocampal areas are smaller than normal)
Evidence of a developmental abnormality

9. D2 receptor theory Qualifications offered:
Why do neuroleptics take 2-3 weeks to work
Initial increase in DA release
Decreased release after 2-3 weeks
A retrograde signal to increase DA release is inhibited over time
i.e., the dopamine-cell depolarization block
The schizophrenias (multiple subtypes)
Positive symptoms and negative symptoms
D2 antagonists more effective in reducing positive symptoms
Improved diagnosis is needed to generate a better theory and more effective treatments