Transcript Dopamine Theory of Schizophrenia

Dopamine Theory of Schizophrenia
Schizophrenia is caused by too much dopamine
(DA)
 DA antagonists are effective neuroleptics
(antischizoprenic drugs)
– Chlorpromazine
– Reserpine
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Evidence
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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)
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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
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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…
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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
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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
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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
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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
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