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Dopamine Theory of Schizophrenia

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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

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