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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 Evidence Neuroleptics take 2-3 weeks to work Parkinson’s disease (PD) side effects PD = reduced DA in striatum

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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

  3. 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…

  4. 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

  5. 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

  6. 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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