How do the atypical antipsychotics work?

Understanding the action of atypical antipsychotics is useful in exploring the pathophysiology of schizophrenia and in synthesizing drugs that improve various domains of psychopathology without unwanted side effects. In animal models, atypical antipsychotic drugs appear to have a preferential action in the limbic dopaminergic system. Regionally specific action has been studied by measuring the amount of Fos protein produced in a particular brain region as a consequence of a drug's effects on the c-fos gene. Evidence suggests that the atypical and typical antipsychotic drug-induced increases in Fos levels in the nucleus accumbens are related to improvements in positive symptoms, whereas Fos increases in the prefrontal cortex, with the atypical antipsychotics only, correlate with negative symptom improvement. The extrapyramidal effects seen with typical antipsychotics are thought to be related to Fos increases in the striatonigral pathway. However, studies of Fos levels in specific brain regions reveal only the site of action, not the mode of action. The finding that atypicality is related to surmountable D2 dopamine receptor blocking provides another venue to define and explore atypical antipsychotic drug action.