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 anima
l models, atypical antipsychotic drugs appear to have a preferential action
in the limbic dopaminergic system. Regionally specific action has been stu
died 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 sug
gests that the atypical and typical antipsychotic drug-induced increases in
Fos levels in the nucleus accumbens are related to improvements in positiv
e symptoms, whereas Fos increases in the prefrontal cortex, with the atypic
al antipsychotics only, correlate with negative symptom improvement. The ex
trapyramidal effects seen with typical antipsychotics are thought to be rel
ated to Fos increases in the striatonigral pathway. However, studies of Fos
levels in specific brain regions reveal only the site of action, not the m
ode of action. The finding that atypicality is related to surmountable D-2
dopamine receptor blocking provides another venue to define and explore aty
pical antipsychotic drug action.