"Hit-and-run" actions at dopamine receptors, part 1: Mechanism of action of atypical antipsychotics

Abstract

Either 5-HT2A antagonism or fast dissociation from D2 receptors may define an atypical antipsychotic. To have little or no motor symptoms from an antipsychotic, it is clear that D2 receptor binding in the striatum must be less than that caused by conventional antipsychotics. Pure 5-HT2A antagonism by itself does not result in robust antipsychotic actions. However, 5-HT2A antagonism can reduce D2 antagonism and thereby reduce motor symptoms without reversing antipsychotic actions. If, however, this 5-HT2A antagonism is overwhelmed by too much D2 antagonism, it cannot result in such atypical antipsychotic actions. Another route to reducing D2 receptor binding appears to be to shorten binding time, also known as rapidly dissociating from the D2 receptor. Many of the agents with atypical antipsychotic clinical properties hit the D2 receptor hard enough to cause antipsychotic effects and then run before they cause extrapyramidal side effects.