Atypical neuroleptics: role of multiple receptors, endogenous dopamine, and receptor linkage

A variety of biological factors may account for the atypical lack of parkinsonism that is a characteristic of the administration of the many 'atypical' neuroleptics. Although dopamine D2 receptor blockade continues to be a dominant feature of successful neuroleptics, the concomitant blockade of muscarinic or serotonergic S2 receptors helps to prevent neuroleptic-induced parkinsonism for some atypical neuroleptics (clozapine, thioridazine, risperidone). The D2-selective benzamides, however, do not block other known receptors (with the possible exception of sigma sites). Therefore, the atypical nature of the benzamides may be based on their sensitivity to the level of endogenous dopamine released in the different regions of the brain. Finally, atypical neuroleptic action may possibly stem from direct linkage between different receptors coupled through components of the G protein system.