Preclinical effects of conventional and atypical antipsychotic drugs: defining the mechanisms of action

Abstract

In clinically effective doses, conventional antipsychotic drugs, such as haloperidol, display around 70% dopamine (DA)-D 2 receptor occupancy in the brain. In contrast, the atypical antipsychotic drug clozapine is effective at only about 45% D 2 receptor occupancy, raising the question that other receptors may be involved in the antipsychotic effect of clozapine and other atypicals. Preclinical, as well as clinical studies, indicate that there may exist several types of profound dysregulation of the mesocorticolimbic DA system in schizophrenia, including a functionally compromised prefrontal DA projection concomitant with a hyperactive or hyperreactive mesolimbic DA projection, as well as a generally reduced variability of cell firing in central DA circuitry. Moreover, experimental studies indicate that atypicals, such as clozapine, better than the typicals may serve to normalize or stabilize such a dysregulated mesocorticolimbic DA system. To this end other effects of the atypicals than their D 2 antagonistic action, such as blockade of 5-HT 2A receptors, α 1- and α 2-receptors, as well as partial agonist activity at 5-HT 1A and D 1 receptors, are highly likely to contribute in different ways. Such effects of atypicals, especially when combined with less prominent D 2 blockage, may also allow for improved reward related, physiological functioning of the DA system, as well as less cognitive impairment. Thus, clinical differences between the effects of atypical and conventional antipsychotics in schizophrenia may be related to qualitatively different actions in the brain rather than simply dose-related. Novel pharmacological means to stabilize dysregulated central DA systems can be envisioned in the future treatment of schizophrenia.