[Pharmacology of second-generation antipsychotics: a validity of the serotonin-dopamine hypothesis]

New atypical antipsychotic drugs such as risperidone, olanzapine and quetiapine, that have been modeled on the prototype agent clozapine and developed since the 1990's, are now referred to as second-generation antipsychotics (SGA). It has been proposed by Meltzer (1989) that the interaction between serotonin (5-HT) and dopamine (DA) systems may play a critical role in the mechanism of action for atypical antipsychotics because potent 5-HT2A receptor antagonism together with relatively weak D2 receptor antagonism could differentiate most atypical antipsychotics from typical antipsychotics. This serotonin-dopamine hypothesis has become a useful model for studying and developing new drugs to achieve a significant antipsychotic effect with lower incidence of extrapyramidal side effects compared to first-generation antipsychotics. In contrast, Kapur and Seeman (2001) argued the alternative "fast-off" theory that clozapine occupies D2 receptors to a similar extent as typical antipsychotics do and then rapidly dissociates from D2 receptors. This paper reviews the current issues on the serotonin-dopamine hypothesis and recent research on the role of 5-HT receptor subtypes in the mechanism of action for SGA. In particular, SGA-induced DA release in the prefrontal cortex, possibly through the functional activation of 5-HT1A receptors by 5-HT2A and D2 receptor-mediated interaction, may be the basis for the cognitive effects of SGA.