title: Neuropharmacology of second-generation antipsychotic drugs: a validity of the serotonin-dopamine hypothesis.
abstract: Newer atypical antipsychotic drugs such as risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole that have been modelled on the prototype agent clozapine and developed since the 1990 s are now referred to as second-generation antipsychotic drugs (SGAs). It has been proposed that the interaction between serotonin (5-HT) and dopamine systems may play a critical role in the mechanism of action of atypical antipsychotic drugs because a relatively potent blockade of 5-HT(2A) receptors coupled with the weaker antagonism of the dopamine D(2) receptors is found to be the only pharmacological feature which most atypical antipsychotic drugs have in common. This so-called 'serotonin-dopamine hypothesis' has become a useful model for developing new SGAs to achieve superior antipsychotic efficacy with a lower incidence of extrapyramidal side effects compared to those with first-generation antipsychotic drugs (FGAs) such as haloperidol and chlorpromazine, although it has not been validated yet. In contrast, it has been proposed as the alternative 'fast-off' theory according to which atypical profile of SGAs can be determined by the loose D(2)-binding kinetics alone, while the blockade of the 5-HT(2A) receptor may be neither necessary nor sufficient. This chapter reviews the current issues on the serotonin-dopamine hypothesis together with further advances in research on the role of 5-HT receptor subtypes in the mechanism of action for SGAs. In particular, SGA-induced dopamine release in the prefrontal cortex, possibly through the functional activation of 5-HT(1A) receptors by 5-HT(2A) and D(2) receptor-mediated interaction, has been thought to be the basis for the neurocognitive effects of these drugs on schizophrenia. Thus, the novel antipsychotic aripiprazole may not only be a simply partial D(2) agonist but also a significant 5-HT(1A) agonist and 5-HT(2A) antagonist. These complex properties of antipsychotic aripiprazole may contribute to dopaminergic activation of the local circuitry in the prefrontal cortex of schizophrenic patients.
authors.affiliation: Clinical Research Division, Hizen Psychiatric Center, 160 Yoshinogari, Kanzaki, Saga 842-0192, Japan. rinkenbucyou@hizen2.hosp.go.jp
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kuroki
authors.forename: Naoko
authors.initials: N
authors.lastname: Nagao
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Nakahara
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D049268:Positron-Emission Tomography; D017397:Prefrontal Cortex / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D020033:Protein Isoforms; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin; D004298:Dopamine