title: Haloperidol, spiperone, pimozide and aripiprazole reduce intracellular dopamine content in PC12 cells and rat mesencephalic cultures: Implication of inhibition of vesicular transport.
abstract: Accumulating evidence suggests that antipsychotics affect dopamine release from dopaminergic neurons, but the precise mechanisms are not fully understood. Besides, there are few studies on the effects of antipsychotics on intracellular dopamine content. In this study, the effects of 8 antipsychotics on dopamine release and intracellular dopamine content in PC12 cells were investigated. Pretreatment with haloperidol, spiperone, pimozide, aripiprazole and risperidone markedly inhibited high potassium-evoked dopamine release. By contrast, pretreatment with chlorpromazine slightly increased high potassium-evoked dopamine release, while pretreatment with sulpiride and olanzapine had no effect. Haloperidol, spiperone, pimozide, chlorpromazine, aripiprazole and olanzapine evoked dopamine release, while sulpiride and risperidone had no effect. In addition, haloperidol, spiperone, pimozide, aripiprazole and risperidone reduced intracellular dopamine content in a concentration-dependent manner. These results suggest that the reduction in high potassium-evoked dopamine release by pretreatment with antipsychotics results from the reduction in vesicular dopamine content. Treatment with the 8 antipsychotics did not affect the expression of total or phosphorylated tyrosine hydroxylase. Instead, haloperidol, spiperone, pimozide and aripiprazole as well as reserpine transiently increased extracellular levels of dopamine metabolites. In addition, haloperidol, spiperone, pimozide, aripiprazole and risperidone reduced vesicular [3H]dopamine transport. These results suggest that the inhibition of vesicular dopamine transport by haloperidol, spiperone, pimozide and aripiprazole results in a reduction in vesicular dopamine content.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, and Department of Neurology and Clinical Research Center, Utano National Hospital, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Matsuo
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Izumi
authors.forename: Seiko
authors.initials: S
authors.lastname: Wakita
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kume
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takada-Takatori
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sawada
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001205:Ascorbic Acid / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D010293:Pargyline / Q000494:pharmacology; D010868:Pimozide / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D013134:Spiperone / Q000494:pharmacology; D022161:Transport Vesicles / Q000187:drug effects* / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D015102:3,4-Dihydroxyphenylacetic Acid; D010868:Pimozide; D013134:Spiperone; D000068180:Aripiprazole; D010293:Pargyline; D014446:Tyrosine 3-Monooxygenase; D006220:Haloperidol; D001205:Ascorbic Acid; D004298:Dopamine; D006719:Homovanillic Acid