title: Dopamine dynamics during emotional cognitive processing: Implications of the specific actions of clozapine compared with haloperidol.
abstract: Clozapine has improved efficacy relative to typical antipsychotics in schizophrenia treatment, particularly regarding emotional symptoms. However, the mechanisms underlying its therapeutic benefits remain unclear. Using a methamphetamine-sensitised rat model, we measured changes in dopamine levels in the amygdalae in response to a fear-conditioned cue, serving as a biochemical marker of emotional cognitive processing disruption in psychosis, for analysing the biochemical mechanisms associated with the clinical benefits of clozapine. We also compared how clozapine and haloperidol affected basal dopamine levels and phasic dopamine release in response to the fear-conditioned cue. Extracellular dopamine was collected from the amygdalae of freely moving rats via microdialysis and was analysed by high-performance liquid chromatography. Clozapine or haloperidol was injected during microdialysis, followed by exposure to the fear-conditioned cue. We analysed the ratio of change in dopamine levels from baseline. Haloperidol treatment increased the baseline dopamine levels in both non-sensitised and sensitised rats. Conversely, clozapine only increased the basal dopamine levels in the non-sensitised rats, but not in the sensitised rats. Although both antipsychotics attenuated phasic dopamine release in both the non-sensitised and sensitised rats, the attenuation extent was greater for clozapine than for haloperidol under both dopaminergic conditions. Our findings indicate that stabilized dopamine release in the amygdalae is a common therapeutic mechanism of antipsychotic action during emotional processing. However, the specific dopaminergic state-dependent action of clozapine on both basal dopamine levels and stress-induced dopamine release may be the underlying mechanism for its superior clinical effect on emotional cognitive processing in patients with schizophrenia.
authors.affiliation: Department of Psychiatry, Tokyo Women's Medical University, Kawada-cho 8-1, Shinjuku-ku, Tokyo 162-8666, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kawano
authors.affiliation: Department of Psychiatry, Tokyo Women's Medical University, Kawada-cho 8-1, Shinjuku-ku, Tokyo 162-8666, Japan. Electronic address: oshibuchi.hidehiro@twmu.ac.jp.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Oshibuchi
authors.affiliation: Department of Psychiatry, Tokyo Women's Medical University, Kawada-cho 8-1, Shinjuku-ku, Tokyo 162-8666, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kawano
authors.affiliation: Department of Psychiatry, Tokyo Women's Medical University, Kawada-cho 8-1, Shinjuku-ku, Tokyo 162-8666, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Muraoka
authors.affiliation: Department of Psychiatry, Tokyo Women's Medical University, Kawada-cho 8-1, Shinjuku-ku, Tokyo 162-8666, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsutsumi
authors.affiliation: Department of Psychiatry, Tokyo Women's Medical University, Kawada-cho 8-1, Shinjuku-ku, Tokyo 162-8666, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Psychiatry, Tokyo Women's Medical University, Kawada-cho 8-1, Shinjuku-ku, Tokyo 162-8666, Japan. Electronic address: inada.ken@twmu.ac.jp.
authors.forename: Ken
authors.initials: K
authors.lastname: Inada
authors.affiliation: Department of Psychiatry, Tokyo Women's Medical University, Kawada-cho 8-1, Shinjuku-ku, Tokyo 162-8666, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ishigooka
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D003213:Conditioning, Psychological / Q000187:drug effects; D003463:Cues; D004298:Dopamine / Q000378:metabolism*; D004644:Emotions / Q000187:drug effects* / Q000502:physiology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005239:Fear / Q000187:drug effects / Q000523:psychology; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D014150:Antipsychotic Agents; D008694:Methamphetamine; D003024:Clozapine; D006220:Haloperidol; D004298:Dopamine
keywords: Clozapine; Dopamine; Fear conditioning; Haloperidol; Methamphetamine; Microdialysis