title: Long-Term Citalopram Treatment Alters the Stress Responses of the Cortical Dopamine and Noradrenaline Systems: the Role of Cortical 5-HT1A Receptors.
abstract: Cortical dopamine and noradrenaline are involved in the stress response. Citalopram, a selective serotonin reuptake inhibitor, has direct and indirect effects on the serotonergic system. Furthermore, long-term treatment with citalopram affects the dopamine and noradrenaline systems, which could contribute to the therapeutic action of antidepressants.
  
  
  
  The effects of long-term treatment with citalopram on the responses of the dopamine and noradrenaline systems in the rat prefrontal cortex to acute handling stress were evaluated using in vivo microdialysis.
  
  
  
  Acute handling stress increased dopamine and noradrenaline levels in the prefrontal cortex. The dopamine and noradrenaline responses were suppressed by local infusion of a 5-HT1A receptor agonist, 7-(Dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol;hydrobromide, into the prefrontal cortex. The dopamine response was abolished by long-term treatment with citalopram, and the abolished dopamine response was reversed by local infusion of a 5-HT1A receptor antagonist, (Z)-but-2-enedioic acid;N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-ylcyclohexanecarboxamide into the prefrontal cortex. On the other hand, long-term treatment with citalopram reduced the basal noradrenaline levels (approximately 40% of the controls), but not the basal dopamine levels. The noradrenaline response was maintained despite the low basal noradrenaline levels. Signaling from the 5-HT1A receptors and α2-adrenoceptors was not involved in the decrease in the basal noradrenaline levels but partially affected the noradrenaline response.
  
  
  
  Chronic citalopram treatment differentially suppresses the dopamine and noradrenaline systems in the prefrontal cortex, and the dopamine stress response was preferentially controlled by upregulating 5-HT1A receptor signaling. Our findings provide insight into how antidepressants modulate the dopamine and noradrenaline systems to overcome acute stress.
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan (Ms Kaneko and Drs Kawahara, Kishikawa, Hanada, and Nishi); Department of Psychiatry, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan (Dr Yamada); Biostatistics Center, Kurume University, Kurume, Fukuoka, Japan (Dr Kakuma); Department of Dental Anesthesiology, School of Dentistry, Tsurumi University, Tsurumi-ku, Yokohama, Kanagawa, Japan (Dr Kawahara).
authors.forename: Fumi
authors.initials: F
authors.lastname: Kaneko
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan (Ms Kaneko and Drs Kawahara, Kishikawa, Hanada, and Nishi); Department of Psychiatry, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan (Dr Yamada); Biostatistics Center, Kurume University, Kurume, Fukuoka, Japan (Dr Kakuma); Department of Dental Anesthesiology, School of Dentistry, Tsurumi University, Tsurumi-ku, Yokohama, Kanagawa, Japan (Dr Kawahara). yukikawa@med.kurume-u.ac.jp.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Kawahara
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan (Ms Kaneko and Drs Kawahara, Kishikawa, Hanada, and Nishi); Department of Psychiatry, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan (Dr Yamada); Biostatistics Center, Kurume University, Kurume, Fukuoka, Japan (Dr Kakuma); Department of Dental Anesthesiology, School of Dentistry, Tsurumi University, Tsurumi-ku, Yokohama, Kanagawa, Japan (Dr Kawahara).
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kishikawa
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan (Ms Kaneko and Drs Kawahara, Kishikawa, Hanada, and Nishi); Department of Psychiatry, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan (Dr Yamada); Biostatistics Center, Kurume University, Kurume, Fukuoka, Japan (Dr Kakuma); Department of Dental Anesthesiology, School of Dentistry, Tsurumi University, Tsurumi-ku, Yokohama, Kanagawa, Japan (Dr Kawahara).
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Hanada
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan (Ms Kaneko and Drs Kawahara, Kishikawa, Hanada, and Nishi); Department of Psychiatry, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan (Dr Yamada); Biostatistics Center, Kurume University, Kurume, Fukuoka, Japan (Dr Kakuma); Department of Dental Anesthesiology, School of Dentistry, Tsurumi University, Tsurumi-ku, Yokohama, Kanagawa, Japan (Dr Kawahara).
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan (Ms Kaneko and Drs Kawahara, Kishikawa, Hanada, and Nishi); Department of Psychiatry, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan (Dr Yamada); Biostatistics Center, Kurume University, Kurume, Fukuoka, Japan (Dr Kakuma); Department of Dental Anesthesiology, School of Dentistry, Tsurumi University, Tsurumi-ku, Yokohama, Kanagawa, Japan (Dr Kawahara).
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Kakuma
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan (Ms Kaneko and Drs Kawahara, Kishikawa, Hanada, and Nishi); Department of Psychiatry, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan (Dr Yamada); Biostatistics Center, Kurume University, Kurume, Fukuoka, Japan (Dr Kakuma); Department of Dental Anesthesiology, School of Dentistry, Tsurumi University, Tsurumi-ku, Yokohama, Kanagawa, Japan (Dr Kawahara).
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawahara
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan (Ms Kaneko and Drs Kawahara, Kishikawa, Hanada, and Nishi); Department of Psychiatry, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan (Dr Yamada); Biostatistics Center, Kurume University, Kurume, Fukuoka, Japan (Dr Kakuma); Department of Dental Anesthesiology, School of Dentistry, Tsurumi University, Tsurumi-ku, Yokohama, Kanagawa, Japan (Dr Kawahara).
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
mesh_terms: D000818:Animals; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D015283:Citalopram; D044282:Receptor, Serotonin, 5-HT1A; D004298:Dopamine; D009638:Norepinephrine
keywords: 5-HT1A receptor; catecholamine; citalopram; microdialysis; prefrontal cortex