title: Serotonin-2C antagonism augments the effect of citalopram on serotonin and dopamine levels in the ventral tegmental area and nucleus accumbens.
abstract: Many patients with major depression do not respond to selective serotonin reuptake inhibitors (SSRIs). Lack of response could be due to inhibition of dopamine (DA) release by serotonin (5-HT) through 5-HT2C receptors. Combining an SSRI with a 5-HT2C antagonist may result in improved efficacy by causing simultaneous increases of 5-HT and DA. In order to test this augmentation strategy, male Wistar rats were treated (s.c.) with an acute dose of the SSRI citalopram (Cit, 5 mg/kg), the 5-HT2C antagonist SB 242084 (SB, 2 mg/kg), or Cit + SB, and the effect on 5-HT and DA release in the nucleus accumbens (NAcc) was assessed by microdialysis. In a separate experiment, animals were treated with vehicle, Cit (20 mg/kg/d), SB (2 mg/kg/d) or Cit + SB for a period of 2 days (s.c.), and the impact on the release of 5-HT and DA in the ventral tegmental area (VTA) and NAcc was studied. On the day of microdialysis, 5-HT2C receptor sensitivity was assessed with an SB challenge. Acutely administered Cit + SB increased 5-HT release in the NAcc more than Cit alone. SB alone increased DA release in the NAcc (not in the VTA), but when administered together with Cit, this effect was abolished. A 2-day treatment with Cit or Cit + SB increased 5-HT release in both VTA and NAcc. Combining Cit with SB augmented the effect of Cit in the VTA. DA release in VTA and NAcc was only significantly increased after 2-days of treatment with Cit + SB. In conclusion, Cit + SB had synergistic effects on 5-HT and DA release after 2-days of treatment, probably related to a decreased tonic inhibition of DA release via 5-HT2C receptors. Regional differences occur and future studies should elucidate if this augmentation strategy is beneficial at the behavioral level.
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Anniek K D
authors.initials: AK
authors.lastname: Visser
authors.affiliation: Department of Biomonitoring and Sensoring, University of Groningen, Antonius Deasinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Jelle
authors.initials: J
authors.lastname: Kleijn
authors.affiliation: Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Martijn H J R
authors.initials: MH
authors.lastname: van Faassen
authors.affiliation: Institutes of Molecular Physiology and Genetics and Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Eliyahu
authors.initials: E
authors.lastname: Dremencov
authors.affiliation: Brains On-Line, P.O. Box 4030, 9701 EA Groningen, The Netherlands.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Flik
authors.affiliation: Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Ido P
authors.initials: IP
authors.lastname: Kema
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; Director Scientific Affairs, PRA Health Sciences, Stationsweg 163, P.O. Box 200, 9470 AE Zuidlaren, The Netherlands.
authors.forename: Johan A
authors.initials: JA
authors.lastname: Den Boer
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Electronic address: a.van.waarde@umcg.nl.
authors.forename: Aren
authors.initials: A
authors.lastname: van Waarde
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Rudi A J O
authors.initials: RA
authors.lastname: Dierckx
authors.affiliation: University Center of Psychiatry, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Fokko J
authors.initials: FJ
authors.lastname: Bosker
mesh_terms: D000818:Animals; D015283:Citalopram / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
chemical_list: D015283:Citalopram; D004298:Dopamine; D044405:Receptor, Serotonin, 5-HT2C; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors
keywords: 5-HT2C receptor; Dopamine; Microdialysis; SSRI augmentation; Serotonin