Serotonin-2C antagonism augments the effect of citalopram on serotonin and dopamine levels in the ventral tegmental area and nucleus accumbens

• Published in: Neurochemistry international Vol. 81; pp. 10 - 15
• Main Authors: Visser, Anniek K.D., Kleijn, Jelle, van Faassen, Martijn H.J.R., Dremencov, Eliyahu, Flik, Gunnar, Kema, Ido P., Den Boer, Johan A., van Waarde, Aren, Dierckx, Rudi A.J.O., Bosker, Fokko J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2015
• Subjects: 5-HT2C receptor; Animals; Citalopram - pharmacology; Dopamine; Dopamine - metabolism; Male; Microdialysis; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2C - drug effects; Serotonin; Serotonin - metabolism; Serotonin Antagonists - pharmacology; Serotonin Uptake Inhibitors - pharmacology; SSRI augmentation; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - metabolism; SSRI augmentation; 5-HT2C receptor; Microdialysis; Dopamine; Serotonin
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2014.12.006

•Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants.•SSRIs increase levels of extracellular serotonin, but decrease those of dopamine.•This side effect can be avoided by combining an SSRI with a 5-HT2C antagonist.•The combination increases both serotonin and dopamine in key areas of rat brain.•Possible behavioral benefits of this combination should still be examined. 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.