Enhancement of cortical extracellular 5-HT by 5-HT1A and 5-HT2C receptor blockade restores the antidepressant-like effect of citalopram in non-responder mice

Eleonora Calcagno, Sara Guzzetti, Alessandro Canetta, Claudia Fracasso, Silvio Caccia, Luigi Cervo, Roberto W. Invernizzi

Research output: Contribution to journalArticle


We recently found that the response of DBA/2 mice to SSRIs in the forced swim test (FST) was impaired and they also had a smaller basal and citalopram-stimulated increase in brain extracellular serotonin (5-HT) than responder strains. We employed intracerebral microdialysis, FST and selective antagonists of 5-HT1A and 5-HT2C receptors to investigate whether enhancing the increase in extracellular 5-HT reinstated the anti-immobility effect of citalopram in the FST. WAY 100635 (0.3 mg/kg s.c.) or SB 242084 (1 mg/kg s.c.), respectively a selective 5-HT1A and 5-HT2C receptor antagonist, raised the effect of citalopram (5 mg/kg) on extracellular 5-HT in the medial prefrontal cortex of DBA/2N mice (citalopram alone 5.20.3 fmol/20 l, WAY 100635+citalopram 9.92.1 fmol/20 l, SB 242084+ citalopram 7.61.0 fmol/20 l) to the level reached in responder mice given citalopram alone. The 5-HT receptor antagonists had no effect on the citalopram-induced increase in extracellular 5-HT in the dorsal hippocampus. The combination of citalopram with WAY 100635 or SB 242084 significantly reduced immobility time in DBA/2N mice that otherwise did not respond to either drug singly. Brain levels of citalopram in mice given citalopram alone or with 5-HT antagonists did not significantly differ. The results confirm that impaired 5-HT transmission accounts for the lack of effect of citalopram in the FST and suggest that enhancing the effect of SSRIs on extracellular 5-HT, through selective blockade of 5-HT1A and 5-HT2C receptors, could be a useful strategy to restore the response in treatment-resistant depression.

Original languageEnglish
Pages (from-to)793-803
Number of pages11
JournalInternational Journal of Neuropsychopharmacology
Issue number6
Publication statusPublished - Jul 2009



  • 5-HT1A receptors
  • 5-HT2C receptors
  • FST
  • Intracerebral microdialysis
  • SSRIs
  • TPH-2

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Psychiatry and Mental health
  • Medicine(all)

Cite this