Abstract
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 language | English |
|---|---|
| Pages (from-to) | 793-803 |
| Number of pages | 11 |
| Journal | International Journal of Neuropsychopharmacology |
| Volume | 12 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jul 2009 |
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Keywords
- 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
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. / Calcagno, Eleonora; Guzzetti, Sara; Canetta, Alessandro; Fracasso, Claudia; Caccia, Silvio; Cervo, Luigi; Invernizzi, Roberto W.
In: International Journal of Neuropsychopharmacology, Vol. 12, No. 6, 07.2009, p. 793-803.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Calcagno, Eleonora
AU - Guzzetti, Sara
AU - Canetta, Alessandro
AU - Fracasso, Claudia
AU - Caccia, Silvio
AU - Cervo, Luigi
AU - Invernizzi, Roberto W.
PY - 2009/7
Y1 - 2009/7
N2 - 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.
AB - 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.
KW - 5-HT1A receptors
KW - 5-HT2C receptors
KW - FST
KW - Intracerebral microdialysis
KW - SSRIs
KW - TPH-2
UR - http://www.scopus.com/inward/record.url?scp=68849105373&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=68849105373&partnerID=8YFLogxK
U2 - 10.1017/S1461145708009760
DO - 10.1017/S1461145708009760
M3 - Article
C2 - 19123962
AN - SCOPUS:68849105373
VL - 12
SP - 793
EP - 803
JO - International Journal of Neuropsychopharmacology
JF - International Journal of Neuropsychopharmacology
SN - 1461-1457
IS - 6
ER -