Abstract
We studied the antidepressant-like effect of paroxetine in strains of mice carrying different isoforms of tryptophan hydroxylase-2 (TPH-2), the enzyme responsible for the synthesis of brain serotonin (5-HT). The effect of paroxetine alone and in combination with pharmacological treatments enhancing or lowering 5-HT synthesis or melatonin was assessed in the forced swimming test in mice carrying allelic variants of TPH-2 (1473C in C57BL/6 and 1473G in DBA/2 and BALB/c). Changes in brain 5-hydroxytryptophan (5-HTP) accumulation and melatonin levels were measured by high-performance liquid chromatography. Paroxetine (2.5 and 5 mg/kg) reduced immobility time in C57BL/6J and C57BL/6N mice but had no such effect in DBA/2J, DBA/2N and BALB/c mice, even at 10 mg/kg. Enhancing 5-HT synthesis with tryptophan reinstated the antidepressant-like effect of paroxetine in DBA/2J, DBA/2N and BALB/c mice whereas inhibition of 5-HT synthesis prevented the effect of paroxetine in C57BL/6N mice. The response to paroxetine was not associated with changes in locomotor activity, brain melatonin or brain levels of the drug measured at the end of the behavioral test. These results support the importance of 5-HT synthesis in the response to SSRIs and suggest that melatonin does not contribute to the ability of tryptophan to rescue the antidepressant-like effect of paroxetine.
| Original language | English |
|---|---|
| Pages (from-to) | 117-124 |
| Number of pages | 8 |
| Journal | European Journal of Pharmacology |
| Volume | 594 |
| Issue number | 1-3 |
| DOIs | |
| Publication status | Published - Oct 10 2008 |
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Keywords
- 5-HT synthesis
- Antidepressant
- Forced swimming test
- Melatonin
- Paroxetine
- SSRI
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Pharmacology
Cite this
Strain differences in paroxetine-induced reduction of immobility time in the forced swimming test in mice : Role of serotonin. / Guzzetti, Sara; Calcagno, Eleonora; Canetta, Alessandro; Sacchetti, Giuseppina; Fracasso, Claudia; Caccia, Silvio; Cervo, Luigi; Invernizzi, Roberto W.
In: European Journal of Pharmacology, Vol. 594, No. 1-3, 10.10.2008, p. 117-124.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Strain differences in paroxetine-induced reduction of immobility time in the forced swimming test in mice
T2 - Role of serotonin
AU - Guzzetti, Sara
AU - Calcagno, Eleonora
AU - Canetta, Alessandro
AU - Sacchetti, Giuseppina
AU - Fracasso, Claudia
AU - Caccia, Silvio
AU - Cervo, Luigi
AU - Invernizzi, Roberto W.
PY - 2008/10/10
Y1 - 2008/10/10
N2 - We studied the antidepressant-like effect of paroxetine in strains of mice carrying different isoforms of tryptophan hydroxylase-2 (TPH-2), the enzyme responsible for the synthesis of brain serotonin (5-HT). The effect of paroxetine alone and in combination with pharmacological treatments enhancing or lowering 5-HT synthesis or melatonin was assessed in the forced swimming test in mice carrying allelic variants of TPH-2 (1473C in C57BL/6 and 1473G in DBA/2 and BALB/c). Changes in brain 5-hydroxytryptophan (5-HTP) accumulation and melatonin levels were measured by high-performance liquid chromatography. Paroxetine (2.5 and 5 mg/kg) reduced immobility time in C57BL/6J and C57BL/6N mice but had no such effect in DBA/2J, DBA/2N and BALB/c mice, even at 10 mg/kg. Enhancing 5-HT synthesis with tryptophan reinstated the antidepressant-like effect of paroxetine in DBA/2J, DBA/2N and BALB/c mice whereas inhibition of 5-HT synthesis prevented the effect of paroxetine in C57BL/6N mice. The response to paroxetine was not associated with changes in locomotor activity, brain melatonin or brain levels of the drug measured at the end of the behavioral test. These results support the importance of 5-HT synthesis in the response to SSRIs and suggest that melatonin does not contribute to the ability of tryptophan to rescue the antidepressant-like effect of paroxetine.
AB - We studied the antidepressant-like effect of paroxetine in strains of mice carrying different isoforms of tryptophan hydroxylase-2 (TPH-2), the enzyme responsible for the synthesis of brain serotonin (5-HT). The effect of paroxetine alone and in combination with pharmacological treatments enhancing or lowering 5-HT synthesis or melatonin was assessed in the forced swimming test in mice carrying allelic variants of TPH-2 (1473C in C57BL/6 and 1473G in DBA/2 and BALB/c). Changes in brain 5-hydroxytryptophan (5-HTP) accumulation and melatonin levels were measured by high-performance liquid chromatography. Paroxetine (2.5 and 5 mg/kg) reduced immobility time in C57BL/6J and C57BL/6N mice but had no such effect in DBA/2J, DBA/2N and BALB/c mice, even at 10 mg/kg. Enhancing 5-HT synthesis with tryptophan reinstated the antidepressant-like effect of paroxetine in DBA/2J, DBA/2N and BALB/c mice whereas inhibition of 5-HT synthesis prevented the effect of paroxetine in C57BL/6N mice. The response to paroxetine was not associated with changes in locomotor activity, brain melatonin or brain levels of the drug measured at the end of the behavioral test. These results support the importance of 5-HT synthesis in the response to SSRIs and suggest that melatonin does not contribute to the ability of tryptophan to rescue the antidepressant-like effect of paroxetine.
KW - 5-HT synthesis
KW - Antidepressant
KW - Forced swimming test
KW - Melatonin
KW - Paroxetine
KW - SSRI
UR - http://www.scopus.com/inward/record.url?scp=50549092205&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=50549092205&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2008.07.031
DO - 10.1016/j.ejphar.2008.07.031
M3 - Article
C2 - 18691569
AN - SCOPUS:50549092205
VL - 594
SP - 117
EP - 124
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1-3
ER -