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Insensitivity of NMRI mice to selective serotonin reuptake inhibitors in the tail suspension test can be reversed by co-treatment with 5-hydroxytryptophan

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Abstract

Rationale

Exploring differences between mouse strains in drug effects in models of antidepressant-like activity may provide clues to the neurobiology of antidepressant responses.

Objectives

The objective of this study was to explore whether insensitivity to selective serotonin reuptake inhibitors (SSRIs) in NMRI mice in the tail suspension test can be related to 5-hydroxytryptamine (5-HT) function.

Materials and methods

We compared NMRI and C57Bl/6 mice, a SSRI-sensitive strain, in the tail suspension test following citalopram, paroxetine, or fluoxetine and determined 5-HT transporter (5-HTT) densities, 5-HT tissue and extracellular levels, 5-HT synthesis, tryptophan hydroxylase 2 (TPH2) genotypes and hypothermia induced by the 5-HT1A agonist 8-OH-DPAT. In NMRI mice, we tested if co-treatment with 5-HTP would increase 5-HT levels and confer SSRI sensitivity in the tail suspension test.

Results

C57Bl/6, but not NMRI, mice responded to SSRIs in the tail suspension test. 5-HTT densities in the frontal cortex and hippocampus were similar between the strains. NMRI mice had lower tissue 5-HT levels in these regions and decreased extracellular 5-HT in the frontal cortex at baseline and following citalopram. C57Bl/6 mice were more sensitive to 8-OH-DPAT-induced hypothermia. Both strains had the 1473C TPH2 genotype and similar 5-HT synthesis. In NMRI mice, 5-HTP co-treatment restored the tail suspension and extracellular 5-HT responses to SSRIs to levels equivalent to those seen in C57Bl/6 mice.

Conclusion

Low 5-HT function in NMRI mice may account for their insensitivity to SSRIs in the tail suspension test. As the tail suspension test is a predictor of clinical efficacy, the current data suggest that 5-HTP adjunct treatment may benefit SSRI treatment refractory patients.

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Abbreviations

5-HT:

5-hydroxytryptamine

5-HTT:

5-HT transporter

5-HTP:

5-hydroxytryptophan

SSRI:

selective serotonin reuptake-inhibitor

SNP:

single nucleotide polymorphism

TPH2:

tryptophan hydroxylase 2

NET:

norepinephrine transporter

two-way RM-ANOVA:

two-way repeated measures ANOVA

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Acknowledgements

The authors wish to thank Jeanette DeWitt Brodersen and Anne Birgitte Fischer for skillful technical assistance.

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Authors and Affiliations

  1. NeuroSearch A/S, Pederstrupvej 93, DK-2750, Ballerup, Denmark

    Elsebet Ø. Nielsen, Rene Hummel, John Paul Redrobe, Naheed Mirza & Pia Weikop

  2. In vivo Pharmacology, NeuroSearch A/S, Pederstrupvej 93, DK-2750, Ballerup, Denmark

    Jacob P. R. Jacobsen

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  1. Jacob P. R. Jacobsen
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  2. Elsebet Ø. Nielsen
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  3. Rene Hummel
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Correspondence to Jacob P. R. Jacobsen.

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Jacobsen, J.P.R., Nielsen, E.Ø., Hummel, R. et al. Insensitivity of NMRI mice to selective serotonin reuptake inhibitors in the tail suspension test can be reversed by co-treatment with 5-hydroxytryptophan. Psychopharmacology 199, 137–150 (2008). https://doi.org/10.1007/s00213-008-1142-7

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