Insensitivity of NMRI mice to selective serotonin reuptake inhibitors in the tail suspension test can be reversed by co-treatment with 5-hydroxytryptophan.
BACKGROUND
Exploring differences between mouse strains in drug effects in models of antidepressant-like activity may provide clues to the neurobiology of antidepressant responses.


OBJECTIVE
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.


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-HT(1A) 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.


CONCLUSIONS
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.
Jacobsen
Jacob P R
JP
In vivo Pharmacology, NeuroSearch A/S, Pederstrupvej 93, Ballerup, Denmark. jacobpade@hotmail.com
Nielsen
Elsebet Ø
EØ
Hummel
Rene
R
Redrobe
John Paul
JP
Mirza
Naheed
N
Weikop
Pia
P
D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D015283:Citalopram / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000378:metabolism; D005838:Genotype; D019417:Hindlimb Suspension / Q000523:psychology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000096:biosynthesis / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013045:Species Specificity; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis / Q000235:genetics
D006916:5-Hydroxytryptophan; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D015283:Citalopram; D005473:Fluoxetine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012701:Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D014446:Tyrosine 3-Monooxygenase; C011386:nisoxetine