The tail suspension test: A new method for screening antidepressants in mice

One of the main theories concerning the mechanism of action of antidepressant drugs (ADs) is based on the notion that the neurochemical background of depression involves an impairment of central noradrenergic transmission with a concomitant decrease of the norepinephrine (NE) in the synaptic gap. Many ADs increase synaptic NE availability by inhibition of the reuptake of NE. Using mice lacking NE transporter (NET À/À ) we examined their baseline phenotype as well as the response in the forced swim test (FST) and in the tail suspension test (TST) upon treatment with ADs that display different pharmacological profiles. In both tests, the NET À/À mice behaved like wild-type (WT) mice acutely treated with ADs. Autoradiographic studies showed decreased binding of the b-adrenergic ligand [ 3 H]CGP12177 in the cerebral cortex of NET À/À mice, indicating the changes at the level of b-adrenergic receptors similar to those obtained with ADs treatment. The binding of [ 3 H]prazosin to a 1 -adrenergic receptors in the cerebral cortex of NET À/À mice was also decreased, most probably as an adaptive response to the sustained elevation of extracellular NE levels observed in these mice. A pronounced NET knockout-induced shortening of the immobility time in the TST (by ca 50%) compared to WT mice was not reduced any further by NET-inhibiting ADs such as reboxetine, desipramine, and imipramine. Citalopram, which is devoid of affinity for the NET, exerted a significant reduction of immobility time in the NET À/À mice. In the FST, reboxetine, desipramine, imipramine, and citalopram administered acutely did not reduce any further the immobility time shortened by NET knockout itself (ca 25%); however, antidepressant-like action of repeatedly (7 days) administered desipramine was observed in NET À/À mice, indicating that the chronic presence of this drug may also affect other neurochemical targets involved in the behavioral reactions monitored by this test. From the present study, it may be concluded that mice lacking the NET may represent a good model of some aspects of depression-resistant behavior, paralleled with alterations in the expression of adrenergic receptors, which result as an adaptation to elevated levels of extracellular NE.

Section: Introductionmentioning

confidence: 61%

“…For the TST (Steru et al, 1985), mice were securely fastened by the distal end of the tail to a flat surface and suspended. The presence or absence of immobility, defined as the absence of limb movement, was assessed over a 6-min session by a highly experienced observer who was not aware of the genotype.…”

Section: Tail Suspension Testmentioning

confidence: 99%

Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

Dziedzicka-Wasylewska

Faron-Górecka

Kuśmider

et al. 2006

“…Female mice were monitored for the phase of estrus cycle by vaginal smears prior to behavioral testing. The TST was a modified version of previously validated procedures (Steru et al, 1985;Mayorga et al, 2001). Mice were transported a short distance from the holding facility to the testing room and left there undisturbed for at least 3 h. Subjects were randomly allocated to treatment conditions and tested in counterbalanced order.…”

Section: Behaviormentioning

confidence: 99%

Sex Differences in the Regulation of Serotonergic Transmission and Behavior in 5-HT Receptor Knockout Mice

Jones

Lucki

2005

Few studies have examined the relationship between genetics, stress, and sex-linked differences in neurotransmitter systems. Examining serotonin (5-HT) receptor knockout mice on stress-induced behavioral depression, female 5-HT 1B receptor knockout mice demonstrated significantly reduced immobility than either male 5-HT 1B receptor knockout mice or male and female wild-type mice on the tail suspension test (TST) and forced swimming test. The behavioral phenotype was identified as likely due to a disinhibition of 5-HT release, because depletion of 5-HT with parachlorophenylalanine selectively reduced immobility of female 5-HT 1B receptor knockout mice in the TST. In contrast, male and female 5-HT 1A receptor knockout mice demonstrated reduced immobility compared with control mice, but the depletion of 5-HT with PCPA did not reverse the antidepressant-like phenotype. Microdialysis studies confirmed significantly higher baseline levels of hippocampal 5-HT in female, but not male, 5-HT 1B receptor knockout mice. Both male and female 5-HT 1B receptor knockout mice demonstrated augmented dialysate responses to fluoxetine. Also, both male and female 5-HT 1B receptor knockout mice demonstrated reductions of immobility in the TST after treatment with fluoxetine. Therefore, female 5-HT 1B receptor knockout mice demonstrate a sex-linked disinhibition of 5-HT release that sustained higher baseline levels of hippocampal 5-HT and behavioral vulnerability to 5-HT depletion.

“…The antidepressant response to citalopram was measured using the tail suspension test (TST), a widely used and reliable method for measuring the pharmacological effects of antidepressant drugs in mice (Cryan et al, 2002(Cryan et al, , 2005Steru et al, 1985). In the TST, a mouse is suspended by the tail from an elevated bar for several minutes.…”

Section: Introductionmentioning

confidence: 99%

“…The frequency or duration of immobility is reduced by antidepressant treatments. The TST has been shown to be sensitive to an array of antidepressant treatments, including tricyclics, SSRIs, monoamine oxidase inhibitors, atypical antidepressants, and electroconvulsive therapy (Perrault et al, 1992;Steru et al, 1985Steru et al, , 1987Teste et al, 1990Teste et al, , 1993. Inbred rodent strains show substantial variability in baseline performance and behavioral response to antidepressant administration in the TST (Bai et al, 2001;Gershenfeld, 2001, 2003;Rippoll et al, 2003; for a review, see Cryan et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

Crowley

Brodkin

Blendy

et al. 2006

The identification of genetic variants regulating antidepressant response in human patients would allow for more individualized, rational, and successful drug treatments. We have previously identified the BALB/cJ inbred mouse strain as highly responsive to the selective serotonin reuptake inhibitor (SSRI) citalopram in the tail suspension test (TST), a widely used and well-established screening paradigm for detecting compounds with antidepressant activity. In contrast, A/J mice did not show a significant response to citalopram in this test despite exposure to equivalent plasma levels of the drug. To identify genetic determinants of this differential response, 506 F 2 mice from an intercross between BALB/cJ and A/J mice were phenotyped. Composite interval mapping of 92 mice from the phenotypic extremes revealed three loci on chromosomes 7, 12, and 19 affecting citalopram response in the TST. The quantitative trait locus (QTL) at the telomeric end of chromosome 19 showed the greatest level of significance. Three candidate genes residing in this locus include those for vesicular monoamine transporter 2 (VMAT2, slc18a2), alpha 2A adrenergic receptor (adra2a), and beta 1 adrenergic receptor (adrb1). The protein coding regions of these three genes in BALB/cJ and A/J mice were sequenced and two polymorphisms were found in VMAT2 (Leu117Pro and Ser505Pro), while the transcribed regions of adra2a and adrb1 were of identical sequence between strains. Follow-up studies are needed to determine if the VMAT2 polymorphisms are functional and if they could explain the chromosome 19 QTL. The present quantitative trait study suggests possible candidate genes for human pharmacogenetic studies of therapeutic responses to SSRIs such as citalopram.