A study in male and female 5-HT transporter knockout rats: An animal model for anxiety and depression disorders

被引：179

作者：

Olivier, J. D. A. ^{[1
,2
]}

Van Der Hart, M. G. C. ^{[4
]}

Van Swelm, R. P. L. ^{[1
]}

Dederen, P. J. ^{[6
]}

Homberg, J. R. ^{[1
,5
]}

Cremers, T. ^{[4
]}

Deen, P. M. T. ^{[2
]}

Cuppen, E. ^{[5
]}

Cools, A. R. ^{[1
]}

Ellenbroek, B. A. ^{[1
,3
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci Psychoneuropharmacol, NL-6525 EZ Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Dept Physiol, NL-6525 EZ Nijmegen, Netherlands

[3] Evotec, Dept Neuropharmacol, Hamburg, Germany

[4] Univ Groningen, Dept Pharm, Groningen, Netherlands

[5] Hubrecht Inst, Utrecht, Netherlands

[6] Radboud Univ Nijmegen, Med Ctr, Dept Anat, NL-6525 EZ Nijmegen, Netherlands

来源：

NEUROSCIENCE | 2008年 / 152卷 / 03期

关键词：

5-HT transporter; knockout rat; anxiety; depression; sex;

D O I：

10.1016/j.neuroscience.2007.12.032

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Human studies have shown that a reduction of 5-HT transporter (SERT) increases the vulnerability for anxiety and depression. Moreover, women are more vulnerable to develop depression and anxiety disorders than men. For that reason we hypothesized that homozygous 5-HT transporter knockout rat (SERT-/-) models, especially female, are valuable and reliable animal models for humans with an increased vulnerability for anxiety- and depression-related disorders. As rats are extensively used in neuroscience research, we used the unique 5-HT transporter knockout rat, that was recently generated using N-ethyl-N-nitrosurea (ENU) -driven mutagenesis, to test this hypothesis. Behavioral testing revealed that male and female SERT-/- rats spent less time in the center of the open field and spent less time on the open arm of the elevated plus maze compared with wild-type 5-HT transporter knockout rats (SERT+/+). In the novelty suppressed feeding test, only male SERT-/- rats showed a higher latency before starting to eat in a bright novel arena compared with SERT+/+ controls. Both male and female SERT-/- rats showed a higher escape latency from their home cage than SERT+/+ littermates. Moreover, SERT-/- rats were less mobile in the forced swim test, and sucrose consumption was reduced in SERT-/- rats relative to SERT+/+ rats. Both effects were sex-independent. Neurochemically, basal extracellular 5-HT levels were elevated to a similar extent in male and female SERT-/- rats, which was not influenced by the selective 5-HT reuptake inhibitor citalopram. 5-HT immunostaining revealed no difference between SERT+/+ and SERT-/- rats in the doral raphe nuclei, in both males and females. These findings demonstrate that SERT-/- rats show anxiety and depression-related behavior, independent of sex. Genetic inactivation of the SERT has apparently such a great impact on behavior, that hardly any differences are found between male and female rats. This knockout rat model may provide a valuable model to study anxiety- and depression-related disorders in male and female rats. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.

引用

页码：573 / 584

页数：12

共 86 条

[31] EFFECTS OF ALPHA-ADRENOCEPTOR AGONISTS AND ANTAGONISTS IN A MAZE-EXPLORATION MODEL OF FEAR-MOTIVATED BEHAVIOR [J].

HANDLEY, SL ;

MITHANI, S .

NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 1984, 327 (01) :1-5

[32]

Heils A, 1996, J NEUROCHEM, V66, P2621

[33] The human serotonin transporter gene polymorphism -: basic research and clinical implications [J].

Heils, A ;

Mössner, R ;

Lesch, KP .

JOURNAL OF NEURAL TRANSMISSION, 1997, 104 (10) :1005-1014

[34] Neuropathological study of the dorsal raphe nuclei in late-life depression and Alzheimer's disease with and without depression [J].

Hendricksen, M ;

Thomas, AJ ;

Ferrier, IN ;

Ince, P ;

O'Brien, JT .

AMERICAN JOURNAL OF PSYCHIATRY, 2004, 161 (06) :1096-1102

[35] A review of the validity and variability of the elevated plus-maze as an animal model of anxiety [J].

Hogg, S .

PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 1996, 54 (01) :21-30

[36] Mice lacking the serotonin transporter exhibit 5-HT1A receptor-mediated abnormalities in tests for anxiety-like behavior [J].

Holmes, A ;

Yang, RJ ;

Lesch, KP ;

Crawley, JN ;

Murphy, DL .

NEUROPSYCHOPHARMACOLOGY, 2003, 28 (12) :2077-2088

[37] Abnormal anxiety-related behaviour in serotonin transporter null mutant mice: the influence of genetic background [J].

Holmes, A ;

Li, Q ;

Murphy, DL ;

Gold, E ;

Crawley, JN .

GENES BRAIN AND BEHAVIOR, 2003, 2 (06) :365-380

[38] Abnormal behavioral phenotypes of serotonin transporter knockout mice: Parallels with human anxiety and depression [J].

Holmes, A ;

Murphy, DL ;

Crawley, JN .

BIOLOGICAL PSYCHIATRY, 2003, 54 (10) :953-959

[39] Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter [J].

Holmes, A ;

Yang, RJ ;

Murphy, DL ;

Crawley, JN .

NEUROPSYCHOPHARMACOLOGY, 2002, 27 (06) :914-923

[40] Characterization of the serotonin transporter knockout rat: A selective change in the functioning of the serotonergic system [J].

Homberg, J. R. ;

Olivier, J. D. A. ;

Smits, B. M. G. ;

Mul, J. D. ;

Mudde, J. ;

Verheul, M. ;

Nieuwenhuizen, O. F. M. ;

Schoffelmeere, A. N. M. ;

Ellenbroeik, B. A. ;

Clippen, E. .

NEUROSCIENCE, 2007, 146 (04) :1662-1676

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