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

J D A Olivier, M G C Van Der Hart, R P L Van Swelm, P J Dederen, J R Homberg, T Cremers, P M T Deen, E Cuppen, A R Cools, B A Ellenbroek

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Abstract

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.

Original languageEnglish
Pages (from-to)573-584
Number of pages12
JournalNeuroscience
Volume152
Issue number3
DOIs
Publication statusPublished - 27-Mar-2008

Keywords

  • 5-HT transporter
  • knockout rat
  • anxiety
  • depression
  • sex
  • DORSAL RAPHE NUCLEUS
  • EARLY-LIFE BLOCKADE
  • FORCED-SWIM TEST
  • SEROTONIN TRANSPORTER
  • PROMOTER POLYMORPHISM
  • MAJOR DEPRESSION
  • BRAIN-SEROTONIN
  • SEX-DIFFERENCES
  • GENE PROMOTER
  • MICE LACKING

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