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

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.