Mice Lacking the Serotonin Transporter Exhibit 5-HT1A Receptor-Mediated Abnormalities in Tests for Anxiety-like Behavior

Abstract

The serotonin transporter (5-HTT) regulates serotonergic neurotransmission via clearance of extracellular serotonin. Abnormalities in 5-HTT expression or function are found in mood and anxiety disorders, and the 5-HTT is a major target for antidepressants and anxiolytics. The 5-HTT is further implicated in the pathophysiology of these disorders by evidence that genetic variation in the promoter region of the HTT (SLC6A4) is associated with individual differences in anxiety and neural responses to fear. To further evaluate the role of the 5-HTT in anxiety, we employed a mouse model in which the 5-HTT gene (htt) was constitutively inactivated. 5-HTT À/À mice were characterized for anxiety-related behaviors using a battery of tests (elevated plus maze, light2dark exploration test, emergence test, and open field test). Male and female 5-HTT À/À mice showed robust phenotypic abnormalities as compared to +/+ littermates, suggestive of increased anxiety-like behavior and inhibited exploratory locomotion. The selective 5-HT 1A receptor antagonist, WAY 100635 (0.05-0.3 mg/kg), produced a significant anxiolytic-like effect in the elevated plus maze in 5-HTT À/À mice, but not +/+ controls. The present findings demonstrate abnormal behavioral phenotypes in 5-HTT null mutant mice in tests for anxiety-like and exploratory behavior, and suggest a role for the 5-HT 1A receptor in mediating these abnormalities. 5-HTT null mutant mice provide a model to investigate the role of the 5-HTT in mood and anxiety disorders.

Reduced Anxiety and Depression-Like Behaviors in Mice Lacking GABA Transporter Subtype 1

“…The phenomenon is consistent with a reduced anxiety-like behavior (ie, increase center time) and increased locomotor exploration (ie, increase horizontal and vertical activities). It has been demonstrated that in exploration-based tests for anxiety-like behaviors, such as the light-dark exploration or emergence tests, animals with anxiety would rather spend more time in the dark compartment (Blanchard et al, 1990;File, 2001;Holmes et al, 2003b). In light-dark exploration tests, the GAT1 À/À mice showed more transitions between light and dark compartments and spent more time in the light compartment than GAT1 + / + mice.…”

“…The emergence test was conducted as described previously (Holmes et al, 2003b;Smith et al, 1998;Takahashi et al, 1989). The apparatus consisted of an opaque black Plexiglas cube (16 Â 16 Â 19 cm 3 ) with an exit (6 Â 4 cm 2 ) on one side at floor level.…”

Neonatal serotonin depletion alters behavioral responses to spatial change and novelty

“…For instance, serotonin transporter gene knock-out mice had a 50% reduction in serotonin and exhibited decreased feeding behavior in a novel situation, despite the absence of a generalized increase in anxiety (Lira et al, 2003). In another study of 5-HT transporter knockout mice, anxiety and impaired exploration were reported and attributed to 5-HT1A receptors (Holmes et al, 2003). This notion receives support from studies on 5-HT1A knockout mice, which showed decreased exploratory activity and increased fear of aversive environments (Ramboz et al, 1998).…”

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…17,18 5-HTT knockout mice show behaviours consistent with anxious and depressive traits; they appear reluctant to explore brightly lit spaces or elevated open platforms and give up struggling early when put in an uncomfortable situation. [19][20][21] Interestingly, the difference from wild-type animals in depression-like giving-up ('behavioural despair') is manifest only after repeated exposure to stressors, analogous to repeated or chronic stressful life events in humans. 20 The 5-HTT knockout animals also show exaggerated neuroendocrine reactions to acute stress similar to the HPA axis over reactivity in depressed humans.…”

“…22,23 The effect of 5-HTT knockout on anxietyand depression-like behaviours may be mediated by the absence of functional serotonin clearance mechanism during a vulnerable developmental period, 24 but can still be selectively reversed by pharmacological 5HT1A receptor blockage later in life suggesting a life-long modulatory involvement of the serotonergic system. 19 The anxious-depressive phenotype in 5-HTT knockout mice is associated with increased dendritic branching in the 'fear circuit' including the amygdala and limbic cortex. 20 On the other hand, mice with transgenically increased 5-HTT expression appear fearless and explore bright-lit and open spaces more daringly than wild-type animals.…”