A study of the effects of 3,5-diiodo-L-thyronine in the tail suspension and forced swim models of depression

Objectives: Recent findings have further highlighted the role of the thyroid system in the pathophysiology of depression and revealed new physiologically relevant elements of the thyroid system. Our previous study showed an antidepressant-like effect of 3,5-diiodo-L-thyronine(T2), which was previously considered to be a physiologically inactive molecule, in mice. Here, we aimed to investigate the antidepressant-like effects of T2 further. Methods: We studied the effects of bolus injections of T2 to C57Bl6 J mice at doses of 0.25 or 0.75 mg/kg with the tail suspension and forced swim models. The effects of the higher dose were investigated in CD1 mice in the forced swim test. Potential behavioral effects of these treatments were also studied using the novel cage and dark-light box tests.Results: A reduction of depressive-like behavior was found in mice treated with 0.75 mg/kg of T2 in the tail suspension test, but not in the forced swim test. Locomotion and anxiety variables were unaltered following treatment with T2. There were no significant changes after bolus administration of 0.25 mg/kg T2 in either test for depressive-like behavior. Thus, bolus injection of T2 at the dose 0.75 mg/kg can induce antidepressant-like effects without affecting other behaviors. Conclusions: A discrepant result in the forced swim test may be due to its different sensitivity to T2 compared with the tail suspension paradigm. Furthermore, the development of procedural modifications of this model can be useful in its application in pre-clinical studies.

Behavioral features of mice fed with a cholesterol-enriched diet: Deficient novelty exploration and unaltered aggressive behavior

Objectives: Previous studies involving mice have demonstrated that a cholesterolenriched diet evokes liver steatosis, dystrophy, inflammation, and aspects of nonalcoholic fatty liver disease(NAFLD). These changes are accompanied by the activation of pro-inflammatory brain and liver molecular pathways, as well as anxiety and depressive-like behaviors. Given previously reported evidence for the neurobiological relationship between the above-mentioned molecular changes and abnormalities in coping with environmental stimuli, such as interactions with other individuals and new environmental contexts, we hypothesized that novelty exploration and aggressive behavior are affected in a mouse NAFLD model. Methods: To test this hypothesis, young female C57BL/6J mice were fed with a regular chow or a diet containing 0.2% cholesterol for 3 weeks. The mice were then assessed for new object and novel cage exploration, and social interaction in a food competition test. Results: We found reduced object exploration in mice on the cholesterol-enriched diet. This reduction was not related to whether the new object was placed in an anxiogenic or non-anxiogenic environment. These changes were accompanied by diminished exploration of the new environment in a novel cage, and delayed approach to food after a period of food deprivation. Mice on the regular chow or cholesterolenriched diet showed no differences in aggressive behavior towards a counter-partner in a food competition test. Food intake and body weight did not differ between the groups, thus, excluding their potential as confounders in the measured behaviors. Conclusions: We conclude that a diet enriched with cholesterol reduces novelty exploration irrespective of the anxiogenic level of the environment and does not induce aggressive behavior in female mice.

Effects of voluntary imipramine intake via food and water in paradigms of anxiety and depression in naive mice

Objective: We sought to investigate the efficacy of oral dosing in mice with imipramine(7mg/kg/day) via water or in food pellets, and to compare its effects in the paradigms of learned helplessness, locomotion, hedonic state, and anxiety. Methods: Water and food consumption were measured to determine daily imipramine dosage in C57BL/6N mice. Next, baseline scores for O-maze, dark/light box, and sucrose tests were measured. Mice were then subjected to a 4-week treatment of voluntary ingestion of drinking water or food pellets containing imipramine. Lastly, all groups were subjected to novel cage, open field, O-maze, dark/light box, sucrose test, and forced swim test to assess the effects of the treatment. Results: In na?ve mice, imipramine delivered via food, induced a reduction of total floating and increased latency in the forced swim test, i.e., antidepressant-like effects. No other significant effects were found. Dosing with water did not change behavior in the forced swim, sucrose preference test, anxiety, or locomotor paradigms, but increased exploration in the novel cage. Conclusions: Voluntary ingestion is an effective method of chronic dosing with imipramine in na?ve mice. Delivery of imipramine with food pellets elicits antidepressant-like effects in the forced swim test, with no effects on anxiety, locomotion, or preference behaviors. In contrast, no such effects were observed with treatment via drinking water, suggesting that a higher dose may be required. Our work argues for a broader use of oral delivery using food-treated pellets, in small rodent models of pre-clinical depression. It may substantially improve animal welfare and overcome potential confounds in translational research, which are frequently associated with adverse chronic invasive pharmacotherapies.