Brain serotonin deficiency and fluoxetine lead to sex-specific effects on binge-like food consumption in mice.

RATIONALE: Although pharmacotherapies are often effective in reducing binge eating in conditions such as bulimia nervosa and binge eating disorder, subsets of patients do not benefit sufficiently from existing treatments, and the reasons for treatment failure remain unclear. OBJECTIVES: This study aimed to evaluate whether genetic reductions in brain serotonin influence binge eating and/or the ability of fluoxetine, a selective serotonin reuptake inhibitor, to reduce binge eating in mice. METHODS: This study used a validated model of binge-like consumption of high-fat diet to compare binge-like food intake in control and fluoxetine-treated wild-type and serotonin-deficient mice from the tryptophan hydroxylase 2 (R439H) knock-in line. In addition, real-time PCR was used to evaluate potential genotype and sex differences in the effects of fluoxetine on gene expression in the raphe nucleus. RESULTS: The results reveal that brain serotonin deficiency is sufficient to increase binge eating in males, but not females. However, while chronic fluoxetine reduced binge eating in both genotypes of males and in wild-type females, it failed to reduce binge eating in serotonin-deficient females. Transcriptional responses to chronic fluoxetine were also characterized by sex and genotype differences. CONCLUSIONS: Overall, this study revealed significant sex differences in the effects of fluoxetine and brain serotonin deficiency on binge-like food intake and suggests that low brain serotonin could impact eating disorders both by promoting binge eating and by limiting the efficacy of fluoxetine to reduce binge eating.

Brain 5-HT Deficiency Prevents Antidepressant-Like Effects of High-Fat-Diet and Blocks High-Fat-Diet-Induced GSK3ß Phosphorylation in the Hippocampus.

Obesity is associated with an increased risk of depression and anxiety disorders, but the nature of the relationship(s) between obesity and mental illness remains highly controversial. Some argue that depression and anxiety lead to increased consumption of "comfort foods," the intake of which reduces negative affect and promotes obesity. In contrast, others have theorized that negative affect results from chronic excessive consumption of highly palatable foods. The brain serotonin (5-HT) system has long been implicated in both the development and treatment of mental illness. Preclinical studies have shown that low brain 5-HT exacerbates depression- and anxiety-like behaviors induced by stress and blocks reductions in depression-like behavior induced by antidepressants, but the effects of brain 5-HT deficiency on responses to high-fat diet (HFD) have not been explored. The current work used genetically modified mice to evaluate the effects of low 5-HT on behavioral and molecular alterations induced by chronic exposure to HFD. Our results reveal that HFD decreases depression-like behavior and increases some anxiety-like behaviors in wild-type (WT) mice. However, genetic brain 5-HT deficiency blocks HFD-induced reductions in forced swim immobility and prevents HFD-induced increases in hippocampal GSK3ß phosphorylation despite having no significant effects on HFD-induced changes in body weight or anxiety-like behavior. Together, our results suggest that brain 5-HT deficiency significantly impacts a subset of behavioral and molecular responses to HFD, a finding that could help explain the complex relationships between obesity and mental illness.