Serotonergic regulation of appetite: 5-HT2C receptors in fluoxetine-ınduced weight change

Introduction: Selective serotonin reuptake inhibitors (SSRIs) represent a primary pharmacological intervention for various psychiatric conditions. The rising global incidence of mood and anxiety disorders, the clinical utilization of these serotonergic agents continues to expand. While these medications offer significant therapeutic benefits, they are frequently associated with a range of metabolic side effects. Among the most clinically concerning adverse events is significant weight gain, which poses a substantial risk factor in the context of the current obesity epidemic. Such metabolic shifts not only negatively affect multiple physiological organ systems but also contribute to a marked escalation in long-term healthcare expenditures.

Aim: Despite their prevalence, the precise biological mechanisms driving weight gain associated with chronic SSRI therapy remain inadequately understood and require further scientific elucidation. The current study was grounded in the hypothesis that SSRI-induced weight gain results from drug-induced alterations in the expression levels of the serotonin 2C receptor (5-HT2C-R). It was proposed that such changes subsequently modify the expression of specific hypothalamic neuropeptides responsible for the homeostatic regulation of eating behaviour and systemic energy balance.o Consequently, the physiological sensation of satiety becomes impaired, disrupting the precision of food intake regulation and ultimately leading to an increase in adipose tissue and body mass.

Methodology: The study focused on fluoxetine, a widely prescribed SSRI inhibitor, and its effects on the body weight of C57BL/6 male mice. Furthermore, the research aimed to determine if these effects could be mitigated through the administration of a selective 5-HT2C-R neutral antagonist. This pharmacological strategy was designed to potentially reverse the receptor desensitization often observed with prolonged SSRI exposure. To evaluate the complex interplay between the SSRI and the 5-HT2C-R neutral antagonist, the mice underwent a series of validated behavioural assessments to monitor potential shifts in cognitive performance and executive function. Following these assessments, molecular analyses were conducted; specifically, the expression levels of hypothalamic neuropeptides and the 5-HT2C-R were quantified using RT-qPCR. This allowed for a detailed examination of the molecular pathways within the hypothalamus that govern metabolic homeostasis. After the Shapiro-Wilk normality test, data analyzed with One-Way ANOVA, and also with Kruskal-Wallis test.

Results: The experimental findings demonstrated that fluoxetine treatment significantly influenced the body weight of the subjects. However, the administration of the 5-HT2C-R neutral antagonist did not produce a statistically significant reversal of this weight change. The behavioural data suggested that therapy with the SSRI might exert subtle cognitive impacts. Crucially, the molecular evidence confirmed that fluoxetine treatment led to measurable changes in 5-HT2C-R expression and altered the levels of neuropeptides directly involved in appetite control.

Conclusion: Results provided further insight into the complex neurochemical landscape of drug-induced metabolic dysfunction and highlight the challenges of targeting specific serotonin receptor subtypes to manage the weight-related side effects of psychiatric medications.

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