Sex-specific effects of fluoxetine on REM sleep deprivation-induced behavioral impairments and BDNF downregulation in rats.

Rapid eye movement (REM) sleep is a critical phase in which most dreaming occurs, and its deprivation (REM SD) can lead to disturbances in mood, cognition, synaptic plasticity, and neuroplasticity-related genes such as brain-derived neurotrophic factor (BDNF). Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is known to modulate BDNF expression, and sex-dependent variations in its effects have been suggested. This study investigated the effects of REM SD, fluoxetine, and their combination on behavioral and molecular outcomes in male and female rats.

Results

Following 24 hours of REM SD, animals exhibited impaired memory, increased immobility, reduced rearing, elevated pain threshold, and decreased locomotor activity, along with reduced BDNF levels in the prefrontal cortex. Females were less sensitive to REM SD regarding pain threshold and locomotor activity. Fluoxetine administration (10 mg/kg, i.p.) reversed the effects of REM SD on immobility and rearing exclusively in females, while also mitigating locomotor deficits induced by REM SD. In both sexes, fluoxetine counteracted REM SD-induced changes in pain threshold, but only in females did it restore BDNF downregulation. In conclusion, the findings suggest sex-specific variations in the consequences of REM SD and in the therapeutic response to fluoxetine. While REM SD broadly impairs cognitive, affective, and molecular parameters, females exhibit partial resilience, particularly in pain threshold and locomotor activity. Moreover, fluoxetine demonstrates sex-dependent protective effects, especially in restoring BDNF expression and behavioral outcomes in females.