Differential effects of hypothalamic ETB receptor blockade in fever, hypolocomotion and serotonin release during systemic inflammation in male and female rats

Systemic inflammation triggers a set of physiological and behavioral changes known as sickness behavior, including fever and hypolocomotion. Previous studies demonstrated that lipopolysaccharide (LPS) induces these responses in both sexes, with sex-specific alterations in hypothalamic serotonin (5-HT) levels—decreased in males and increased in females. These effects were reversed by intracerebroventricular (i.c.v.) administration of BQ788, an endothelin-1 type B (ET B ) receptor antagonist. This study investigated whether direct intra-hypothalamic (i.h.) administration of BQ788 could modulate 5-HT levels and attenuate sickness behavior. Wistar rats were implanted with temperature sensors and received hypothalamic microinjections of BQ788 or saline, followed by intraperitoneal LPS or vehicle. Body temperature was monitored for five hours, locomotor activity assessed via open field test, and hypothalamic 5-HT and its metabolite 5- hydroxyindoleacetic acid (5-HIAA) levels quantified by HPLC. LPS induced fever and hypolocomotion in both sexes, with reduced 5-HT/5-HIAA in males and increased levels in females. In males, i.h. BQ788 reversed these effects, suggesting direct hypothalamic action. In females, i.h. BQ788 normalized 5-HT levels but did not affect fever or hypolocomotion. However, i.c.v. BQ788 reduced these responses in females, indicating that ET-1 signaling sites differ between sexes. These findings highlight a sexually dimorphic neuroimmune response to systemic inflammation, with hypothalamic ET-1 signaling mediating sickness behavior in males, but not in females. This underscores the importance of sex-specific approaches in neuroinflammatory research.