Vitexin modulates anxiety-related behavior via 5-HT1A-dependent mechanisms

Anxiety disorders are a major global health challenge and are closely linked to dysregulation of serotonergic neurotransmission, a system involved in stress responsiveness, emotional processing, and anxiety-related behavior. The dorsal raphe nucleus is particularly relevant in this context because it provides widespread serotonergic projections to limbic and cortical regions that regulate defensive responses. Vitexin, or apigenin-8-C-glucoside, is a naturally occurring flavonoid with reported anxiolytic-like effects in preclinical models. However, the neural substrates and serotonergic mechanisms underlying these effects remain insufficiently understood. This study investigated whether 5-HT1A receptors in the dorsomedial subdivision of the dorsal raphe nucleus mediate the anxiolytic-like effects of vitexin. Adult male Wistar rats received intra-dorsomedial dorsal raphe microinjections of vitexin alone or after pretreatment with the selective 5-HT1A receptor antagonist WAY-100635. Anxiety-like behavior was evaluated using the elevated plus maze and open field tests. Vitexin increased open-arm exploration in the elevated plus maze and reduced risk assessment behaviors, without altering locomotor-related measures, indicating a specific anxiolytic-like effect rather than nonspecific motor activation. In the open field test, vitexin produced a tendency toward increased central zone exploration, although this effect was not statistically significant. Importantly, pretreatment with WAY-100635 prevented the behavioral effects induced by vitexin in the elevated plus maze, indicating that 5-HT1A receptor signaling within the dorsomedial dorsal raphe nucleus contributes to its anxiolytic-like action. These findings suggest that vitexin modulates anxiety-related behavior, at least in part, through serotonergic mechanisms involving 5-HT1A receptors.