Abstract
Systemic injections of the flavonoid chrysin (5,7-dihydroxyflavone) exert anxiolytic-like effects in ovariectomised and cycling female rats through actions on gamma-aminobutyric acid-A (GABAA) receptors; however, it is unknown if chrysin directly acts on brain structures that are involved in regulating emotional processes, such as the hippocampus. The present study evaluated the effects of intrahippocampal microinjections of 0.25, 0.5, and 1 μg of chrysin on anxiety-like behaviour in the elevated plus maze (EPM) and locomotor activity test (LAT) in female rats in proestrus and dioestrus. Similar doses of the neurosteroid allopregnanolone were used as a reference GABAergic anxiolytic drug. The participation of the GABAA/benzodiazepine receptor complex was evaluated by administering the antagonists picrotoxin, bicuculline and flumazenil. In proestrus, 0.5 and 1 μg of chrysin and allopregnanolone induced anxiogenic-like behaviour. In dioestrus, chrysin, and allopregnanolone (0.5 μg) induced anxiolytic-like effects. Picrotoxin, bicuculline and flumazenil prevented the effects of chrysin and allopregnanolone in both proestrus and dioestrus. None of the treatments significantly affected locomotor activity. These results indicate that the GABAA/benzodiazepine receptor complex in the dorsal hippocampus regulates the effects of chrysin on anxiety-like behaviour, similar to the actions of allopregnanolone. The divergent effects of treatments across the oestrous cycle phases suggest complex interactions between GABAA receptors and compounds with an anxiolytic potential.
Highlights
Some anxiety disorders affect a higher percentage of women than men worldwide (Piggott et al, 2019), which have been associated with hormonal, biochemical, psychological and sociocultural factors (Velasco et al, 2019)
The present study explored the effects of the dorsal hippocampus in chrysin and allopregnanolone on anxiety-like behaviour associated with low and high concentrations of ovarian hormones and the involvement of the gamma-aminobutyric acid-A (GABAA)/benzodiazepine receptor complex in such effects
This is the first report to show that chrysin, similar to allopregnanolone, regulates anxiety-like behaviour by targeting a brain structure involved in the physiopathology of anxiety, which depends on the endocrine state associated with the ovarian cycle
Summary
Some anxiety disorders affect a higher percentage of women than men worldwide (Piggott et al, 2019), which have been associated with hormonal, biochemical, psychological and sociocultural factors (Velasco et al, 2019). Anxiety-like behaviour is higher during metoestrus-dioestrus, characterised by low concentrations of steroid hormones than proestrus-oestrus which, in contrast, presents high hormonal concentrations (Marcondes et al, 2001) This naturally occurring anxiety-like behaviour prompted the evaluation of substances that relieve anxiety associated with metestrus-dioestrus (Ravenelle et al, 2018; García-Ríos et al, 2019; Rodríguez-Landa et al, 2021), which is a physiological state similar to the premenstrual period in women (Lovick, 2008). The systemic administration of chrysin (5,7dihydroxyflavone) produces anxiolytic-like effects in male rats (Salgueiro et al, 1997; Zanoli et al, 2000), ovariectomised and cycling female rats (Rodríguez-Landa et al, 2019, 2021) Such effects are blocked by gamma-aminobutyric acid-A (GABAA) receptor complex antagonists, suggesting that chrysin shares similar mechanisms of action with anxiolytic drugs and neurosteroids (Crocetti and Guerrini, 2020). This flavonoid exerts neurochemical and neurotrophic effects in brain structures involved in the neurobiology of anxiety and depression, such as the prefrontal cortex and limbic cortex (Filho et al, 2015; Germán-Ponciano et al, 2021)
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