GABAA/Benzodiazepine Receptor Complex in the Dorsal Hippocampus Mediates the Effects of Chrysin on Anxiety-Like Behaviour in Female Rats

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.

Pharmacological, Neurochemical, and Behavioral Mechanisms Underlying the Anxiolytic- and Antidepressant-like Effects of Flavonoid Chrysin

“…They can cross the blood–brain barrier and interact with several neurotransmission systems and, thereby activating signaling pathways in specific brain structures involved in the physiopathology of anxiety and depression disorders [ 10 ]. In particular, the flavonoid chrysin (5,7-dihydroxyflavone) has been studied for its antioxidant properties; however, its neuropharmacological effects in specific brain structures involved in the physiopathology of several neuropsychiatric disorders, such as anxiety and depression, need to be studied [ 9 , 10 , 14 ].…”

“…It is likely that the activation of anti-inflammatory and antioxidant signaling pathways may also be involved in these effects. Although these effects have been principally evaluated in pre-clinical research [ 14 , 16 , 17 , 18 , 24 , 25 , 26 ], they show the potential therapeutic use of chrysin for anxiety, depression, and other neuropsychiatric disorders.…”

“… Mechanism of action of the flavonoid chrysin potentially involved in its anxiolytic-like effects. ( A ) It has been confirmed that chrysin produces its anxiolytic-like effect through its action on the GABA A /benzodiazepine receptor complex producing configurational changes in the receptor and regulating the opening of the Cl − ion channel [ 14 , 15 , 17 , 24 , 35 ], which may produce inhibitory effects in the GABAergic system associated with its anxiolytic-like effects. These effects can be blocked by specific antagonists of the GABA A receptor, such as picrotoxin, bicuculline, and flumazenil [ 14 ].…”

“…In vitro and in vivo studies on the pharmacological action of the flavonoid chrysin have identified multiple effects of it on different systems in the organism [ 8 , 9 , 10 ], including the central nervous system (CNS). Chrysin exerts a neuropharmacological effect in brain structures such as the amygdala, hippocampus (HP), prefrontal cortex (PFC), and raphe nucleus, which are involved in the physiopathology of several neuropsychiatric disorders, such as anxiety and depression [ 11 , 12 , 13 , 14 ]. The effects include the activation of the GABAergic system by modulating the GABA A /benzodiazepine receptor complex [ 14 , 15 , 16 , 17 ]; changes in serotonin levels and modification in the expression of their receptors, such as 5-HT 1A and 5-HT 2A in the raphe nucleus and HP [ 13 , 18 ]; and restoration of dopamine and noradrenaline levels in the CNS [ 12 , 19 ].…”

“…Chrysin exerts a neuropharmacological effect in brain structures such as the amygdala, hippocampus (HP), prefrontal cortex (PFC), and raphe nucleus, which are involved in the physiopathology of several neuropsychiatric disorders, such as anxiety and depression [ 11 , 12 , 13 , 14 ]. The effects include the activation of the GABAergic system by modulating the GABA A /benzodiazepine receptor complex [ 14 , 15 , 16 , 17 ]; changes in serotonin levels and modification in the expression of their receptors, such as 5-HT 1A and 5-HT 2A in the raphe nucleus and HP [ 13 , 18 ]; and restoration of dopamine and noradrenaline levels in the CNS [ 12 , 19 ]. In addition, chrysin activates neurotrophic factors that increase brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels, thereby activating signaling pathways in the brain [ 11 , 20 ].…”