**Flavonoid Actions on Receptors for the Inhibitory Neurotransmitter GABA**

Tina Hinton, Jane R. Hanrahan and Graham A.R. Johnston

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67971

#### **Abstract**

Flavonoids, both naturally occurring and synthetic, are known to have multiple effects on the activation of ionotropic receptors for γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in our brains. They can act as positive or negative allosteric modulators, enhancing or reducing the effect of GABA. They can elicit a direct activation of the receptors. They can also act to modulate the action of other modulators. This ability to influence function via their actions on GABA receptors permits a range of effects of flavonoids, including relief of anxiety, anticonvulsant, analgesic and sedative actions.

**Keywords:** apigenin, hispidulin, luteolin, EGCG, synthetic flavonoids, synergism

### **1. Introduction**

Flavonoids have shown a range of effects, such as anxiolytic, sedative, anticonvulsant and analgesic properties, via their actions on the central nervous system (CNS). These effects occur through a variety of interactions with different receptors and signalling systems, including γ-aminobutyric acid (GABA) receptors. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the mammalian brain, released by up to 40% of neurons [1]. GABA acts on two classes of receptors—ionotropic and metabotropic [2]. Ionotropic receptors for GABA are ligand-gated chloride channels located in the neuronal membrane. When activated by GABA, these channels permit the passage of chloride ions down their electrochemical gradient. This usually results in the inward flow of chloride ions and the inhibition of neuronal firing. Metabotropic receptors for GABA are G-protein-coupled receptors that modulate neuronal activity via a variety of second messengers. While an extensive literature on the

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interactions of flavonoids with ionotropic GABA receptors exists [3], there are no examples of flavonoids acting on metabotropic GABA receptors, though they are known to act on other G-protein-coupled receptors such as adrenergic receptors [4].

This overview highlights the effects of some representative flavonoids on ionotropic GABA receptors acting as positive or negative allosteric modulators, increasing or decreasing the effect of GABA, as directly acting allosteric agonists, and as second-order modulators influencing the action of other modulators. Of particular interest are flavonoids that show subtype selectivity on GABA receptors. This overview also highlights the pre-clinical evidence for these representative flavonoids as anxiolytics, sedatives and anticonvulsants through their interactions with the GABAergic system. Further, the synergistic actions of flavonoids are reviewed.
