Serotonin hydroxytryptamine HT is a monoamine with dual func

Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine with dual functions in the developing and matured brain. 5-HT regulates development of the MRT68921 as a neurotrophic factor and is involved in emotion and cognition as a neurotransmitter in adulthood (Gaspar et al., 2003; Daubert and Condron, 2010; Dayer, 2014). 5-HT neurons are located in the raphe nuclei of brainstem and project to widespread brain regions including the cerebral cortex, amygdala and hippocampus. 5-HT receptors are classified into 7 families with at least 14 different subtypes (Hoyer et al., 1994; Barnes and Sharp, 1999). It has been shown using 5-HT1A receptor knock-out (KO) mice that deletion of the 5-HT1A receptor during postnatal period increases anxiety-like behavior in adulthood (Gross et al., 2002). In addition, 5-HT1A auto-receptor in the developing raphe nucleus is required for formation of the neural circuits of adult anxiety-like behavior (Richardson-Jones et al., 2010, 2011). Furthermore, 5-HT1A receptor KO mice showed poor spatial learning and memory, suggesting that 5-HT1A receptor is also involved in cognition (Sarnyai et al., 2000). Similar to 5-HT, brain-derived neurotrophic factor (BDNF) contributes to various functions in the developing and matured brain (Park and Poo, 2013). In addition to the formation of neural connections during brain development, BDNF has been shown to regulate neuropsychiatric-like behavioral phenotypes in adulthood. For example, pharmacological inhibition of BDNF impairs learning and memory of rodents (Bartoletti et al., 2002), and dysfunction of BDNF is related to depression (Nestler et al., 2002). Stress decreases the expression of BDNF in the rat hippocampus, and antidepressants recover the stress-induced reduction of BDNF in rats (Nestler et al., 2002). In addition, injection of BDNF into the hippocampus has an antidepressant effect in rat experiments (Siuciak et al., 1997). Finally, BDNF and 5-HT co-regulate one another such that 5-HT stimulates the expression of BDNF, and BDNF enhances the growth, differentiation and survival of 5-HT neurons (Mattson et al., 2004; Martinowich and Lu, 2008). Another candidate molecule which regulates anxiety is the GABA-A receptor. The GABA-A receptor is a target of anxiolytics, benzodiazepines. Benzodiazepines have acute effects in the treatment of patients with generalized anxiety disorder, social anxiety disorder, and panic disorder (Griebel and Holmes, 2013), whereas selective 5-HT reuptake inhibitors (SSRIs) show their anxiolytic effects after several weeks of the treatment (Vaswani et al., 2003). Among 19 GABA-A receptor subunits, α2 and α3 subunits modulate anxiety-like behavior. Diazepam-induced anxiolytic effect is absent in mice with the point mutation of α2 subunit, suggesting α2 subunit has anxiolytic effect in response to diazepam (Low et al., 2000).
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Acknowledgements This study was supported by a Grant-in-Aid for Scientific Research (26640024, 17K08487) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. We would like to thank Dr. T. Masuda, University of Tsukuba, for valuable suggestions regarding this study.
Introduction Flavonoids can act on ionotropic receptors for the inhibitory neurotransmitter GABA in many ways. They can act as positive, negative, and neutralizing allosteric modulators as well as agents that modulate other allosteric agonists. They appear to act at a variety of modulatory sites on GABAA receptors. Initially thought to act on classical benzodiazepine modulatory sites, it is clear that many flavonoid actions of GABAA receptors are insensitive to the classical benzodiazepine antagonist flumazenil. In this overview, we highlight some recent advances in the interaction of flavonoids with ionotropic GABA receptors since our 2011 review on this topic (Hanrahan, Chebib, & Johnston, 2011). We concentrate on flavonoids that have relatively specific action on subtypes of ionotropic GABA receptors. Furthermore, behavioral effects of some flavonoids are explored in terms of their effects on ionotropic GABA receptors. The emphasis is on relating chemical structure to activity.