Administration of L-theanine induced upregulation of hippocampal BDNF. Though TrkB and p75 were not altered by L- theanine administration, BDNF levels increased significantly. Vehicle or L-theanine (0.4 mg / kg) was subchronically administered (i.p.) to 5-week-old C57BL / 6 male mice every other day for 3 weeks. The hippocampus was removed 24 hours after the last administration. (Please see [91] for details). 

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... of the downstream molecules of BDNF / TrkB signaling, with no change in BDNF receptor levels (TrkB and p75) ([65] and see Figure 2). DA receptor agonists have been proposed as an inter- vention for treatment-refractory depression, and some studies report its e ffi cacy[66–69]. Understanding the mechanism behind the antidepressive properties of the dopaminergic system may help to unravel the puzzling pathology of depression. BDNF and glutamate, an excitatory neurotransmitter, work together in the central nervous system to a ff ect neuronal function. Many studies have found that BDNF plays a critical role in glutamatergic neurotransmis- sion and synaptic plasticity[70]. For example, regulation of NMDA and α -amino-3-hydroxy-5-methyl-4- isoxazole propionic acid (AMPA) receptor subunits is one important function of BDNF[71, 72]. Recently, we have demonstrated BDNF-dependent upregulation of synaptic proteins, including NR2A, possibly caused by activation of ERK signaling[73]. It is well known that BDNF enhances glutamatergic neurotransmission[74, 75]. Previously, we also reported that BDNF induces release of glutamate in cultured neurons[76, 77]. In our system, we demonstrated that PLC γ pathway activation, an essential signaling pathway for BDNF-induced glutamate release, is downregulated after chronic exposure to glucocorticoids, which are stress hormones involved in major depressive disorder[4, 78]. In turn, glutamate stimulation upregulates BDNF expression. Simmons et al. [79] reported that ampakine, a modulator of AMPA glutamate receptors, has a positive impact on BDNF expression in the mouse model of Huntington’s disease (HD). In the HD mice (CAG140 mice, human exon 1 with about 140 repeats of the trinucleotide CAG inserted into the huntingtin gene), the expression of BDNF was lower relative to that of wild-type mice[79]. Importantly, ampakine application reversed the downregulation of BDNF and rescued synaptic plasticity and memory in HD mice[79]. S18986, a modulator of AMPA glutamate receptors, has a neuroprotective ef- fect against excitotoxicity[80]. The neuroprotection by S18986 in ibotenate-induced brain lesions of newborn mice was blocked in the presence of inhibitors for ERK and PI3K / Akt pathways, and in the presence of neu- tralizing anti-BDNF antibody. Furthermore, neocortical BDNF mRNA was increased by S18986 application, suggesting a neuroprotective role for S18986-induced BDNF synthesis[80]. Historically, much attention has been given to the therapeutic potential of the glutamatergic system in the regulation of depressive disorder[81]. Specifically, preclinical studies have found antidepressant-like ef- fects of NMDA receptor antagonists[82–85]. Com- petitive (2-amino-7-phosphonoheptanoic acid) and non- competitive (dizocilpine [MK-801]) NMDA antagonists elicit antidepressant-like e ff ects in the inescapable stressed animal[82]. Clinical studies also indicate potential for the antidepressant-like e ff ect of NMDA glutamate receptor blockers, including ketamine[81]. Placebo-controlled, double-blinded trials found a significant improvement in depressive symptoms 72 hours after ketamine infusion[86]. Zarate et al. (2006) also showed the rapid (within 110 min) positive influence of ketamine in treatment-resistant major depressive disorder patients[87]. Importantly, Autry et al. reported that blockade of NMDA glutamate receptors produce a behavioral antidepressant response[88]. In their mouse model, ketamine induced rapid antidepressant-like ef- fects via increasing BDNF proteins. They demonstrated that ketamine-dependent blockade of NMDA receptors reduced phosphorylation of eukaryotic elongation factor 2, inhibiting suppression of BDNF translation[88]. In humans, chronic ketamine administration was found to increase serum levels of BDNF, though NGF was not changed by ketamine use[89]. Furthermore, it has been reported that oroxylin A (5,7-dihydroxy-6- methoxyfavone, a flavonoid compound) has antagonis- tic e ff ects on GABA A receptors. Phosphorylation of ERK1 / 2 and CREB as well as production of oroxylinA- stimulated BDNF was inhibited by NMDA receptor inhibitors, suggesting that activation of NMDA receptors through blocking GABA A receptors is involved in the mechanism of oroxylin A action[90]. We recently reported that L-theanine, an amino acid uniquely found in green tea, exerts antipsychotic-like and antidepressant- like e ff ects in mice[91]. Single pre-administration of L-theanine reverses MK-801-induced deficits in the prepulse inhibition test, which is established as a model for schizophrenia. Furthermore, subchronic L-theanine administration for 3-weeks reduced immobility time in the FST, suggesting that L-theanine has an antidepressant- like e ff ect. Interestingly, western blotting revealed an increased expression of BDNF protein in the hippocampus after chronic L-theanine treatment, implying that the L-theanine action is induced via upregulation of hippocampal BDNF ([91] and see Figure 3). Several reports demonstrate that activation of neurotrophin receptors are stimulated in the absence of the neurotrophin ligand. Adenosine, which exerts its neuronal e ff ect via G protein-coupled receptors, induces activation of TrkA (receptor for NGF) in PC12 cells and of TrkB in hippocampal neurons[92]. Pituitary adenylate cyclase-activating polypeptide (PACAP) also stimulates Trks activation in basal forebrain neurons[93]. Interestingly, Trks activation in response to PACAP is pre- dominantly observed in intracellular locations associ- ated with Golgi membranes. Recently, zinc-dependent transactivation of TrkB has been reported[94, 95]. In their system, zinc activates TrkB via increasing activity of Src family kinase and enhances the e ffi cacy of the hippocampal mossy fiber-CA3 synapse through the TrkB-dependent mechanism. Glucocorticoid, an important stress hormone, has both positive and negative e ff ects on the nervous system and is suggested to be involved in the pathophysiology of mental disorders including depression[4, 96]. Interestingly, Jeanneteau et al. showed that acute DEX (a synthetic glucocorticoid receptor (GR) selective agonist) administration induces TrkB phosphorylation in the dentate gyrus of hippocampal tissue, though such DEX application did not change neurotrophin protein levels[97]. Furthermore, using cultured hippocampal and cortical neurons, DEX-dependent survival promo- tion was confirmed[97]. On the other hand, we showed a negative impact of DEX on neuronal function[78]. Pretreatment with DEX for 48 hours significantly inhibited BDNF-induced glutamate release in cultured cortical neurons. In our system, it is possible that the interaction of GR with TrkB plays a role in intracellular signaling stimulated by BDNF for glutamate release[78]. It has been demonstrated that activation of TrkB is induced by antidepressant drugs independently of TrkB- specific ligands. Rantamaki et al. showed that in vivo application of imipramine induces TrkB phosphorylation in conditional BDNF knock-out mice, suggesting that the ligand BDNF is not required to elicit an antidepressive e ff ect[98]. Interestingly, they observed that fluoxetine, a serotonin reuptake inhibitor, achieves similar activation of TrkB in the brains of wild-type and serotonin transporter knock-out mice, suggesting that the monoamine transmitter is not involved in TrkB activation by fluoxetine[98]. As mentioned above, antidepressants are recognized as monoamine reuptake inhibitors and increase BDNF levels after long-term treatment. It is possible that several mechanisms contribute to antidepressant-dependent Trk activation. In this review, we summarized current issues on the interaction between BDNF production and 5-HT, NA, DA, and glutamate systems. Many studies indicate that stimulation of 5-HT, NA, DA, and glutamate systems leads to upregulation of BDNF levels. Because the e ffi ciency of BDNF crossing the blood brain barrier is very low, the number of studies investigating chemicals that produce BDNF within the brain is increasing. As shown above, it has been demonstrated that ketamine, a NMDA glutamate receptor antagonist useful for induction of schizophrenia-like behavior[99], rapidly increases BDNF translation and has antidepressant-like e ff ects[88]. As alterations in BDNF function may be involved in the pathogenesis of mental disorders such as schizophrenia and depression[100], further clarifica- tion on the detailed molecular mechanisms underlying BDNF upregulation should be elucidated. This research was supported by the Core Research for Evolutional Science and Technology Program (CREST) Japan Science and Technology Agency (JST) (T. N. N. A. and H. K.), the Takeda Science Foundation (T. N.), Health and Labor Sciences Research Grants (Comprehensive Research on Disability, Health, and Welfare) (H. K.), the Japan Health Sciences Foundation (Research on Health Sciences focusing on Drug Inno- vation) (H. K.), Intramural Research Grants (20-3, 21- 9) for Neurological and Psychiatric Disorders of NCNP (H. K.), and Grants-in-Aid for Scientific ...