Behavioral and molecular evidence for psychotropic effects in l-theanine
l-Theanine (N-ethyl-l-glutamine) is an amino acid uniquely found in green tea and historically considered to be a relaxing agent. It is a glutamate derivative and has an affinity for glutamatergic receptors. However, its psychotropic effects remain unclear.
To elucidate effects of l-theanine on psychiatric disease-related behaviors in mice and its molecular basis focusing on brain-derived neurotrophic factor (BDNF) and N-methyl-d-aspartate (NMDA) receptor.
We examined the effects of l-theanine on behaviors in mice by using the open-field test (OFT), forced swim test (FST), elevated plus-maze test (EPMT), and prepulse inhibition (PPI) of acoustic startle. By western blot analysis, we looked at the effect of l-theanine on the expression of BDNF and related proteins in the hippocampus and cerebral cortex. To determine whether l-theanine has agonistic action on the NMDA receptor, we performed Fluo-3 intracellular Ca2+ imaging in cultured cortical neurons.
Single administration of l-theanine significantly attenuated MK-801-induced deficits in PPI. Subchronic administration (3-week duration) of l-theanine significantly reduced immobility time in the FST and improved baseline PPI. Western blotting analysis showed increased expression of BDNF protein in the hippocampus after subchronic administration of l-theanine. In cultured cortical neurons, l-theanine significantly increased the intracellular Ca2+ concentration, and this increase was suppressed by competitive and non-competitive NMDA receptor antagonists (AP-5 and MK-801, respectively).
Our results suggest that l-theanine has antipsychotic-like and possibly antidepressant-like effects. It exerts these effects, at least in part, through induction of BDNF in the hippocampus and the agonistic action of l-theanine on the NMDA receptor.
Keywordsl-theanine MK-801 (dizocilpine) N-methyl d-aspartate (NMDA) receptor Schizophrenia Prepulse inhibition Brain-derived neurotrophic factor (BDNF) Behavior Glutamate Antidepressant
Forced swim test
Elevated plus-maze test
Brain-derived neurotrophic factor
This study was supported by the Health and Labor Sciences Research Grants (Comprehensive Research on Disability, Health, and Welfare), Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS), CREST, JST, and “Understanding of molecular and environmental bases for brain health” carried out under the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan.
All authors repot no biomedical financial interests or potential conflicts of interest.
- Furuta M, Kunugi H (2008) Animal models for schizophrenia: a brief overview. In: Turck CW (ed) Biomarkers for psychiatric disorders. Springer, New York, pp 163–184Google Scholar
- Green MJ, Matheson SL, Shepherd A, Weickert CS, Carr VJ (2010) Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry (in press)Google Scholar
- Ishii D, Matsuzawa D, Kanahara N, Matsuda S, Sutoh C, Ohtsuka H, Nakazawa K, Kohno M, Hashimoto K, Iyo M, Shimizu E (2010) Effects of aripiprazole on MK-801-induced prepulse inhibition deficits and mitogen-activated protein kinase signal transduction pathway. Neurosci Lett 471:53–57PubMedCrossRefGoogle Scholar
- Kanahara N, Shimizu E, Ohgake S, Fujita Y, Kohno M, Hashimoto T, Matsuzawa D, Shirayama Y, Hashimoto K, Iyo M (2008) Glycine and d-serine, but not d-cycloserine, attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801. Psychopharmacology (Berl) 198:363–374CrossRefGoogle Scholar
- Kumamaru E, Numakawa T, Adachi N, Yagasaki Y, Izumi A, Niyaz M, Kudo M, Kunugi H (2008) Glucocorticoid prevents brain-derived neurotrophic factor-mediated maturation of synaptic function in developing hippocampal neurons through reduction in the activity of mitogen-activated protein kinase. Mol Endocrinol 22:546–558PubMedCrossRefGoogle Scholar
- Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology (Berl) 92:180–185Google Scholar
- Matsumoto T, Numakawa T, Yokomaku D, Adachi N, Yamagishi S, Numakawa Y, Kunugi H, Taguchi T (2006) Brain-derived neurotrophic factor-induced potentiation of glutamate and GABA release: different dependency on signaling pathways and neuronal activity. Mol Cell Neurosci 31:70–84PubMedCrossRefGoogle Scholar
- Numakawa T, Nakayama H, Suzuki S, Kubo T, Nara F, Numakawa Y, Yokomaku D, Araki T, Ishimoto T, Ogura A, Taguchi T (2003) Nerve growth factor-induced glutamate release is via p75 receptor, ceramide, and Ca2+ from ryanodine receptor in developing cerebellar neurons. J Biol Chem 278:41259–41269PubMedCrossRefGoogle Scholar
- Park SK, Jung IC, Lee WK, Lee YS, Park HK, Go HJ, Kim K, Lim NK, Hong JT, Ly SY, Rho SS (2011) A combination of green tea extract and l-theanine improves memory and attention in subjects with mild cognitive impairment: a double-blind placebo-controlled study. J Med Food 14:334–343PubMedCrossRefGoogle Scholar
- Ritsner MS, Miodownik C, Ratner Y, Shleifer T, Mar M, Pintov L, Lerner V (2011) l-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: an 8-week, randomized, double-blind, placebo-controlled, 2-center study. J Clin Psychiatry 72:34–42PubMedCrossRefGoogle Scholar
- Weiner I, Schiller D, Gaisler-Salomon I, Green A, Joel D (2003) A comparison of drug effects in latent inhibition and the forced swim test differentiates between the typical antipsychotic haloperidol, the atypical antipsychotics clozapine and olanzapine, and the antidepressants imipramine and paroxetine. Behav Pharmacol 14:215–222PubMedCrossRefGoogle Scholar
- Yin C, Gou L, Liu Y, Yin X, Zhang L, Jia G, Zhuang X (2011) Antidepressant-like effects of l-theanine in the forced swim and tail suspension tests in mice. Phytother Res (in press)Google Scholar
- Zafra F, Castren E, Thoenen H, Lindholm D (1991) Interplay between glutamate and gamma-aminobutyric acid transmitter systems in the physiological regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons. Proc Natl Acad Sci USA 88:10037–10041PubMedCrossRefGoogle Scholar