Behavioral and molecular evidence for psychotropic effects in l-theanine

Abstract

Rationale

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.

Objectives

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.

Methods

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.

Results

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).

Conclusions

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.

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Abbreviations

OFT:

Open-field test

PPI:

Prepulse inhibition

FST:

Forced swim test

EPMT:

Elevated plus-maze test

NMDA:

N-methyl-d-aspartate

GABA:

Gamma-aminobutyric acid

AMPA:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

BDNF:

Brain-derived neurotrophic factor

PCP:

Phencyclidine

AP-5:

d-(−)-2-amino-5-phosphonopentanoic acid

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Acknowledgments

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.

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All authors repot no biomedical financial interests or potential conflicts of interest.

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Correspondence to Hiroshi Kunugi.

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Wakabayashi, C., Numakawa, T., Ninomiya, M. et al. Behavioral and molecular evidence for psychotropic effects in l-theanine. Psychopharmacology 219, 1099–1109 (2012). https://doi.org/10.1007/s00213-011-2440-z

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Keywords

  • l-theanine
  • MK-801 (dizocilpine)
  • N-methyl d-aspartate (NMDA) receptor
  • Schizophrenia
  • Prepulse inhibition
  • Brain-derived neurotrophic factor (BDNF)
  • Behavior
  • Glutamate
  • Antidepressant