Aromatic amino acid-leucine dipeptides exhibit anxiolytic-like activity in young mice

We previously reported that Tyr-Leu (YL) exhibits potent anxiolytic-like activity comparable to diazepam in mice. In the current study, we revealed that aromatic amino acid-Leu, Phe-Leu and Trp-Leu (FL and WL, respectively), exhibited anxiolytic-like activity in the elevated plus-maze and open-field tests. FL and WL were orally active. Retro-sequence peptides of FL and WL were inactive. Similarly to YL, the anxiolytic-like activities of FL and WL were inhibited by WAY100135, SCH-23390 and bicuculline, antagonists of serotonin 5-HT1A, dopamine D1 and GABAA receptors, respectively, implying that FL and WL activate a common anxiolytic pathway to that of YL. Taken together, aromatic amino acid-Leu dipeptides such as YL, FL, and WL may exhibit anxiolytic-like activity in a manner dependent on the activation of 5-HT1A, D1 and GABAA receptors.

[1]  Istvan Mody,et al.  GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum , 2005, The Journal of Neuroscience.

[2]  M. Yoshikawa,et al.  Central prostaglandin D(2) exhibits anxiolytic-like activity via the DP(1) receptor in mice. , 2009, Prostaglandins & other lipid mediators.

[3]  S. Donaldson,et al.  Role of dopamine D1 receptors in novelty seeking in adult female Long-Evans rats , 2007, Brain Research Bulletin.

[4]  G. Homanics,et al.  GABAA receptor γ2 subunit knockdown mice have enhanced anxiety-like behavior but unaltered hypnotic response to benzodiazepines , 2005, BMC Neuroscience.

[5]  M. Yoshikawa,et al.  Rubimetide (Met-Arg-Trp) derived from Rubisco exhibits anxiolytic-like activity via the DP1 receptor in male ddY mice , 2008, Peptides.

[6]  U. Wollert,et al.  [3H] Flunitrazepam: its advantages as a ligand for the identification of benzodiazepine receptors in rat brain membranes. , 1978, Research communications in chemical pathology and pharmacology.

[7]  D. Middlemiss.  Stereoselective blockade at [3H]5-HT binding sites and at the 5-HT autoreceptor by propranolol. , 1984, European journal of pharmacology.

[8]  Masaaki Yoshikawa,et al.  β‐Lactotensin derived from bovine β‐lactoglobulin exhibits anxiolytic‐like activity as an agonist for neurotensin NTS2 receptor via activation of dopamine D1 receptor in mice , 2011, Journal of neurochemistry.

[9]  A. Asakawa,et al.  Ins2Akita mice exhibit hyperphagia and anxiety behavior via the melanocortin system. , 2007, International journal of molecular medicine.

[10]  Norimasa Kanegawa,et al.  Dipeptide Tyr‐Leu (YL) exhibits anxiolytic‐like activity after oral administration via activating serotonin 5‐HT1A, dopamine D1 and GABAA receptors in mice , 2010, FEBS letters.

[11]  Ayako Yamada,et al.  Characterization of Tyr‐Leu‐Gly, a novel anxiolytic‐like peptide released from bovine αS‐casein , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  T. Mizushige,et al.  Complement C5a exhibits anxiolytic-like activity via the prostaglandin D2-DP1 receptor system coupled to adenosine A2A and GABAA receptors. , 2012, Prostaglandins & other lipid mediators.

[13]  K. Kino,et al.  Novel CCK-dependent vasorelaxing dipeptide, Arg-Phe, decreases blood pressure and food intake in rodents. , 2012, Molecular nutrition & food research.

[14]  S. Narumiya,et al.  Central PGE2 exhibits anxiolytic‐like activity via EP1 and EP4 receptors in a manner dependent on serotonin 5‐HT1A, dopamine D1 and GABAA receptors , 2011, FEBS letters.

[15]  R Hen,et al.  Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[16]  S. File,et al.  Comparative Study of Pre- and Postsynaptic 5-HT1AReceptor Modulation of Anxiety in Two Ethological Animal Tests , 1996, The Journal of Neuroscience.

[17]  Kousaku OHINATA,et al.  Soymorphins, Novel μ Opioid Peptides Derived from Soy β-Conglycinin β-Subunit, Have Anxiolytic Activities , 2007 .

[18]  Masaaki Yoshikawa,et al.  Rubiscolin-6, a δ opioid peptide derived from spinach Rubisco, has anxiolytic effect via activating σ1 and dopamine D1 receptors , 2007, Peptides.

[19]  C. Ledent,et al.  Receptor Crosstalk: Characterization of Mice Deficient in Dopamine D1 and Adenosine A2A Receptors , 2006, Neuropsychopharmacology.

[20]  R. N. Takahashi,et al.  Blockade of adenosine and dopamine receptors inhibits the development of rapid tolerance to ethanol in mice , 2005, Psychopharmacology.

[21]  M Toth,et al.  Increased anxiety of mice lacking the serotonin1A receptor. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Yoshihiro Urade,et al.  Characterization of ovolin, an orally active tryptic peptide released from ovalbumin with anxiolytic‐like activity , 2012, Journal of neurochemistry.

[23]  M. Caron,et al.  Molecular cloning and expression of the gene for a human D1 dopamine receptor , 1990, Nature.

[24]  A. Lipkowski,et al.  Rubiscolin, a δ selective opioid peptide derived from plant Rubisco , 2001 .