L-Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats

Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15370-5. doi: 10.1073/pnas.2436556100. Epub 2003 Dec 15.


The purpose of this investigation was to determine whether a nutritionally essential amino acid, l-lysine, acts like a serotonin receptor 4 (5-HT4) antagonist, and if l-lysine is beneficial in animal models of serotonin (5-HT)-induced anxiety, diarrhea, ileum contractions, and tachycardia and in stress-induced fecal excretion. The radioligand-binding assay was used to test the binding of l-lysine to various 5-HT receptors. The effects of l-lysine on 5-HT-induced contractions of isolated guinea pig ileum were studied in vitro. The effects of oral administration of l-lysine on diarrhea, stress-induced fecal excretion, and 5-HT-induced corticosterone release, tachycardia, and anxiety (an elevated plus maze paradigm) were studied in rats in vivo. l-Lysine (0.8 mmol/dl) inhibited (9.17%) binding of 5-HT to the 5-HT4 receptor, without any effect on 5-HT1A,2A,2B,2C,3 binding. l-Lysine (0.07 and 0.7 mmol/dl) blocked 5-HT-induced contractions of an isolated guinea pig ileum in vitro (P < 0.05 and P < 0.01). Orally applied l-lysine (1 g/kg of body weight) inhibited (P < 0.12) diarrhea triggered by coadministration of restraint stress and 5-hydroxytryptophane (10 mg/kg of body weight), and significantly blocked anxiety induced by the 5-HT4 receptor agonist (3.0 mmol/liter) in rats in vivo. No effects of l-lysine or the 5-HT4 receptor agonist on plasma corticosterone and heart rate were recorded. l-Lysine may be a partial 5-HT4 receptor antagonist and suppresses 5-HT4 receptor-mediated intestinal pathologies and anxiety in rats. An increase in nutritional load of l-lysine might be a useful tool in treating stress-induced anxiety and 5-HT-related diarrhea-type intestinal dysfunctions.

MeSH terms

  • Animals
  • Anxiety / prevention & control*
  • Diarrhea / physiopathology
  • Diarrhea / prevention & control
  • Guinea Pigs
  • Ileum / drug effects
  • Ileum / physiology
  • Lysine
  • Male
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Muscle, Smooth / physiopathology
  • Rats
  • Rats, Wistar
  • Receptors, Serotonin, 5-HT4 / drug effects
  • Receptors, Serotonin, 5-HT4 / physiology*
  • Restraint, Physical
  • Serotonin / pharmacology
  • Serotonin / physiology*
  • Serotonin Antagonists / pharmacology*
  • Serotonin Receptor Agonists / pharmacology
  • Stress, Psychological / prevention & control


  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Receptors, Serotonin, 5-HT4
  • Serotonin
  • Lysine