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. 2003 Dec 23;100(26):15370-5.
doi: 10.1073/pnas.2436556100. Epub 2003 Dec 15.

L-Lysine Acts Like a Partial Serotonin Receptor 4 Antagonist and Inhibits Serotonin-Mediated Intestinal Pathologies and Anxiety in Rats

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L-Lysine Acts Like a Partial Serotonin Receptor 4 Antagonist and Inhibits Serotonin-Mediated Intestinal Pathologies and Anxiety in Rats

Miro Smriga et al. Proc Natl Acad Sci U S A. .
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Abstract

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.

Figures

Fig. 1.
Fig. 1.
Effect of Lys on the weight of fecal pellets excreted during the first hour (filled columns) and the second hour (open columns) of wrap-restraint stress in rats. Lys or water was administered 40 min before exposure to wrap-restraint stress. Means of 20 rats + SEM are shown. The bars with different superscript letters differ significantly at P < 0.05.
Fig. 2.
Fig. 2.
Effect of Lys (1 g/kg p.o.) on the incident of diarrhea triggered by a combined application of wrap-restraint stress (1 h) and 5-HTP in fasted rats. Lys was infused 1 h before 5-HTP injection. Wrap-restraint stress was initiated immediately after s.c. treatment. Data are means of 10 rats + SEM. The bars with different superscript letters differ significantly at P < 0.05.
Fig. 3.
Fig. 3.
Effect Lys or 5-HT4 receptor agonist (RS 67333 HCl, 3.0 mmol/dl) on plasma corticosterone (CORT), epinephrine (EPI), and norepinephrine (NE) in rats. Rats were treated orally with Lys or water and 60 min later injected with RS 67333 HCl (s.c.) or saline (s.c.). Thirty minutes thereafter, rats were anesthetized with ether, and blood samples were collected from the posterior vena cava. Data are means of six rats + SEM.
Fig. 4.
Fig. 4.
Rearing score in the closed arms and exploration time in the open arms of the elevated plus maze. Rats were divided into two groups (n = 14 per group) and orally infused with water or Lys (1 g/kg of body weight). One hour later, rats were subdivided into four groups (n = 7 per group) and injected with 5-HT4 receptor agonist (RS 67333 HCl, 3.0 mmol/dl s.c.) or saline (s.c.). Thirty minutes thereafter, rats were tested for 10 min, as described (24). Data are means of seven rats + SEM. The bars with different superscript letters differ significantly at P < 0.05.

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