Amitriptyline and clomipramine increase the concentration of administered L-tryptophan in the rat brain

The tricyclic antidepressant amitriptyline has been shown to reduce concent rations of large neutral amino acids (LNAA) in rat plasma. Compounds with t hat property might interact with such amino acids used as therapeutic agent s with a central sire of action by causing a change in the relationship bet ween the administered LNAA and its endogenous LNAA competitors for carrier- mediated transport through the blood-brain barrier into the brain. This stu dy was performed to investigate if the antidepressant agents amitriptyline and clomipramine could, by such a mechanism, increase brain concentrations of administered tryptophan. Intraperitoneal administration of L-tryptophan alone (100mgkg(-1)) resulted in an increase in the concentration of tryptophan in the rat brain from 14 +/- 0.7 to 100 +/- 4.3 nmolg(-1) compared with rats given saline only. Whe n rats were given tryptophan with amitriptyline (25 mgkg(-1) i.p.) or clomi pramine (25 mgkg(-1) i.p.) brain concentrations of tryptophan were increase d even further, to 150 +/- 4.5 and 157 +/- 10.2 nmolg(-1) respectively. Adm inistration of L-tryptophan alone resulted in an increase in the rat plasma tryptophan ratio [(concentration of tryptophan)/(total concentration of LN AAs)] from 0.14 +/- 0.003 to 0.42 +/- 0.011 compared with rats given saline only. When rats were given tryptophan with amitriptyline or clomipramine t he plasma tryptophan ratios were increased even further to 0.52 +/- 0.017 a nd 0.54 +/- 0.025, respectively. Ap these effects were statistically signif icant (P < 0.001). These findings support the hypothesis that tricyclic antidepressants could interact with administered tryptophan by changing the relationship in plasm a between tryptophan and its endogenous LNAA competitors for transport into the brain, resulting in higher concentrations of tryptophan in the brain. It is possible that this could be the mechanism of the previously reported finding that clomipramine and tryptophan potentiate each other in the treat ment of depression.