Challenging the Serotonin System: A Mechanistic Approach to the Method of Acute Tryptophan Depletion in Rodents

Objective: The method of acute tryptophan depletion (ATD) currently represents the most extensively applied challenge test to investigate the implication of the serotonin (5-HT) system in cognitive functions and psychiatric disorders. ATD consists of manipulating the availability of the essential amino acid tryptophan (TRP), the dietary 5-HT precursor, through administration of a TRP-free diet, which leads to a decreased availability of TRP in the brain and its synthesis into 5-HT. It is, therefore, assumed that a decrease in 5-HT release and subsequent blunted neurotransmission is the underlying mechanism for the behavioral effects of ATD. Methods: This paper reviews the behavioral effects of ATD and whether they can be directly related to a serotonergic dysfunction in the brain. Results: Direct evidence that ATD decreases extracellular 5-HT concentrations is, however, lacking, and several studies support the contribution of alternative mechanisms such as decreased nitric oxide synthase activity and cerebrovascular abnormalities that might underlie the behavioral effects of ATD. This may question the utility of the method as a selective serotonergic challenge tool. Conclusion: As the ATD method seems important in the investigation of 5-HT-related functions and dysfunctions, the potential of such alternative mechanisms and possible confounding factors should be taken into account for an adequate interpretation of data resulting from application of the method of ATD in both clinical and preclinical settings.