Acute and chronic tryptophan depletion differentially regulate central 5-HT1A and 5-HT2A receptor binding in the rat

Rationale Tryptophan depletion is used to reduce central serotonergic function and to investigate its role in psychiatric illness. Despite widespread clinical use, its effects on serotonin (5-HT) receptors have not been well characterized. Objective The aim of this study was to examine the effect of acute (ATD) and chronic tryptophan depletion (CTD) on free-plasma tryptophan (TRP), central TRP and 5-HT and brain 5-HT1A and 5-HT2A receptor binding in the rat. Methods TRP and 5-HT were measured by high-performance liquid chromatography and receptor levels determined by homogenate radioligand binding and in-vitro receptor autoradiography. Results Free-plasma TRP, central TRP and central 5-HT levels were significantly and similarly reduced by ATD and 1- and 3-week CTD compared to controls. ATD significantly reduced 5-HT1A binding in the dorsal raphe (14%) but did not significantly alter postsynaptic 5-HT1A binding (frontal cortex, remaining cortex and hippocampus) or 5-HT2A binding (cortex and striatum). One-week CTD did not significantly alter cortical 5-HT2A binding or postsynaptic 5-HT1A binding. Furthermore, 3-week CTD did not significantly alter 5-HT1A binding but significantly increased cortical 5-HT2A binding without affecting striatal or hippocampal levels. In the CTD 1 and 3-week groups, rat body weight was significantly decreased as compared to controls. However, weight loss was not a confounding factor for decreased cortical 5-HT2A-receptor binding. Conclusion ATD-induced reduction in somatodendritic 5-HT1A autoreceptor binding may represent an intrinsic 'homeostatic response' reducing serotonergic feedback in dorsal raphe projection areas. In contrast, the increase in 5-HT2A receptor after CTD may be a compensatory response to a long-term reduction in 5-HT.