Characterization of serotonergic mechanisms involved in the behavioural inhibition induced by 5-hydroxytryptophan in a modified light-dark test in mice.

In a modified light-dark exploration test in mice, 5-hydroxytryptophan, at doses (25-50 mg/kg) that approximately doubled the 5-HT content in the cerebral cortex, reduced the time spent by mice in the white compartment, suggesting an anxiogenic effect. Depletion of brain 5-HT content with p-chlorophenylalanine (300 mg/kg/day for three consecutive days) resulted in an anxiolytic-like effect. Conversely, the 5-HT reuptake blocker fluoxetine reduced the time spent by mice in the white compartment. No significant interaction of either p-chlorophenylalanine or fluoxetine with 5-hydroxytryptophan was found. Several 5-HT agents, some of them with an intrinsic anxiolytic-like effect in this test, were studied in combination with 5-hydroxytryptophan. All of the drugs with a selective affinity at 5-HT1A receptors interacted significantly with 5-hydroxytryptophan. The suppressant effect of 5-hydroxytryptophan was antagonized or reversed by buspirone, a partial agonist at postsynaptic 5-HT1A receptors, and also by the "silent" 5-HT1A receptor antagonist WAY 100635, but not by the full agonist 8-OH-DPAT. The 5-HT2 receptor antagonist ritanserin partly counteracted the 5-hydroxytryptophan effect at the lower dose used. The 5-HT3 receptor antagonist ondansetron was able to prevent, at a low dose, the anxiogenic effect of 5-hydroxytryptophan; however, the 5-HT3 antagonists VA21B7 and granisetron as well as the 5-HT3/5-HT4 antagonist tropisetron and the selective 5-HT4 receptor antagonist RS 23597-190 were ineffective. The results appear to be consistent with the hypothesis that relates increased activity of the 5-HT systems to increased anxiety. Even though different 5-HT receptor subtypes may be involved in the anxiogenic effect of a high dose of 5-hydroxytryptophan, postsynaptic 5-HT1A receptors appear to play a prominent role. Administration of 5-hydroxytryptophan may consequently represent a valid approach to analyse further the role of 5-HT agents, in particular those acting at 5-HT1A receptors, in animal models of anxiety.