INDOLE-PYRUVIC ACID, A TRYPTOPHAN KETOANALOG, ANTAGONIZES THE ENDOCRINE BUT NOT THE BEHAVIORAL-EFFECTS OF REPEATED STRESS IN A MODEL OF DEPRESSION

Increased glucocorticoid secretion is frequent in mood disorders and i s normalized by long-term antidepressant therapy. Many antidepressants act by increasing central serotonin transmission. We investigated the effects of a serotonin precursor, indole-pyruvic acid (IPA), in an an imal model of depression based on repeated exposure to unpredictable s tress. Rats were divided in groups, and IPA (20 mg/kg), the tricyclic antidepressant imipramine (IMI) (5 mg/kg), or vehicle was administered daily during 3 weeks of repeated exposure to various stressors accord ing to the procedure described by Katz et al [Katz RJ, Roth KA, Carrol l BJ (1981): Neurosci Biobehav Rev 5:247-251]. After treatment, rats w ere evaluated for stress-induced exploratory behavior and killed 24 hr later. Serum corticosterone levels and glucocorticoid receptor (GR) i mmunoreactivity (IR) in the nuclei of neurons located in the hippocamp al subregion CA1 were also measured. Rats exposed to repeated stress s howed a lower exploratory behavior score (p < 0.01), higher basal cort icosterone levels (p < 0.01), and stronger GR IR in the hippocampus (p < 0.05) than control rats. All of these effects were antagonized by I MI treatment. IPA administration did not affect the behavioral respons e induced by repeated stress (p < 0.01) but normalized serum corticost erone levels. In addition, IPA treatment produced a decrease in GR IR (p < 0.05 versus control group) that was not modified by exposure to r epeated stress. Differences in the drug effects suggest that (1) the d ose of IPA used for treatment was not sufficient to produce behavior e ffects; (2) a side product of IPA in vivo transformation, kynurenic ac id, may have affected glutamate transmission, interacting with the beh avioral outcomes; (3) the serotonin precursor IPA and the uptake block er IMI may have produced different adaptive changes in hippocampal ser otonin transmission, as indicated by nuclear GR IR measurements.