HIGH SEROTONIN AND 5-HYDROXYINDOLEACETIC ACID LEVELS IN LIMBIC BRAIN-REGIONS IN A RAT MODEL OF DEPRESSION - NORMALIZATION BY CHRONIC ANTIDEPRESSANT TREATMENT

Although alterations in serotonin levels and neurotransmission are ass ociated with depressive disorders and effective antidepressant therapy , the exact cause of these disorders and the mode of action of antidep ressant drugs are poorly understood. In a genetic rat model of depress ion [Flinders sensitive line (FSL) rats], deviations from normal serot onin (5-HT) levels and metabolism in specific brain regions were deter mined. The levels of 5-HT and its metabolite, 5-hydroxyindoleacetic ac id (5-HIAA), in tissue punches of Various brain regions were quantitat ed simultaneously with an HPLC apparatus coupled to an electrochemical detector. In the nucleus accumbens, prefrontal cortex, hippocampus, a nd hypothalamus of FSL rats, the levels of 5-HT and 5-HIAA were three- to eightfold higher than in control Sprague-Dawley rats. Significant d ifferences in the levels of 5-HT and 5-HIAA in the striatum and raphe nucleus of the ''depressed'' and normal rats were not observed. After chronic treatment with the antidepressant desipramine (5 mg/kg/day for 18 days), the immobility score in a swim test, as a measure of a beha vioral deficit, and 5-HT revels of the FSL rats became normalized, but these parameters in the control rats did not change. The [5-HIAA]/[S- HT] ratio was lower in the nucleus accumbens and hypothalamus of the F SL than in the control rats, and increased after desipramine treatment only in the nucleus accumbens of the FSL rats. These results indicate that the behavioral deficits expressed in the FSL model for depressio n correlate with increased 5-HT levels in specific limbic sites and su ggest the FSL rats as a novel model for clarification of the molecular mechanism of clinically used antidepressant drugs.